research articles for stem cells

Stem Cell Research & Therapy

Call for Papers: Clinical and Preclinical Evidence in Regenerative Cardiology

Edited by: Armin Attar, MD, PhD , Shiraz University of Medical Sciences, Iran Submission Status: Open until 15 April 2025

Call for Papers: Mesenchymal Stem Cell (MSCs) and MSC-Derived Extracellular Vesicles: Roles in Regenerative Medicine and Beyond

Edited by:  Hongcui Cao, PhD , Zhejiang University, China Submission Status: Open until 15 April 2025

Call for Papers: Clinical Trials in Regenerative Medicine and Their Challenges

Edited by:  Akihiro Umezawa, PhD, National Research Institute for Child Health and Development, Japan Submission Status: Open until 31 March 2025

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Metabolic switching, growth kinetics and cell yields in the scalable manufacture of stem cell-derived insulin-producing cells

Critical contribution of mitochondria in the development of cardiomyopathy linked to desmin mutation

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DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy

Authors: Nan Dai, Xiaorong Su, Aihua Li, Jinglan Li, Deqi Jiang and Yong Wang

Expandable hESC-derived cardiovascular progenitor cells generate functional cardiac lineage cells for microtissue construction

Authors: Siamak Rezaeiani, Malihe Rezaee, Mojtaba Shafaghi, Mohammad Karami, Roghayeh Hamidi, Hamid Khodayari, Sadaf Vahdat, Sara Pahlavan and Hossein Baharvand

Modulation of human induced neural stem cell-derived dopaminergic neurons by DREADD reveals therapeutic effects on a mouse model of Parkinson’s disease

Authors: Xueyao Wang, Deqiang Han, Tianqi Zheng, Jinghong Ma and Zhiguo Chen

Microenvironment of spermatogonial stem cells: a key factor in the regulation of spermatogenesis

Authors: Wei Liu, Li Du, Junjun Li, Yan He and Mengjie Tang

Psychedelic LSD activates neurotrophic signal but fails to stimulate neural stem cells

Authors: Xiaoxu Dong, He Lin, Yuting Li, Gang Pei and Shichao Huang

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Stem cells: past, present, and future

Authors: Wojciech Zakrzewski, Maciej Dobrzyński, Maria Szymonowicz and Zbigniew Rybak

Ethical issues in stem cell research and therapy

Authors: Nancy MP King and Jacob Perrin

Platelet-rich plasma preparation for regenerative medicine: optimization and quantification of cytokines and growth factors

Authors: Paola Romina Amable, Rosana Bizon Vieira Carias, Marcus Vinicius Telles Teixeira, Ítalo da Cruz Pacheco, Ronaldo José Farias Corrêa do Amaral, José Mauro Granjeiro and Radovan Borojevic

CAR T cells in solid tumors: challenges and opportunities

Authors: Faroogh Marofi, Roza Motavalli, Vladimir A. Safonov, Lakshmi Thangavelu, Alexei Valerievich Yumashev, Markov Alexander, Navid Shomali, Max Stanley Chartrand, Yashwant Pathak, Mostafa Jarahian, Sepideh Izadi, Ali Hassanzadeh, Naghmeh Shirafkan, Safa Tahmasebi and Farhad Motavalli Khiavi

Stem cells: a potential treatment option for kidney diseases

Authors: Dongwei Liu, Fei Cheng, Shaokang Pan and Zhangsuo Liu

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Topical collection Clinical and Preclinical Evidence in Regenerative Cardiology Edited by Armin Attar

Topical collection Mesenchymal Stem Cell (MSCs) and MSC-Derived Extracellular Vesicles: Roles in Regenerative Medicine and Beyond Edited by Hongcui Cao

Topical collection Clinical Trials in Regenerative Medicine and Their Challenges Edited by Akihiro Umezawa

Topical collection Stromal cells and progenitor cells for osteoarticular regeneration Edited by Christian Jorgensen Topical collection Organoids and Tissue/Organ Chips Edited by Albert J Banes and Rajashekhar Gangaraju

Thematic series Adult stem cells in retinal diseases: where do we go from here? Edited by Rajashekhar Gangaraju

Thematic series Stem cell therapy of COVID-19 and other respiratory diseases   Edited by Hong-Long James Ji, Michael A. Matthay and Yuanlin Song

Thematic series NK cells as the next option for cancer treatment   Edited by Michael O'Dwyer

Cross-journal collection Coronavirus research highlights

Thematic series Stem cells and gene editing Edited by Stephen H. Tsang

Cross-journal collection Pluripotent Stem Cells

Thematic series Regenerative neurology Edited by Simon Koblar and Anne Hamilton-Bruce

Thematic series Extracellular vesicles and regenerative medicine Edited by Jeffrey Karp, Kelvin Ng and Armand Keating

Cross-journal collection Mesenchymal stem/stromal cells – an update Edited by Richard Schäfer and Selim Kuci

Cross-journal collection Biology and clinical applications of stem cells for autoimmune and musculoskeletal disorders Edited by Christian Jorgensen and Anthony Hollander

Thematic series Functional imaging in regenerative medicine Edited by Timothy O'Brien and Rocky Tuan

Thematic series Emerging investigators Edited by Timothy O'Brien and Rocky Tuan

Thematic series Stem cells and genitourinary regeneration Edited by John D Jackson

Thematic series Cardiovascular regeneration Edited by Ronald Li

Thematic series Physical influences on stem cells Edited by Gordana Vunjak-Novakovic

Thematic series Stem cell research in the Asia-Pacific Edited by Oscar Lee, Songtao Shi, Yufang Shi and Ying Jin

Thematic series Clinical applications of stem cells Edited by Mahendra Rao

Review series Immunology and stem cells Edited by Christian Jorgensen

Review series Epigenetics and regulation

Review series Stem cell niche

Review series Induced pluripotent stem cells

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Stem Cell Research & Therapy: 10th Anniversary

To mark the 10th year anniversary, we have reviewed the milestone achievements and highlighted some of the best content selected by our Editors-in-Chief and Associate Editors. Read more here .

Editors-in-Chief

Rocky S Tuan, The Chinese University of Hong Kong, Hong Kong SAR, China  Timothy O'Brien, University of Galway, Ireland:  Prof Timothy O’Brien is the Established Professor of Medicine in the College of Medicine, Nursing and Health Sciences at University of Galway and Consultant Endocrinologist in University Hospital Galway. He established the Regenerative Medicine Institute (REMEDI) with Prof Frank Barry in 2004 and is currently co-PI of the SFI-funded Centre for Research and Medical Devices (CÚRAM). Prof O’Brien’s research explores the synergies between gene therapy, stem/stromal cell therapy and biomaterials science with a key interest in the development of therapies for diabetic complications. The objective of his research is to translate research findings in the laboratory to clinical trials.

Journal submission information

Before you submit your manuscript to Stem Cell Research & Therapy , please ensure you have read and noted the below: 

• Authors are requested to provide institutional email addresses. At the minimum, at least the corresponding author and submitting author should provide an institutional email address.
• Image integrity and standards: Cropped gels and blots can be included in the main text if it improves the clarity and conciseness of the presentation. In such cases, the cropping of the blot must be clearly evident and must be mentioned in the figure legend. Corresponding uncropped full-length gels and blot must be included in the supplementary files. These uncropped images should indicate where they were cropped, be labelled as in the main text and placed in a single supplementary figure. The manuscript's figure legends should state that 'Full-length blots/gels are presented in Supplementary Figure X'. Further information can be found under 'Digital image integrity' which are detailed on our  Standards of Reporting  page.
• Authors should clearly declare in the Acknowledgement Section if there is any work that was outsourced or data not collected by authors. 
• Authors might be asked to provide original source data (raw data / original data / individual data points) if the reviewers or editors have any question.
• Authors should provide these information in the ethics declaration if the study involve human participants, human material, human data, or animals: (1) Title of the approved project; (2) Name of the institutional approval committee or unit; (3) Approval number; (4) Date of approval. Authors might be asked to provide ethics approval documents if the reviewers or editors have any question. 

Aims and scope

Stem Cell Research & Therapy is the major forum for translational research into stem cell therapies. An international peer-reviewed journal, it publishes high-quality open access research articles with a special emphasis on basic, translational and clinical research into stem cell therapeutics and regenerative therapies, including animal models and clinical trials. The journal also provides reviews, viewpoints, commentaries, reports and methods.

Topics covered include, but are not limited to: 

• Adult stem cells
• Animal models
• Biophysics and mechanobiology
• Cancer stem cells
• Cell culture and manufacture
• Clinical studies
• Disease modeling and drug screening
• Embryonic stem cells
• Ethical, legal and social aspects
• Genetics and epigenetics
• Genomics/proteomics/metabolomics
• Induced pluripotent stem cells
• Regenerative medicine
• Stem cell differentiation, proliferation and migration
• Stem cell therapy/transplantation
• Technologies
• Tissue engineering and biomaterials

Announcing the launch of In Review

Stem Cell Research & Therapy , in partnership with Research Square, is now offering  In Review.  Authors choosing this free optional service will be able to:

• Share their work with fellow researchers to read, comment on, and cite even before publication
• Showcase their work to funders and others with a citable DOI while it is still under review
• Track their manuscript - including seeing when reviewers are invited, and when reports are received 

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Stem cells: past, present, and future

Affiliations.

• 1 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland. [email protected].
• 2 Department of Conservative Dentistry and Pedodontics, Krakowska 26, Wrocław, 50-425, Poland.
• 3 Department of Experimental Surgery and Biomaterials Research, Wroclaw Medical University, Bujwida 44, Wrocław, 50-345, Poland.
• PMID: 30808416
• PMCID: PMC6390367
• DOI: 10.1186/s13287-019-1165-5

In recent years, stem cell therapy has become a very promising and advanced scientific research topic. The development of treatment methods has evoked great expectations. This paper is a review focused on the discovery of different stem cells and the potential therapies based on these cells. The genesis of stem cells is followed by laboratory steps of controlled stem cell culturing and derivation. Quality control and teratoma formation assays are important procedures in assessing the properties of the stem cells tested. Derivation methods and the utilization of culturing media are crucial to set proper environmental conditions for controlled differentiation. Among many types of stem tissue applications, the use of graphene scaffolds and the potential of extracellular vesicle-based therapies require attention due to their versatility. The review is summarized by challenges that stem cell therapy must overcome to be accepted worldwide. A wide variety of possibilities makes this cutting edge therapy a turning point in modern medicine, providing hope for untreatable diseases.

Keywords: Differentiation; Growth media; Induced pluripotent stem cell (iPSC); Pluripotency; Stem cell derivation; Stem cells; Teratoma formation assay; Tissue banks; Tissue transplantation.

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Oocyte development and formation of…

Oocyte development and formation of stem cells: the blastocoel, which is formed from…

Changes in the potency of…

Changes in the potency of stem cells in human body development. Potency ranges…

Spontaneous differentiation of hESCs causes…

Spontaneous differentiation of hESCs causes the formation of a heterogeneous cell population. There…

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Culturing of pluripotent stem cells in vitro. Three days after fertilization, totipotent cells…

Retroviral-mediated transduction induces pluripotency in…

Retroviral-mediated transduction induces pluripotency in isolated patient somatic cells. Target cells lose their…

Stem cell experiments on animals.…

Stem cell experiments on animals. These experiments are one of the many procedures…

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Use of inner cell mass…

Use of inner cell mass pluripotent stem cells and their stimulation to differentiate…

• Sukoyan MA, Vatolin SY, et al. Embryonic stem cells derived from morulae, inner cell mass, and blastocysts of mink: comparisons of their pluripotencies. Embryo Dev. 1993;36(2):148–58 - PubMed
• Larijani B, Esfahani EN, Amini P, Nikbin B, Alimoghaddam K, Amiri S, Malekzadeh R, Yazdi NM, Ghodsi M, Dowlati Y, Sahraian MA, Ghavamzadeh A. Stem cell therapy in treatment of different diseases. Acta Medica Iranica. 2012:79–96 https://www.ncbi.nlm.nih.gov/pubmed/22359076 . - PubMed
• Sullivan S, Stacey GN, Akazawa C, et al. Quality guidelines for clinical-grade human induced pluripotent stem cell lines. Regenerative Med. 2018; 10.2217/rme-2018-0095. - PubMed
• Amps K, Andrews PW, et al. Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotechnol. 2011;29(12):1121–1144. - PMC - PubMed
• Amit M, Itskovitz-Eldor J. Atlas of human pluripotent stem cells: derivation and culturing. New York: Humana Press; 2012.

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Brain Builders: How Stem Cell Research Is Rewriting the Genetic Code of Mental Health

Neurodevelopmental and psychiatric disorders such as schizophrenia, bipolar disorder, autism, and depression have profound impacts on affected individuals and society.

The National Institute of Mental Health has launched the SSPsyGene consortium, which unites top researchers to study 250 high-risk genes believed to contribute to these disorders. By mutating these genes in human stem cells and analyzing the effects, researchers aim to unravel the genetic factors of these conditions and pave the way for more effective treatments.

Understanding the Genetic Basis of Neurodevelopmental Disorders

Neurodevelopmental and psychiatric disorders (NPD) including schizophrenia, bipolar disorder, autism, and depression are detrimental to individuals, their families, and society as a whole, and in many cases still lack effective treatments. It’s becoming more and more clear that genetic mutations in certain genes can increase the likelihood of developing NPD, and several hundreds of those “risk genes” have been identified to date, but their role related to NPD remains a mystery.

“Very little is known about the basic function of most of these genes, and what we do know often comes from work in cancer cell lines rather than brain cell types,” s ays David Panchision, Chief of the Developmental and Genomic Neuroscience Research Branch at the National Institute of Mental Health (NIMH), who spearheaded the SSPsyGene program aiming to tackle this challenge.

“As such, we still don’t have a clear understanding of how alterations in these genes may work individually or in combination to contribute to neurodevelopmental and psychiatric disorders.”

Launch of SSPsyGene: A New Initiative in Mental Health Research

To get to the bottom of this, the National Institute of Mental Health (NIMH) initiated a consortium called SSPsyGene in 2023, uniting research teams from renowned US universities with the joint goal of characterizing the genetic origins of NPD, focusing on 250 selected high-risk genes.

Among the contributors are Jubao Duan, Endeavor Health (formerly NorthShore University Health System) and University of Chicago , USA and Zhiping Pang, Rutgers University, USA with their teams, who developed a method for mutating NPD risk genes in human stem cells at large scale. In the modified cells, a selected NPD risk gene is mutated so that it no longer makes a functional protein. The modified stem cells can subsequently be turned into neurons and other brain cells to model the consequences of risk gene mutations in a simplified, lab-based version of the human brain.

In the initial phase of the project, the teams tested 23 NPD risk genes, reported in work published in a recent article in the journal Stem Cell Reports . The resulting stem cell lines will be made available to other researchers worldwide to facilitate research on those risk genes and their contribution to NPD.

In future works, Pang, Duan and the other members of the consortium will join forces to generate mutated stem cell lines for a much larger number of risk genes, with the ultimate goal of understanding the genetic causes for NPD and for generating better treatments.

“The hope is that this collaborative work will generate a highly impactful resource for the neuroscience and psychiatric research community,” Panchision says.

Reference: “Scaled and Efficient Derivation of Loss of Function Alleles in Risk Genes for Neurodevelopmental and Psychiatric Disorders in Human iPSC” 12 September 2024, Stem Cell Reports . DOI: 10.1016/j.stemcr.2024.08.003

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“In the modified cells, a selected NPD risk gene is mutated so that it no longer makes a functional protein. The modified stem cells can subsequently be turned into neurons and other brain cells to model the consequences of risk gene mutations in a simplified, lab-based version of the human brain.” In other words, they have a tissue culture of stem cells that are mutated to stop making one protein, and then see what happens when the cell is made to differentiate into a brain cell type. This is supposed to somehow help us understand mental illness.

The genetic reductionism of modern medicine is frightening, and myopic. There is more to the brain than genes and their proteins. And just as cells in tissue culture don’t behave like cells in a real brain, the brain does not behave independently of the rest of the body, and the body does not behave independently of the culture. People have depression, anxiety, and other mental illness due mostly to the culture and the lifestyles it gives us, including drugs, stress, bad diet, poisoned food/water/air, and recently, COVID lockdowns. You can’t study the impact of real life and real culture on mental illness by looking at mutated cells in tissue culture. Too bad this is where mental health money is going, instead of addressing the reasons why people become mentally ill.

Of course, this is all about technology development, especially in genetics. “Among the contributors are Jubao Duan, Endeavor Health (formerly NorthShore University Health System) and University of Chicago, USA and Zhiping Pang, Rutgers University, USA with their teams, who developed a method for mutating NPD risk genes in human stem cells at large scale.” Technology is driving the research, not the other way around.

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Stem cells: what they are and what they do.

Stem cells offer promise for new medical treatments. Learn about stem cell types, current and possible uses, and the state of research and practice.

You've heard about stem cells in the news, and perhaps you've wondered if they might help you or a loved one with a serious disease. Here are some answers to frequently asked questions about stem cells.

What are stem cells?

Stem cells: The body's master cells

Stem cells are the body's master cells. All other cells arise from stem cells, including blood cells, nerve cells and other cells.

Stem cells are a special type of cells that have two important properties. They are able to make more cells like themselves. That is, they self-renew. And they can become other cells that do different things in a process known as differentiation. Stem cells are found in almost all tissues of the body. And they are needed for the maintenance of tissue as well as for repair after injury.

Depending on where the stem cells are, they can develop into different tissues. For example, hematopoietic stem cells reside in the bone marrow and can produce all the cells that function in the blood. Stem cells also can become brain cells, heart muscle cells, bone cells or other cell types.

There are various types of stem cells. Embryonic stem cells are the most versatile since they can develop into all the cells of the developing fetus. The majority of stem cells in the body have fewer abilities to give rise to cells and may only help maintain and repair the tissues and organs in which they reside.

No other cell in the body has the natural ability to generate new cell types.

Why is there such an interest in stem cells?

Researchers are studying stem cells to see if they can help to:

• Increase understanding of how diseases occur. By watching stem cells mature into cells in bones, heart muscle, nerves, and other organs and tissue, researchers may better understand how diseases and conditions develop.

Generate healthy cells to replace cells affected by disease (regenerative medicine). Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease.

People who might benefit from stem cell therapies include those with leukemia, Hodgkin disease, non-Hodgkin lymphoma and some solid tumor cancers. Stem cell therapies also might benefit people who have aplastic anemia, immunodeficiencies and inherited conditions of metabolism.

Stem cells are being studied to treat type 1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, heart failure, osteoarthritis and other conditions.

Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine.

Test new drugs for safety and effectiveness. Before giving drugs in development to people, researchers can use some types of stem cells to test the drugs for safety and quality. This type of testing may help assess drugs in development for toxicity to the heart.

New areas of study include the effectiveness of using human stem cells that have been programmed into tissue-specific cells to test new drugs. For the testing of new drugs to be accurate, the cells must be programmed to acquire properties of the type of cells targeted by the drug. Techniques to program cells into specific cells are under study.

Where do stem cells come from?

There are several sources of stem cells:

Embryonic stem cells. These stem cells come from embryos that are 3 to 5 days old. At this stage, an embryo is called a blastocyst and has about 150 cells.

These are pluripotent (ploo-RIP-uh-tunt) stem cells, meaning they can divide into more stem cells or can become any type of cell in the body. This allows embryonic stem cells to be used to regenerate or repair diseased tissue and organs.

• Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow or fat. Compared with embryonic stem cells, adult stem cells have a more limited ability to give rise to various cells of the body.

Adult cells altered to have properties of embryonic stem cells. Scientists have transformed regular adult cells into stem cells using genetic reprogramming. By altering the genes in the adult cells, researchers can make the cells act similarly to embryonic stem cells. These cells are called induced pluripotent stem cells (iPSCs).

This new technique may allow use of reprogrammed cells instead of embryonic stem cells and prevent immune system rejection of the new stem cells. However, scientists don't yet know whether using altered adult cells will cause adverse effects in humans.

Researchers have been able to take regular connective tissue cells and reprogram them to become functional heart cells. In studies, animals with heart failure that were injected with new heart cells had better heart function and survival time.

Perinatal stem cells. Researchers have discovered stem cells in amniotic fluid as well as umbilical cord blood. These stem cells can change into specialized cells.

Amniotic fluid fills the sac that surrounds and protects a developing fetus in the uterus. Researchers have identified stem cells in samples of amniotic fluid drawn from pregnant women for testing or treatment — a procedure called amniocentesis.

Why is there controversy about using embryonic stem cells?

The National Institutes of Health created guidelines for human stem cell research in 2009. The guidelines define embryonic stem cells and how they may be used in research and include recommendations for the donation of embryonic stem cells. Also, the guidelines state that embryonic stem cells from embryos created by in vitro fertilization can be used only when the embryo is no longer needed.

Where do these embryos come from?

The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in women's uteruses. The stem cells are donated with informed consent from donors. The stem cells can live and grow in special solutions in test tubes or petri dishes in laboratories.

Why can't researchers use adult stem cells instead?

Progress in cell reprogramming and the formation of iPSCs has greatly enhanced research in this field. However, reprogramming is an inefficient process. When possible, iPSCs are used instead of embryonic stem cells since this avoids the ethical issues about use of embryonic stem cells that may be morally objectionable for some people.

Although research into adult stem cells is promising, adult stem cells may not be as versatile and durable as are embryonic stem cells. Adult stem cells may not be able to be manipulated to produce all cell types, which limits how adult stem cells can be used to treat diseases.

Adult stem cells are also more likely to contain irregularities due to environmental hazards, such as toxins, or from errors acquired by the cells during replication. However, researchers have found that adult stem cells are more adaptable than was first thought.

What are stem cell lines, and why do researchers want to use them?

A stem cell line is a group of cells that all descend from a single original stem cell and are grown in a lab. Cells in a stem cell line keep growing but don't become specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or shared with other researchers.

What is stem cell therapy (regenerative medicine), and how does it work?

Stem cell therapy, also known as regenerative medicine, promotes the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. It is the next chapter in organ transplantation and uses cells instead of donor organs, which are limited in supply.

Researchers grow stem cells in a lab. These stem cells are manipulated to specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells.

The specialized cells can then be implanted into a person. For example, if the person has heart disease, the cells could be injected into the heart muscle. The healthy transplanted heart muscle cells could then contribute to repairing the injured heart muscle.

Researchers have already shown that adult bone marrow cells guided to become heart-like cells can repair heart tissue in people, and more research is ongoing.

Have stem cells already been used to treat diseases?

Yes. Doctors have performed stem cell transplants, also known as bone marrow transplants, for many decades. In hematopoietic stem cell transplants, stem cells replace cells damaged by chemotherapy or disease or serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases. Leukemia, lymphoma, neuroblastoma and multiple myeloma often are treated this way. These transplants use adult stem cells or umbilical cord blood.

Researchers are testing adult stem cells to treat other conditions, including some degenerative diseases such as heart failure.

What are the potential problems with using embryonic stem cells in humans?

For embryonic stem cells to be useful, researchers must be certain that the stem cells will differentiate into the specific cell types desired.

Researchers have discovered ways to direct stem cells to become specific types of cells, such as directing embryonic stem cells to become heart cells. Research is ongoing in this area.

Embryonic stem cells also can grow irregularly or specialize in different cell types spontaneously. Researchers are studying how to control the growth and development of embryonic stem cells.

Embryonic stem cells also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or the stem cells might simply fail to function as expected, with unknown consequences. Researchers continue to study how to avoid these possible complications.

What is therapeutic cloning, and what benefits might it offer?

Therapeutic cloning, also called somatic cell nuclear transfer, is a way to create versatile stem cells independent of fertilized eggs. In this technique, the nucleus is removed from an unfertilized egg. This nucleus contains the genetic material. The nucleus also is removed from the cell of a donor.

This donor nucleus is then injected into the egg, replacing the nucleus that was removed, in a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This process creates a line of stem cells that is genetically identical to the donor's cells — in essence, a clone.

Some researchers believe that stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because cloned cells are less likely to be rejected once transplanted back into the donor. And it may allow researchers to see exactly how a disease develops.

Has therapeutic cloning in people been successful?

No. Researchers haven't been able to successfully perform therapeutic cloning with humans despite success in a number of other species.

Researchers continue to study the potential of therapeutic cloning in people.

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New research on plant stem cells shines light on how plants grow stronger

by Anna Zarra Aldrich, University of Connecticut

Stem cell research is a hot topic. With applications for a host of human medical advancements, researchers have been working with animal and human stem cells for years.

But animals aren't the only ones with stem cells.

Huanzhong Wang, professor of plant molecular biology in the College of Agriculture, Health and Natural Resources (CAHNR), wants people to know that plants have stem cells too. Just like in the medical world, plant stem cells could support human growth and development when used to improve the food supply.

"It's not just humans and animals," Wang says. "Plants have stem cells too, and we should be paying attention to them."

In their roots, shoots, and vasculature, stem cells control cell division and differentiation for plants. Plant stem cells play a vital role in growth and development.

"Plants can grow for many, many years because different types of stem cells basically ensure they can grow up in the air and deep into the ground," Wang says. "To grow a thicker stem or trunk, they need another type of stem cell."

Plant stem cells have largely been overlooked because they don't have applications for human biomedical research. But that doesn't make them any less fascinating. And Wang has demonstrated that better understanding how these cells work can support a more resilient food supply.

Wang's lab has been working with plant stem cells for years trying to understand how they control their stem cells, specifically the stem cells that give rise to vascular bundles—the structures that carry water and other nutrients throughout the plant.

Recently the group published a paper in New Phytologist that sheds light on this question. Wang's lab discovered a transcription factor gene called HVA that controls cell division in vascular stem cells.

When this gene is overexpressed, the researchers observed an increase in the number of vascular bundles and overall stem cell activity.

The researchers compared plants with no overexpression of HVA gene, those with one copy of overexpressed HVA gene and one regular gene, and finally plants with two copies of overexpressed HVA genes.

In the group with no overexpression, the plants had five to eight vascular bundles. In the plants with one copy of the overexpressed HVA gene, they had more than 20 bundles, and with two copies of overexpressed HVA genes they had more than 50.

Aside from advancing science's understanding of how plants work, Wang's findings have important implications for agriculture.

Plants with more vascular bundles are stronger and more resistant to wind. This knowledge could be used to intentionally generate sturdier cultivars with the overexpression mutation.

This is especially relevant for tall, slender crops like corn, the biggest crop in the U.S.

"When plants grow taller, there is a risk that they could topple over," Wang says. "Having more vascular bundles ensures the plant can stand still and resist those conditions."

Even though Wang's lab conducted the study using a model organism in the mustard family, the HVA gene is found in other plants as well, making this research broadly applicable.

HVA is one of hundreds of transcription factors in a large family in the plant's genome. Wang is interested in discovering what some of the other genes in this family do.

"We are interested in studying other closely related genes to find out their function," Wang says. "It will be interesting to study further how this gene family affects vascular development.

Journal information: New Phytologist

Provided by University of Connecticut

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UConn Today

September 12, 2024 | Anna Zarra Aldrich, College of Agriculture, Health and Natural Resources

New Research on Plant Stem Cells Shines Light on How Plants Grow Stronger

We shouldn't ignore the potential of stem cells in plants, according to new UConn research

(Francesco Gallarotti for Unsplash)

Stem cell research is a hot topic. With applications for a host of human medical advancements, researchers have been working with animal and human stem cells for years.

But animals aren’t the only ones with stem cells.

Huanzhong Wang, professor of plant molecular biology in the College of Agriculture, Health and Natural Resources (CAHNR), wants people to know that plants have stem cells too. Just like in the medical world, plant stem cells could support human growth and development when used to improve the food supply.

“It’s not just humans and animals,” Wang says. “Plants have stem cells too, and we should be paying attention to them.”

In their roots, shoots, and vasculature, stem cells control cell division and differentiation for plants. Plant stem cells play a vital role in growth and development.

“Plants can grow for many, many years because different types of stem cells basically ensure they can grow up in the air and deep into the ground,” Wang says. “To grow a thicker stem or trunk, they need another type of stem cell.”

Plant stem cells have largely been overlooked because they don’t have applications for human biomedical research. But that doesn’t make them any less fascinating. And Wang has demonstrated that better understanding how these cells work can support a more resilient food supply.

Wang’s lab has been working with plant stem cells for years trying to understand how they control their stem cells, specifically the stem cells that give rise to vascular bundles – the structures that carry water and other nutrients throughout the plant.

Recently the group published a paper in New Phytologist that sheds light on this question.

Wang’s lab discovered a transcription factor gene called HVA that controls cell division in vascular stem cells.

When this gene is overexpressed, the researchers observed an increase in the number of vascular bundles and overall stem cell activity.

The researchers compared plants with no overexpression of HVA gene, those with one copy of overexpressed HVA gene and one regular gene, and finally plants with two copies of overexpressed HVA genes.

In the group with no overexpression, the plants had five to eight vascular bundles. In the plants with one copy of overexpressed HVA gene, they had more than 20 bundles, and with two copies of overexpressed HVA genes they had more than 50.

Aside from advancing science’s understanding of how plants work, Wang’s findings have important implications for agriculture.

Plants with more vascular bundles are stronger and more resistant to wind. This knowledge could be used to intentionally generate sturdier cultivars with the overexpression mutation.

This is especially relevant for tall, slender crops like corn, the biggest crop for the U.S.

“When plants grow taller, there is a risk that they could topple over,” Wang says. “Having more vascular bundles ensures the plant can stand still and resist those conditions.”

Even though Wang’s lab conducted the study using a model organism in the mustard family, the HVA gene is found in other plants as well, making this research broadly applicable.

HVA is one of hundreds of transcription factors in a large family in the plant’s genome. Wang is interested in discovering what some of the other genes in this family do.

“We are interested in studying other closely related genes to find out their function,” Wang says. “It will be interesting to study further how this gene family affects vascular development.

This work relates to CAHNR’s Strategic Vision area focused on Ensuring a Vibrant and Sustainable Agricultural Industry and Food Supply.

Follow UConn CAHNR on social media

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• Published: 10 September 2024

The role of the haematopoietic stem cell niche in development and ageing

• Terri L. Cain   ORCID: orcid.org/0000-0002-5590-2103 1 ,
• Marta Derecka   ORCID: orcid.org/0000-0001-6265-9781 1 &
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• Haematopoiesis
• Haematopoietic stem cells
• Stem-cell niche

Blood production depends on rare haematopoietic stem cells (HSCs) and haematopoietic stem and progenitor cells (HSPCs) that ultimately take up residence in the bone marrow during development. HSPCs and HSCs are subject to extrinsic regulation by the bone marrow microenvironment, or niche. Studying the interactions between HSCs and their niche is critical for improving ex vivo culturing conditions and genetic manipulation of HSCs, which is pivotal for improving autologous HSC therapies and transplantations. Additionally, understanding how the complex molecular network in the bone marrow is altered during ageing is paramount for developing novel therapeutics for ageing-related haematopoietic disorders. HSCs are unique amongst stem and progenitor cell pools in that they engage with multiple physically distinct niches during their ontogeny. HSCs are specified from haemogenic endothelium in the aorta, migrate to the fetal liver and, ultimately, colonize their final niche in the bone marrow. Recent studies employing single-cell transcriptomics and microscopy have identified novel cellular interactions that govern HSC specification and engagement with their niches throughout ontogeny. New lineage-tracing models and microscopy tools have raised questions about the numbers of HSCs specified, as well as the functional consequences of HSCs interacting with each developmental niche. Advances have also been made in understanding how these niches are modified and perturbed during ageing, and the role of these altered interactions in haematopoietic diseases. In this Review, we discuss these new findings and highlight the questions that remain to be explored.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Disease (R01DK116835 and R01DK104028, to S.M.-F.), National Heart, Lung, and Blood Institute (F31HL170678, to T.L.C.), American Lebanese Syrian Associated Charities (to S.M.-F. and M.D.), Leukaemia Research Foundation (to M.D.) and WES Foundation (to M.D.). S.M.-F. is a Scholar of The Leukaemia & Lymphoma Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.

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A key adhesion protein and transcription factor in the Wnt signalling pathway.

(AGM). An embryonic mesodermal region from which haematopoietic stem cells (HSCs) emerge in mammals.

Cytokines produced by adipose tissue that have roles in inflammatory and metabolic signalling.

A mouse model that has significantly reduced white and brown adipose tissue.

(CS). A classification system of 23 stages developed as a standard timeline of human embryonic development.

An aromatic amine that serves as a neurotransmitter, such as dopamine and adrenaline.

A bioinformatics algorithm that predicts cell-to-cell communications via ligand–receptor interactions based on single-cell RNA sequencing (scRNA-seq) or spatial transcriptomics data.

A bioinformatic algorithm that can predict ligand–receptor cellular interactions based on single-cell RNA sequencing (scRNA-seq) expression of the ligands, receptors and associated signalling pathway genes across annotated cellular populations.

A microenvironment on the outer edge of the bone marrow comprising many cell types, including haematopoietic stem cells (HSCs).

Interactions between ligand and receptor pairs occurring on the same cell.

A narrow section of the embryonic mesoderm from which haematopoietic stem cells (HSCs) emerge in zebrafish, and ultimately gives rise to the urogenital systems.

A toxic alkaloid found in some plant species.

A haematological disorder in which there is a clinical decrease in the number of lymphocytes present in the blood.

Enzymes found in the intercellular space that break down extracellular proteins.

Occurs when an individual haematopoietic stem cell (HSC) has an increased relative contribution of myeloid lineage progeny compared with lymphoid lineage progeny.

A group of multipotent stem cells that migrate during development and give rise to large groups of tissues, such as connective tissue, skin pigmentation cells and craniofacial bones.

A regulator of many developmentally relevant processes in a tissue-dependent manner, including cell proliferation and growth.

The transplantation of organs or tissues, such as blood, between two different species.

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Cain, T.L., Derecka, M. & McKinney-Freeman, S. The role of the haematopoietic stem cell niche in development and ageing. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00770-8

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Hair Follicle Stem Cell and its Niche in Normal vs Cancerous Development

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Hair follicles (HF) regenerate throughout adult life, involving a 2-way signaling between epithelial stem cells and its niche. The niche includes mesenchymal cells such as dermal papillae and fibroblasts, immune cells, endothelial cells, melanocytes, and adipocytes to name a few. HF induction by dermal papillae involves a plethora of signaling molecules such as Wnt and Bmp crosstalk together with Fgf, Shh, Igf. Tgfb and other metabolic pathways. Misexpression of some of these factors cause abnormal receptor-ligand interaction leading to abnormal hair cycling or could potentially result in tumorigenic outcome with a specific "cell of origin" for cancer. Basal Cell Carcinoma (BCC) is a vivid example of malignancy derived from hair follicle or touch dome stem cells due to uncontrolled hedgehog signaling. While Ras mutations are shown to be integrated and contained by HFSCs, the non-cycling upper epidermis is driven towards oncogenic outgrowth. Keratoacanthomas is a disease of abnormal hair follicle regression suggesting a HFSC disease. On the other hand, Fgfr2b epidermal KO mice show signs of dysplasia and develops spontaneous papilloma suggesting a tumor protective role of Fgf signaling in skin. Another common type of skin cancer, melanoma, can be driven by various signaling changes, including abnormal MAPK signaling, uncontrolled cell cycle progression, alterations in the AKT pathway, and other less common mutations for sporadic cases. Hair follicle compartmentalization often provides "physical or immunologic barrier" to the spread of tumor cells deep down in the skin implying dermal-epidermal junctions as an important signaling checkpoint. Immune cells and adipocytes enable the mechanical and nutritional sensing of the tissue architecture while nerves/vasculature help transmit the signal to facilitate niche response. Understanding the epithelial stem cells and their niche interactions in the context of normal vs cancerous stem cell renewal and maintenance thus remains an interesting research question to explore. The goal of this research topic is to enhance the understanding of the complex interactions between stem cells and their niches in pathological condition such as cancers, with a focus on skin stem cells e.g., HFSC and epidermal stem cells. Stem cells of the skin are essential and are continuously replenished during hair cycle, hair loss and skin regeneration, ageing and repair. However, malfunctions in stem cell machinery and balance can be deleterious and lead to tumor initiation, triggered by replication error or external stimuli such as ultraviolet (UV) radiation. For instance, squamous cell carcinoma results from UV-induced clonal expansion of epidermal cells, while excess melanocyte proliferation leads to malignant melanoma.Intrinsic factors like stem cell plasticity are crucial for tissue survival under injury, inflammation, genetic predisposition, or other pathological conditions. Yet, this plasticity can also turn into an unwanted tumorigenic force, as seen in intestinal tumor resulting from YAP/TAZ activation. The ability of stem cells to de-differentiate and revert to a stem cell state under adverse conditions can also initiate tumors. In this issue, we expect authors to explore stem cell-niche interactions within the cancer microenvironment. We are particularly interested in studies utilizing mouse models of tumors that exhibit progressive hair phenotypes followed by oncogenic invasion, highlighting the role of various altered signaling molecules. We aim to focus on how the niche reprograms itself to either combat or facilitate cancer initiation. Depending on the tumor type and the “cell-of-origin,” authors should examine how niche responses differ and how they are influenced by aging or other pathological conditions. Additionally, we seek insights into whether disrupting cancer-specific niche responses can restore normal stem cell growth. Contributors should aim to delineate the specific signaling switches that drive stem cells from normal to cancerous states and propose interventions to revive normal niche interactions. We invite researchers to submit original research articles, reviews, and perspectives that address the following themes: • Mechanisms of stem cell-niche interactions in the cancer microenvironment • The role of niche reprogramming in either resisting or promoting cancer initiation • Differences in niche responses based on tumor type and cell-of-origin • Impact of aging and other pathological conditions on niche responses • Strategies to disrupt cancer-specific niche interactions and restore normal stem cell growth • Identification of signaling pathways and molecular switches involved in the transition from normal to cancerous states By contributing to this Research Topic, authors will help advance our understanding of stem cell biology and cancer, potentially leading to new therapeutic strategies for enhancing tissue repair and preventing tumorigenesis.

Keywords : HFSC, Niche, Mesenchyme, DP, Fibroblasts, immune cells, squamous cell carcinoma

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Article Contents

Rbpms promotes contractile phenotype splicing in human embryonic stem cell derived vascular smooth muscle cells.

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Aishwarya G Jacob, Ilias Moutsopoulous, Alex Petchey, Rafael Kollyfas, Vincent R Knight-Schrijver, Irina Mohorianu, Sanjay Sinha, Christopher W J Smith, RBPMS promotes contractile phenotype splicing in human embryonic stem cell derived vascular smooth muscle cells, Cardiovascular Research , 2024;, cvae198, https://doi.org/10.1093/cvr/cvae198

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Differentiated Vascular Smooth Muscle Cells (VSMCs) express a unique network of mRNA isoforms via smooth muscle specific alternative splicing (SM-AS) in functionally critical genes, including those comprising the contractile machinery. We previously described RNA Binding Protein Multiple Splicing (RBPMS) as a potent driver of differentiated SM-AS in the rat PAC1 VSMC cell line. What is unknown is how RBPMS affects VSMC phenotype and behaviour. Here, we aimed to dissect the role of RBPMS in SM-AS in human cells and determine the impact on VSMC phenotypic properties.

We used human embryonic stem cell-derived VSMCs (hESC-VSMCs) as our platform. hESC-VSMCs are inherently immature and we found that they display only partially differentiated SM-AS patterns while RBPMS protein levels are low. We found that RBPMS overexpression induces SM-AS patterns in hESC-VSMCs akin to the contractile tissue VSMC splicing patterns. We present in silico and experimental findings that support RBPMS’ splicing activity as mediated through direct binding and via functional cooperativity with splicing factor RBFOX2 on a significant subset of targets. We also demonstrate that RBPMS can alter the motility and the proliferative properties of hESC-VSMCs to mimic a more differentiated state.

Overall, this study emphasizes a critical role for RBPMS in establishing the contractile phenotype splicing program of human VSMCs.

• smooth muscle
• embryonic stem cells
• muscle, smooth, vascular
• alternative splicing
• cell motility
• muscle contraction
• protein isoforms
• rna splicing
• rna, messenger
• rna-binding proteins
• protein overexpression

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A new study aims, for the first time, to pinpoint the very moment the immune system recognizes a tumour to try to stop the disease earlier than previously possible.

This research has the potential to give an entirely new perspective on the role of the immune system in cancer progression Heather Machado

Currently cancer is usually diagnosed when tumours are already developed requiring, often significant, treatment to remove them and prevent further growth.

 However, a research team at the University of Cambridge will receive over £1.5m from Cancer Research UK over the next six years to investigate how the immune system evolves, targets and kills cancer cells as tumours are developing.

 They hope by detecting the trigger point when our own body starts to recognize cancerous cells, it may help find a way to spark our own immune system into action so it kills cancer cells before tumours can even begin.

This could vastly reduce the amount of treatment people diagnosed with cancer require, which can often have significant side effects. The pioneering work could benefit millions of cancer patients before the disease becomes life-threatening or spreads.

Dr Heather Machado is leading a team of scientists at the Department of Pathology, looking at the body's immune system's ability to fight cancer.  Dr Machado’s work on T cells – part of the immune system which fight infection and disease, including cancer – will provide an insight into how long before a diagnosis these cells recognize and respond to cancer.

The study will specifically examine how T cells respond to cancer when they first recognise and respond to a tumour in the kidneys or the liver.

The breakthrough study has the potential to unlock the mystery as to how our immune cells work to fight cancer.

Dr Machado said: “Using mutations that naturally accumulate in each of our cells as we age, we can essentially build a family tree of T-cells, and this family tree has information about when T-cells met cancer for the first time. This research is only now possible as a result of advancements in DNA sequencing technology.

“This research has the potential to give an entirely new perspective on the role of the immune system in cancer progression, findings that we hope to use to further improve lifesaving cancer immunotherapies.”

Her aim is to see if they could lead to specific immunotherapy treatments and ways of detecting the cancer earlier.

She added: “Most cancers are diagnosed years or decades after early tumour development, which can often be too late. Our methods will allow us to go back in the cancer’s timeline to understand the immune response in these early stages of cancer development. Beyond improving immunotherapies, we hope that this understanding helps us detect cancer earlier, at stages where survival rates are much higher.”

The body’s immune system is the first line of defence against cancer but previously it has been difficult to observe this early response in humans.

Dr Machado will use genome sequencing which determines the genetic makeup of an organism to study how a tumour and the immune cells co-evolve over the course of tumour development. 

She will time T cell clonal expansions using evolutionary trees built from the genomes of individual T cells, exploiting recent advancements in single-cell whole genome sequencing. Dr Machado will then perform these experiments using early-stage kidney and liver cancer resections and by sampling throughout the course of immunotherapy in metastatic kidney cancer.”

She added: “The study is believed to be the first of its kind in the world and it has the potential to be groundbreaking research as we have never been able to examine these evolutionary dynamics in humans before. How long before a tumour is diagnosed has the immune system been responding is an incredibly hard problem to solve because these immune dynamics play out years prior to diagnosis.

“Normal cells evolve into tumours, and we are blind to much of that process and yet the immune system is one of our best tools for fighting cancer.

Dr Machado studied for her PhD at Stanford University and completed her post doctorate research at the Wellcome Sanger Institute in Hinxton, UK. She added: “We are using cutting edge technology that is only available now and we are going to be able to discover how the immune system responds to tumours unlike we have ever seen before and that, is potentially life changing in terms of improving immunotherapies for better health and patient prognosis.”

Find out how Cambridge is changing the story of cancer

Adapted from a press release from Cancer Research UK

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Stem Cells Applications in Regenerative Medicine and Disease Therapeutics

Ranjeet singh mahla.

Department of Biological Sciences, Indian Institute of Science Education and Research (IISER), Bhopal, Madhya Pradesh 462066, India

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of tissues or organs for the patient suffering from severe injuries or chronic disease. The spectacular progress in the field of stem cell research has laid the foundation for cell based therapies of disease which cannot be cured by conventional medicines. The indefinite self-renewal and potential to differentiate into other types of cells represent stem cells as frontiers of regenerative medicine. The transdifferentiating potential of stem cells varies with source and according to that regenerative applications also change. Advancements in gene editing and tissue engineering technology have endorsed the ex vivo remodelling of stem cells grown into 3D organoids and tissue structures for personalized applications. This review outlines the most recent advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells regenerative application in wildlife conservation.

1. Introduction

Regenerative medicine, the most recent and emerging branch of medical science, deals with functional restoration of specific tissue and/or organ of the patients suffering with severe injuries or chronic disease conditions, in the state where bodies own regenerative responses do not suffice [ 1 ]. In the present scenario donated tissues and organs cannot meet the transplantation demands of aged and diseased populations that have driven the thrust for search for the alternatives. Stem cells are endorsed with indefinite cell division potential, can transdifferentiate into other types of cells, and have emerged as frontline regenerative medicine source in recent time, for reparation of tissues and organs anomalies occurring due to congenital defects, disease, and age associated effects [ 1 ]. Stem cells pave foundation for all tissue and organ system of the body and mediates diverse role in disease progression, development, and tissue repair processes in host. On the basis of transdifferentiation potential, stem cells are of four types, that is, (1) unipotent, (2) multipotent, (3) pluripotent, and (4) totipotent [ 2 ]. Zygote, the only totipotent stem cell in human body, can give rise to whole organism through the process of transdifferentiation, while cells from inner cells mass (ICM) of embryo are pluripotent in their nature and can differentiate into cells representing three germ layers but do not differentiate into cells of extraembryonic tissue [ 2 ]. Stemness and transdifferentiation potential of the embryonic, extraembryonic, fetal, or adult stem cells depend on functional status of pluripotency factors like OCT4, cMYC, KLF44, NANOG, SOX2, and so forth [ 3 – 5 ]. Ectopic expression or functional restoration of endogenous pluripotency factors epigenetically transforms terminally differentiated cells into ESCs-like cells [ 3 ], known as induced pluripotent stem cells (iPSCs) [ 3 , 4 ]. On the basis of regenerative applications, stem cells can be categorized as embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and iPSCs ( Figure 1 ; Table 1 ). The transplantation of stem cells can be autologous, allogenic, and syngeneic for induction of tissue regeneration and immunolysis of pathogen or malignant cells. For avoiding the consequences of host-versus-graft rejections, tissue typing of human leucocyte antigens (HLA) for tissue and organ transplant as well as use of immune suppressant is recommended [ 6 ]. Stem cells express major histocompatibility complex (MHC) receptor in low and secret chemokine that recruitment of endothelial and immune cells is enabling tissue tolerance at graft site [ 6 ]. The current stem cell regenerative medicine approaches are founded onto tissue engineering technologies that combine the principles of cell transplantation, material science, and microengineering for development of organoid; those can be used for physiological restoration of damaged tissue and organs. The tissue engineering technology generates nascent tissue on biodegradable 3D-scaffolds [ 7 , 8 ]. The ideal scaffolds support cell adhesion and ingrowths, mimic mechanics of target tissue, support angiogenesis and neovascularisation for appropriate tissue perfusion, and, being nonimmunogenic to host, do not require systemic immune suppressant [ 9 ]. Stem cells number in tissue transplant impacts upon regenerative outcome [ 10 ]; in that case prior ex vivo expansion of transplantable stem cells is required [ 11 ]. For successful regenerative outcomes, transplanted stem cells must survive, proliferate, and differentiate in site specific manner and integrate into host circulatory system [ 12 ]. This review provides framework of most recent ( Table 1 ; Figures ​ Figures1 1 ​ ​ ​ ​ ​ ​ – 8 ) advancement in transplantation and tissue engineering technologies of ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs in regenerative medicine. Additionally, this review also discusses stem cells as the tool of regenerative applications in wildlife conservation.

Promises of stem cells in regenerative medicine: the six classes of stem cells, that is, embryonic stem cells (ESCs), tissue specific progenitor stem cells (TSPSCs), mesenchymal stem cells (MSCs), umbilical cord stem cells (UCSCs), bone marrow stem cells (BMSCs), and induced pluripotent stem cells (iPSCs), have many promises in regenerative medicine and disease therapeutics.

ESCs in regenerative medicine: ESCs, sourced from ICM of gastrula, have tremendous promises in regenerative medicine. These cells can differentiate into more than 200 types of cells representing three germ layers. With defined culture conditions, ESCs can be transformed into hepatocytes, retinal ganglion cells, chondrocytes, pancreatic progenitor cells, cone cells, cardiomyocytes, pacemaker cells, eggs, and sperms which can be used in regeneration of tissue and treatment of disease in tissue specific manner.

TSPSCs in regenerative medicine: tissue specific stem and progenitor cells have potential to differentiate into other cells of the tissue. Characteristically inner ear stem cells can be transformed into auditory hair cells, skin progenitors into vascular smooth muscle cells, mesoangioblasts into tibialis anterior muscles, and dental pulp stem cells into serotonin cells. The 3D-culture of TSPSCs in complex biomaterial gives rise to tissue organoids, such as pancreatic organoid from pancreatic progenitor, intestinal tissue organoids from intestinal progenitor cells, and fallopian tube organoids from fallopian tube epithelial cells. Transplantation of TSPSCs regenerates targets tissue such as regeneration of tibialis muscles from mesoangioblasts, cardiac tissue from AdSCs, and corneal tissue from limbal stem cells. Cell growth and transformation factors secreted by TSPSCs can change cells fate to become other types of cell, such that SSCs coculture with skin, prostate, and intestine mesenchyme transforms these cells from MSCs into epithelial cells fate.

MSCs in regenerative medicine: mesenchymal stem cells are CD73 + , CD90 + , CD105 + , CD34 − , CD45 − , CD11b − , CD14 − , CD19 − , and CD79a − cells, also known as stromal cells. These bodily MSCs represented here do not account for MSCs of bone marrow and umbilical cord. Upon transplantation and transdifferentiation these bodily MSCs regenerate into cartilage, bones, and muscles tissue. Heart scar formed after heart attack and liver cirrhosis can be treated from MSCs. ECM coating provides the niche environment for MSCs to regenerate into hair follicle, stimulating hair growth.

UCSCs in regenerative medicine: umbilical cord, the readily available source of stem cells, has emerged as futuristic source for personalized stem cell therapy. Transplantation of UCSCs to Krabbe's disease patients regenerates myelin tissue and recovers neuroblastoma patients through restoring tissue homeostasis. The UCSCs organoids are readily available tissue source for treatment of neurodegenerative disease. Peritoneal fibrosis caused by long term dialysis, tendon tissue degeneration, and defective hyaline cartilage can be regenerated by UCSCs. Intravenous injection of UCSCs enables treatment of diabetes, spinal myelitis, systemic lupus erythematosus, Hodgkin's lymphoma, and congenital neuropathies. Cord blood stem cells banking avails long lasting source of stem cells for personalized therapy and regenerative medicine.

BMSCs in regenerative medicine: bone marrow, the soft sponge bone tissue that consisted of stromal, hematopoietic, and mesenchymal and progenitor stem cells, is responsible for blood formation. Even halo-HLA matched BMSCs can cure from disease and regenerate tissue. BMSCs can regenerate craniofacial tissue, brain tissue, diaphragm tissue, and liver tissue and restore erectile function and transdifferentiation monocytes. These multipotent stem cells can cure host from cancer and infection of HIV and HCV.

iPSCs in regenerative medicine: using the edge of iPSCs technology, skin fibroblasts and other adult tissues derived, terminally differentiated cells can be transformed into ESCs-like cells. It is possible that adult cells can be transformed into cells of distinct lineages bypassing the phase of pluripotency. The tissue specific defined culture can transform skin cells to become trophoblast, heart valve cells, photoreceptor cells, immune cells, melanocytes, and so forth. ECM complexation with iPSCs enables generation of tissue organoids for lung, kidney, brain, and other organs of the body. Similar to ESCs, iPSCs also can be transformed into cells representing three germ layers such as pacemaker cells and serotonin cells.

Stem cells in wildlife conservation: tissue biopsies obtained from dead and live wild animals can be either cryopreserved or transdifferentiated to other types of cells, through culture in defined culture medium or in vivo maturation. Stem cells and adult tissue derived iPSCs have great potential of regenerative medicine and disease therapeutics. Gonadal tissue procured from dead wild animals can be matured, ex vivo and in vivo for generation of sperm and egg, which can be used for assistive reproductive technology oriented captive breeding of wild animals or even for resurrection of wildlife.

Application of stem cells in regenerative medicine: stem cells (ESCs, TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs) have diverse applications in tissue regeneration and disease therapeutics.

2. ESCs in Regenerative Medicine

For the first time in 1998, Thomson isolated human ESCs (hESCs) [ 13 ]. ESCs are pluripotent in their nature and can give rise to more than 200 types of cells and promises for the treatment of any kinds of disease [ 13 ]. The pluripotency fate of ESCs is governed by functional dynamics of transcription factors OCT4, SOX2, NANOG, and so forth, which are termed as pluripotency factors. The two alleles of the OCT4 are held apart in pluripotency state in ESCs; phase through homologues pairing during embryogenesis and transdifferentiation processes [ 14 ] has been considered as critical regulatory switch for lineage commitment of ESCs. The diverse lineage commitment potential represents ESCs as ideal model for regenerative therapeutics of disease and tissue anomalies. This section of review on ESCs discusses transplantation and transdifferentiation of ESCs into retinal ganglion, hepatocytes, cardiomyocytes, pancreatic progenitors, chondrocytes, cones, egg sperm, and pacemaker cells ( Figure 2 ; Table 1 ). Infection, cancer treatment, and accidents can cause spinal cord injuries (SCIs). The transplantation of hESCs to paraplegic or quadriplegic SCI patients improves body control, balance, sensation, and limbal movements [ 15 ], where transplanted stem cells do homing to injury sites. By birth, humans have fixed numbers of cone cells; degeneration of retinal pigment epithelium (RPE) of macula in central retina causes age-related macular degeneration (ARMD). The genomic incorporation of COCO gene (expressed during embryogenesis) in the developing embryo leads lineage commitment of ESCs into cone cells, through suppression of TGF β , BMP, and Wnt signalling pathways. Transplantation of these cone cells to eye recovers individual from ARMD phenomenon, where transplanted cone cells migrate and form sheet-like structure in host retina [ 16 ]. However, establishment of missing neuronal connection of retinal ganglion cells (RGCs), cones, and PRE is the most challenging aspect of ARMD therapeutics. Recently, Donald Z Jacks group at John Hopkins University School of Medicine has generated RGCs from CRISPER-Cas9-m-Cherry reporter ESCs [ 17 ]. During ESCs transdifferentiation process, CRIPER-Cas9 directs the knock-in of m-Cherry reporter into 3′UTR of BRN3B gene, which is specifically expressed in RGCs and can be used for purification of generated RGCs from other cells [ 17 ]. Furthermore, incorporation of forskolin in transdifferentiation regime boosts generation of RGCs. Coaxing of these RGCs into biomaterial scaffolds directs axonal differentiation of RGCs. Further modification in RGCs generation regime and composition of biomaterial scaffolds might enable restoration of vision for ARMD and glaucoma patients [ 17 ]. Globally, especially in India, cardiovascular problems are a more common cause of human death, where biomedical therapeutics require immediate restoration of heart functions for the very survival of the patient. Regeneration of cardiac tissue can be achieved by transplantation of cardiomyocytes, ESCs-derived cardiovascular progenitors, and bone marrow derived mononuclear cells (BMDMNCs); however healing by cardiomyocytes and progenitor cells is superior to BMDMNCs but mature cardiomyocytes have higher tissue healing potential, suppress heart arrhythmias, couple electromagnetically into hearts functions, and provide mechanical and electrical repair without any associated tumorigenic effects [ 18 , 19 ]. Like CM differentiation, ESCs derived liver stem cells can be transformed into Cytp450-hepatocytes, mediating chemical modification and catabolism of toxic xenobiotic drugs [ 20 ]. Even today, availability and variability of functional hepatocytes are a major a challenge for testing drug toxicity [ 20 ]. Stimulation of ESCs and ex vivo VitK12 and lithocholic acid (a by-product of intestinal flora regulating drug metabolism during infancy) activates pregnane X receptor (PXR), CYP3A4, and CYP2C9, which leads to differentiation of ESCs into hepatocytes; those are functionally similar to primary hepatocytes, for their ability to produce albumin and apolipoprotein B100 [ 20 ]. These hepatocytes are excellent source for the endpoint screening of drugs for accurate prediction of clinical outcomes [ 20 ]. Generation of hepatic cells from ESCs can be achieved in multiple ways, as serum-free differentiation [ 21 ], chemical approaches [ 20 , 22 ], and genetic transformation [ 23 , 24 ]. These ESCs-derived hepatocytes are long lasting source for treatment of liver injuries and high throughput screening of drugs [ 20 , 23 , 24 ]. Transplantation of the inert biomaterial encapsulated hESCs-derived pancreatic progenitors (CD24 + , CD49 + , and CD133 + ) differentiates into β -cells, minimizing high fat diet induced glycemic and obesity effects in mice [ 25 ] ( Table 1 ). Addition of antidiabetic drugs into transdifferentiation regime can boost ESCs conservation into β -cells [ 25 ], which theoretically can cure T2DM permanently [ 25 ]. ESCs can be differentiated directly into insulin secreting β -cells (marked with GLUT2, INS1, GCK, and PDX1) which can be achieved through PDX1 mediated epigenetic reprogramming [ 26 ]. Globally, osteoarthritis affects millions of people and occurs when cartilage at joints wears away, causing stiffness of the joints. The available therapeutics for arthritis relieve symptoms but do not initiate reverse generation of cartilage. For young individuals and athletes replacement of joints is not feasible like old populations; in that case transplantation of stem cells represents an alternative for healing cartilage injuries [ 27 ]. Chondrocytes, the cartilage forming cells derived from hESC, embedded in fibrin gel effectively heal defective cartilage within 12 weeks, when transplanted to focal cartilage defects of knee joints in mice without any negative effect [ 27 ]. Transplanted chondrocytes form cell aggregates, positive for SOX9 and collagen II, and defined chondrocytes are active for more than 12 wks at transplantation site, advocating clinical suitability of chondrocytes for treatment of cartilage lesions [ 27 ]. The integrity of ESCs to integrate and differentiate into electrophysiologically active cells provides a means for natural regulation of heart rhythm as biological pacemaker. Coaxing of ESCs into inert biomaterial as well as propagation in defined culture conditions leads to transdifferentiation of ESCs to become sinoatrial node (SAN) pacemaker cells (PCs) [ 28 ]. Genomic incorporation TBox3 into ESCs ex vivo leads to generation of PCs-like cells; those express activated leukocyte cells adhesion molecules (ALCAM) and exhibit similarity to PCs for gene expression and immune functions [ 28 ]. Transplantation of PCs can restore pacemaker functions of the ailing heart [ 28 ]. In summary, ESCs can be transdifferentiated into any kinds of cells representing three germ layers of the body, being most promising source of regenerative medicine for tissue regeneration and disease therapy ( Table 1 ). Ethical concerns limit the applications of ESCs, where set guidelines need to be followed; in that case TSPSCs, MSCs, UCSCs, BMSCs, and iPSCs can be explored as alternatives.

3. TSPSCs in Regenerative Medicine

TSPSCs maintain tissue homeostasis through continuous cell division, but, unlike ESCs, TSPSCs retain stem cells plasticity and differentiation in tissue specific manner, giving rise to few types of cells ( Table 1 ). The number of TSPSCs population to total cells population is too low; in that case their harvesting as well as in vitro manipulation is really a tricky task [ 29 ], to explore them for therapeutic scale. Human body has foundation from various types of TSPSCs; discussing the therapeutic application for all types is not feasible. This section of review discusses therapeutic application of pancreatic progenitor cells (PPCs), dental pulp stem cells (DPSCs), inner ear stem cells (IESCs), intestinal progenitor cells (IPCs), limbal progenitor stem cells (LPSCs), epithelial progenitor stem cells (EPSCs), mesoangioblasts (MABs), spermatogonial stem cells (SSCs), the skin derived precursors (SKPs), and adipose derived stem cells (AdSCs) ( Figure 3 ; Table 1 ). During embryogenesis PPCs give rise to insulin-producing β -cells. The differentiation of PPCs to become β -cells is negatively regulated by insulin [ 30 ]. PPCs require active FGF and Notch signalling; growing more rapidly in community than in single cell populations advocates the functional importance of niche effect in self-renewal and transdifferentiation processes. In 3D-scaffold culture system, mice embryo derived PPCs grow into hollow organoid spheres; those finally differentiate into insulin-producing β -cell clusters [ 29 ]. The DSPSCs, responsible for maintenance of teeth health status, can be sourced from apical papilla, deciduous teeth, dental follicle, and periodontal ligaments, have emerged as regenerative medicine candidate, and might be explored for treatment of various kinds of disease including restoration neurogenic functions in teeth [ 31 , 32 ]. Expansion of DSPSCs in chemically defined neuronal culture medium transforms them into a mixed population of cholinergic, GABAergic, and glutaminergic neurons; those are known to respond towards acetylcholine, GABA, and glutamine stimulations in vivo. These transformed neuronal cells express nestin, glial fibrillary acidic protein (GFAP), β III-tubulin, and voltage gated L-type Ca 2+ channels [ 32 ]. However, absence of Na + and K + channels does not support spontaneous action potential generation, necessary for response generation against environmental stimulus. All together, these primordial neuronal stem cells have possible therapeutic potential for treatment of neurodental problems [ 32 ]. Sometimes, brain tumor chemotherapy can cause neurodegeneration mediated cognitive impairment, a condition known as chemobrain [ 33 ]. The intrahippocampal transplantation of human derived neuronal stem cells to cyclophosphamide behavioural decremented mice restores cognitive functions in a month time. Here the transplanted stem cells differentiate into neuronal and astroglial lineage, reduce neuroinflammation, and restore microglial functions [ 33 ]. Furthermore, transplantation of stem cells, followed by chemotherapy, directs pyramidal and granule-cell neurons of the gyrus and CA1 subfields of hippocampus which leads to reduction in spine and dendritic cell density in the brain. These findings suggest that transplantation of stem cells to cranium restores cognitive functions of the chemobrain [ 33 ]. The hair cells of the auditory system produced during development are not postmitotic; loss of hair cells cannot be replaced by inner ear stem cells, due to active state of the Notch signalling [ 34 ]. Stimulation of inner ear progenitors with ϒ -secretase inhibitor (LY411575) abrogates Notch signalling through activation of transcription factor atonal homologue 1 (Atoh1) and directs transdifferentiation of progenitors into cochlear hair cells [ 34 ]. Transplantation of in vitro generated hair cells restores acoustic functions in mice, which can be the potential regenerative medicine candidates for the treatment of deafness [ 34 ]. Generation of the hair cells also can be achieved through overexpression of β -catenin and Atoh1 in Lrg5 + cells in vivo [ 35 ]. Similar to ear progenitors, intestine of the digestive tract also has its own tissue specific progenitor stem cells, mediating regeneration of the intestinal tissue [ 34 , 36 ]. Dysregulation of the common stem cells signalling pathways, Notch/BMP/TGF- β /Wnt, in the intestinal tissue leads to disease. Information on these signalling pathways [ 37 ] is critically important in designing therapeutics. Coaxing of the intestinal tissue specific progenitors with immune cells (macrophages), connective tissue cells (myofibroblasts), and probiotic bacteria into 3D-scaffolds of inert biomaterial, crafting biological environment, is suitable for differentiation of progenitors to occupy the crypt-villi structures into these scaffolds [ 36 ]. Omental implementation of these crypt-villi structures to dogs enhances intestinal mucosa through regeneration of goblet cells containing intestinal tissue [ 36 ]. These intestinal scaffolds are close approach for generation of implantable intestinal tissue, divested by infection, trauma, cancer, necrotizing enterocolitis (NEC), and so forth [ 36 ]. In vitro culture conditions cause differentiation of intestinal stem cells to become other types of cells, whereas incorporation of valproic acid and CHIR-99021 in culture conditions avoids differentiation of intestinal stem cells, enabling generation of indefinite pool of stem cells to be used for regenerative applications [ 38 ]. The limbal stem cells of the basal limbal epithelium, marked with ABCB5, are essential for regeneration and maintenance of corneal tissue [ 39 ]. Functional status of ABCB5 is critical for survival and functional integrity of limbal stem cells, protecting them from apoptotic cell death [ 39 ]. Limbal stem cells deficiency leads to replacement of corneal epithelium with visually dead conjunctival tissue, which can be contributed by burns, inflammation, and genetic factors [ 40 ]. Transplanted human cornea stem cells to mice regrown into fully functional human cornea, possibly supported by blood eye barrier phenomena, can be used for treatment of eye diseases, where regeneration of corneal tissue is critically required for vision restoration [ 39 ]. Muscle degenerative disease like duchenne muscular dystrophy (DMD) can cause extensive thrashing of muscle tissue, where tissue engineering technology can be deployed for functional restoration of tissue through regeneration [ 41 ]. Encapsulation of mouse or human derived MABs (engineered to express placental derived growth factor (PDGF)) into polyethylene glycol (PEG) fibrinogen hydrogel and their transplantation beneath the skin at ablated tibialis anterior form artificial muscles, which are functionally similar to those of normal tibialis anterior muscles [ 41 ]. The PDGF attracts various cell types of vasculogenic and neurogenic potential to the site of transplantation, supporting transdifferentiation of mesoangioblasts to become muscle fibrils [ 41 ]. The therapeutic application of MABs in skeletal muscle regeneration and other therapeutic outcomes has been reviewed by others [ 42 ]. One of the most important tissue specific stem cells, the male germline stem cells or spermatogonial stem cells (SSCs), produces spermatogenic lineage through mesenchymal and epithets cells [ 43 ] which itself creates niche effect on other cells. In vivo transplantation of SSCs with prostate, skin, and uterine mesenchyme leads to differentiation of these cells to become epithelia of the tissue of origin [ 43 ]. These newly formed tissues exhibit all physical and physiological characteristics of prostate and skin and the physical characteristics of prostate, skin, and uterus, express tissue specific markers, and suggest that factors secreted from SSCs lead to lineage conservation which defines the importance of niche effect in regenerative medicine [ 43 ]. According to an estimate, more than 100 million people are suffering from the condition of diabetic retinopathy, a progressive dropout of vascularisation in retina that leads to loss of vision [ 44 ]. The intravitreal injection of adipose derived stem cells (AdSCs) to the eye restores microvascular capillary bed in mice. The AdSCs from healthy donor produce higher amounts of vasoprotective factors compared to glycemic mice, enabling superior vascularisation [ 44 ]. However use of AdSCs for disease therapeutics needs further standardization for cell counts in dose of transplant and monitoring of therapeutic outcomes at population scale [ 44 ]. Apart from AdSCs, other kinds of stem cells also have therapeutic potential in regenerative medicine for treatment of eye defects, which has been reviewed by others [ 45 ]. Fallopian tubes, connecting ovaries to uterus, are the sites where fertilization of the egg takes place. Infection in fallopian tubes can lead to inflammation, tissue scarring, and closure of the fallopian tube which often leads to infertility and ectopic pregnancies. Fallopian is also the site where onset of ovarian cancer takes place. The studies on origin and etiology of ovarian cancer are restricted due to lack of technical advancement for culture of epithelial cells. The in vitro 3D organoid culture of clinically obtained fallopian tube epithelial cells retains their tissue specificity, keeps cells alive, which differentiate into typical ciliated and secretory cells of fallopian tube, and advocates that ectopic examination of fallopian tube in organoid culture settings might be the ideal approach for screening of cancer [ 46 ]. The sustained growth and differentiation of fallopian TSPSCs into fallopian tube organoid depend both on the active state of the Wnt and on paracrine Notch signalling [ 46 ]. Similar to fallopian tube stem cells, subcutaneous visceral tissue specific cardiac adipose (CA) derived stem cells (AdSCs) have the potential of differentiation into cardiovascular tissue [ 47 ]. Systemic infusion of CA-AdSCs into ischemic myocardium of mice regenerates heart tissue and improves cardiac function through differentiation to endothelial cells, vascular smooth cells, and cardiomyocytes and vascular smooth cells. The differentiation and heart regeneration potential of CA-AdSCs are higher than AdSCs [ 48 ], representing CA-AdSCs as potent regenerative medicine candidates for myocardial ischemic therapy [ 47 ]. The skin derived precursors (SKPs), the progenitors of dermal papilla/hair/hair sheath, give rise to multiple tissues of mesodermal and/or ectodermal origin such as neurons, Schwann cells, adipocytes, chondrocytes, and vascular smooth muscle cells (VSMCs). VSMCs mediate wound healing and angiogenesis process can be derived from human foreskin progenitor SKPs, suggesting that SKPs derived VSMCs are potential regenerative medicine candidates for wound healing and vasculature injuries treatments [ 49 ]. In summary, TSPSCs are potentiated with tissue regeneration, where advancement in organoid culture ( Figure 3 ; Table 1 ) technologies defines the importance of niche effect in tissue regeneration and therapeutic outcomes of ex vivo expanded stem cells.

4. MSCs/Stromal Cells in Regenerative Medicine

MSCs, the multilineage stem cells, differentiate only to tissue of mesodermal origin, which includes tendons, bone, cartilage, ligaments, muscles, and neurons [ 50 ]. MSCs are the cells which express combination of markers: CD73 + , CD90 + , CD105 + , CD11b − , CD14 − , CD19 − , CD34 − , CD45 − , CD79a − , and HLA-DR, reviewed elsewhere [ 50 ]. The application of MSCs in regenerative medicine can be generalized from ongoing clinical trials, phasing through different state of completions, reviewed elsewhere [ 90 ]. This section of review outlines the most recent representative applications of MSCs ( Figure 4 ; Table 1 ). The anatomical and physiological characteristics of both donor and receiver have equal impact on therapeutic outcomes. The bone marrow derived MSCs (BMDMSCs) from baboon are morphologically and phenotypically similar to those of bladder stem cells and can be used in regeneration of bladder tissue. The BMDMSCs (CD105 + , CD73 + , CD34 − , and CD45 − ), expressing GFP reporter, coaxed with small intestinal submucosa (SIS) scaffolds, augment healing of degenerated bladder tissue within 10 wks of the transplantation [ 51 ]. The combinatorial CD characterized MACs are functionally active at transplantation site, which suggests that CD characterization of donor MSCs yields superior regenerative outcomes [ 51 ]. MSCs also have potential to regenerate liver tissue and treat liver cirrhosis, reviewed elsewhere [ 91 ]. The regenerative medicinal application of MSCs utilizes cells in two formats as direct transplantation or first transdifferentiation and then transplantation; ex vivo transdifferentiation of MSCs deploys retroviral delivery system that can cause oncogenic effect on cells. Nonviral, NanoScript technology, comprising utility of transcription factors (TFs) functionalized gold nanoparticles, can target specific regulatory site in the genome effectively and direct differentiation of MSCs into another cell fate, depending on regime of TFs. For example, myogenic regulatory factor containing NanoScript-MRF differentiates the adipose tissue derived MSCs into muscle cells [ 92 ]. The multipotency characteristics represent MSCs as promising candidate for obtaining stable tissue constructs through coaxed 3D organoid culture; however heterogeneous distribution of MSCs slows down cell proliferation, rendering therapeutic applications of MSCs. Adopting two-step culture system for MSCs can yield homogeneous distribution of MSCs in biomaterial scaffolds. For example, fetal-MSCs coaxed in biomaterial when cultured first in rotating bioreactor followed with static culture lead to homogeneous distribution of MSCs in ECM components [ 7 ]. Occurrence of dental carries, periodontal disease, and tooth injury can impact individual's health, where bioengineering of teeth can be the alternative option. Coaxing of epithelial-MSCs with dental stem cells into synthetic polymer gives rise to mature teeth unit, which consisted of mature teeth and oral tissue, offering multiple regenerative therapeutics, reviewed elsewhere [ 52 ]. Like the tooth decay, both human and animals are prone to orthopedic injuries, affecting bones, joint, tendon, muscles, cartilage, and so forth. Although natural healing potential of bone is sufficient to heal the common injuries, severe trauma and tumor-recession can abrogate germinal potential of bone-forming stem cells. In vitro chondrogenic, osteogenic, and adipogenic potential of MSCs advocates therapeutic applications of MSCs in orthopedic injuries [ 53 ]. Seeding of MSCs, coaxed into biomaterial scaffolds, at defective bone tissue, regenerates defective bone tissues, within four wks of transplantation; by the end of 32 wks newly formed tissues integrate into old bone [ 54 ]. Osteoblasts, the bone-forming cells, have lesser actin cytoskeleton compared to adipocytes and MSCs. Treatment of MSCs with cytochalasin-D causes rapid transportation of G-actin, leading to osteogenic transformation of MSCs. Furthermore, injection of cytochalasin-D to mice tibia also promotes bone formation within a wk time frame [ 55 ]. The bone formation processes in mice, dog, and human are fundamentally similar, so outcomes of research on mice and dogs can be directional for regenerative application to human. Injection of MSCs to femur head of Legg-Calve-Perthes suffering dog heals the bone very fast and reduces the injury associated pain [ 55 ]. Degeneration of skeletal muscle and muscle cramps are very common to sledge dogs, animals, and individuals involved in adventurous athletics activities. Direct injection of adipose tissue derived MSCs to tear-site of semitendinosus muscle in dogs heals injuries much faster than traditional therapies [ 56 ]. Damage effect treatment for heart muscle regeneration is much more complex than regeneration of skeletal muscles, which needs high grade fine-tuned coordination of neurons with muscles. Coaxing of MSCs into alginate gel increases cell retention time that leads to releasing of tissue repairing factors in controlled manner. Transplantation of alginate encapsulated cells to mice heart reduces scar size and increases vascularisation, which leads to restoration of heart functions. Furthermore, transplanted MSCs face host inhospitable inflammatory immune responses and other mechanical forces at transplantation site, where encapsulation of cells keeps them away from all sorts of mechanical forces and enables sensing of host tissue microenvironment, and respond accordingly [ 57 ]. Ageing, disease, and medicine consumption can cause hair loss, known as alopecia. Although alopecia has no life threatening effects, emotional catchments can lead to psychological disturbance. The available treatments for alopecia include hair transplantation and use of drugs, where drugs are expensive to afford and generation of new hair follicle is challenging. Dermal papillary cells (DPCs), the specialized MSCs localized in hair follicle, are responsible for morphogenesis of hair follicle and hair cycling. The layer-by-layer coating of DPCs, called GAG coating, consists of coating of geletin as outer layer, middle layer of fibroblast growth factor 2 (FGF2) loaded alginate, and innermost layer of geletin. GAG coating creates tissue microenvironment for DPCs that can sustain immunological and mechanical obstacles, supporting generation of hair follicle. Transplantation of GAG-coated DPCs leads to abundant hair growth and maturation of hair follicle, where GAG coating serves as ECM, enhancing intrinsic therapeutic potential of DPCs [ 58 ]. During infection, the inflammatory cytokines secreted from host immune cells attract MSCs to the site of inflammation, which modulates inflammatory responses, representing MSCs as key candidate of regenerative medicine for infectious disease therapeutics. Coculture of macrophages (M ϕ ) and adipose derived MSCs from Leishmania major (LM) susceptible and resistant mice demonstrates that AD-MSCs educate M ϕ against LM infection, differentially inducing M1 and M2 phenotype that represents AD-MSC as therapeutic agent for leishmanial therapy [ 93 ]. In summary, the multilineage differentiation potential of MSCs, as well as adoption of next-generation organoid culture system, avails MSCs as ideal regenerative medicine candidate.

5. UCSCs in Regenerative Medicine

Umbilical cord, generally thrown at the time of child birth, is the best known source for stem cells, procured in noninvasive manner, having lesser ethical constraints than ESCs. Umbilical cord is rich source of hematopoietic stem cells (HSCs) and MSCs, which possess enormous regeneration potential [ 94 ] ( Figure 5 ; Table 1 ). The HSCs of cord blood are responsible for constant renewal of all types of blood cells and protective immune cells. The proliferation of HSCs is regulated by Musashi-2 protein mediated attenuation of Aryl hydrocarbon receptor (AHR) signalling in stem cells [ 95 ]. UCSCs can be cryopreserved at stem cells banks ( Figure 5 ; Table 1 ), in operation by both private and public sector organization. Public stem cells banks operate on donation formats and perform rigorous screening for HLA typing and donated UCSCs remain available to anyone in need, whereas private stem cell banks operation is more personalized, availing cells according to donor consent. Stem cell banking is not so common, even in developed countries. Survey studies find that educated women are more eager to donate UCSCs, but willingness for donation decreases with subsequent deliveries, due to associated cost and safety concerns for preservation [ 96 ]. FDA has approved five HSCs for treatment of blood and other immunological complications [ 97 ]. The amniotic fluid, drawn during pregnancy for standard diagnostic purposes, is generally discarded without considering its vasculogenic potential. UCSCs are the best alternatives for those patients who lack donors with fully matched HLA typing for peripheral blood and PBMCs and bone marrow [ 98 ]. One major issue with UCSCs is number of cells in transplant, fewer cells in transplant require more time for engraftment to mature, and there are also risks of infection and mortality; in that case ex vivo propagation of UCSCs can meet the demand of desired outcomes. There are diverse protocols, available for ex vivo expansion of UCSCs, reviewed elsewhere [ 99 ]. Amniotic fluid stem cells (AFSCs), coaxed to fibrin (required for blood clotting, ECM interactions, wound healing, and angiogenesis) hydrogel and PEG supplemented with vascular endothelial growth factor (VEGF), give rise to vascularised tissue, when grafted to mice, suggesting that organoid cultures of UCSCs have promise for generation of biocompatible tissue patches, for treating infants born with congenital heart defects [ 59 ]. Retroviral integration of OCT4, KLF4, cMYC, and SOX2 transforms AFSCs into pluripotency stem cells known as AFiPSCs which can be directed to differentiate into extraembryonic trophoblast by BMP2 and BMP4 stimulation, which can be used for regeneration of placental tissues [ 60 ]. Wharton's jelly (WJ), the gelatinous substance inside umbilical cord, is rich in mucopolysaccharides, fibroblast, macrophages, and stem cells. The stem cells from UCB and WJ can be transdifferentiated into β -cells. Homogeneous nature of WJ-SCs enables better differentiation into β -cells; transplantation of these cells to streptozotocin induced diabetic mice efficiently brings glucose level to normal [ 7 ]. Easy access and expansion potential and plasticity to differentiate into multiple cell lineages represent WJ as an ideal candidate for regenerative medicine but cells viability changes with passages with maximum viable population at 5th-6th passages. So it is suggested to perform controlled expansion of WJ-MSCS for desired regenerative outcomes [ 9 ]. Study suggests that CD34 + expression leads to the best regenerative outcomes, with less chance of host-versus-graft rejection. In vitro expansion of UCSCs, in presence of StemRegenin-1 (SR-1), conditionally expands CD34 + cells [ 61 ]. In type I diabetic mellitus (T1DM), T-cell mediated autoimmune destruction of pancreatic β -cells occurs, which has been considered as tough to treat. Transplantation of WJ-SCs to recent onset-T1DM patients restores pancreatic function, suggesting that WJ-MSCs are effective in regeneration of pancreatic tissue anomalies [ 62 ]. WJ-MSCs also have therapeutic importance for treatment of T2DM. A non-placebo controlled phase I/II clinical trial demonstrates that intravenous and intrapancreatic endovascular injection of WJ-MSCs to T2DM patients controls fasting glucose and glycated haemoglobin through improvement of β -cells functions, evidenced by enhanced c-peptides and reduced inflammatory cytokines (IL-1 β and IL-6) and T-cells counts [ 63 ]. Like diabetes, systematic lupus erythematosus (SLE) also can be treated with WJ-MSCs transplantation. During progression of SLE host immune system targets its own tissue leading to degeneration of renal, cardiovascular, neuronal, and musculoskeletal tissues. A non-placebo controlled follow-up study on 40 SLE patients demonstrates that intravenous infusion of WJ-MSC improves renal functions and decreases systematic lupus erythematosus disease activity index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), and repeated infusion of WJ-MSCs protects the patient from relapse of the disease [ 64 ]. Sometimes, host inflammatory immune responses can be detrimental for HSCs transplantation and blood transfusion procedures. Infusion of WJ-MSC to patients, who had allogenic HSCs transplantation, reduces haemorrhage inflammation (HI) of bladder, suggesting that WJ-MSCs are potential stem cells adjuvant in HSCs transplantation and blood transfusion based therapies [ 100 ]. Apart from WJ, umbilical cord perivascular space and cord vein are also rich source for obtaining MSCs. The perivascular MSCs of umbilical cord are more primitive than WJ-MSCs and other MSCs from cord suggest that perivascular MSCs might be used as alternatives for WJ-MSCs for regenerative therapeutics outcome [ 101 ]. Based on origin, MSCs exhibit differential in vitro and in vivo properties and advocate functional characterization of MSCs, prior to regenerative applications. Emerging evidence suggests that UCSCs can heal brain injuries, caused by neurodegenerative diseases like Alzheimer's, Krabbe's disease, and so forth. Krabbe's disease, the infantile lysosomal storage disease, occurs due to deficiency of myelin synthesizing enzyme (MSE), affecting brain development and cognitive functions. Progression of neurodegeneration finally leads to death of babies aged two. Investigation shows that healing of peripheral nervous system (PNS) and central nervous system (CNS) tissues with Krabbe's disease can be achieved by allogenic UCSCs. UCSCs transplantation to asymptomatic infants with subsequent monitoring for 4–6 years reveals that UCSCs recover babies from MSE deficiency, improving myelination and cognitive functions, compared to those of symptomatic babies. The survival rate of transplanted UCSCs in asymptomatic and symptomatic infants was 100% and 43%, respectively, suggesting that early diagnosis and timely treatment are critical for UCSCs acceptance for desired therapeutic outcomes. UCSCs are more primitive than BMSCs, so perfect HLA typing is not critically required, representing UCSCs as an excellent source for treatment of all the diseases involving lysosomal defects, like Krabbe's disease, hurler syndrome, adrenoleukodystrophy (ALD), metachromatic leukodystrophy (MLD), Tay-Sachs disease (TSD), and Sandhoff disease [ 65 ]. Brain injuries often lead to cavities formation, which can be treated from neuronal parenchyma, generated ex vivo from UCSCs. Coaxing of UCSCs into human originated biodegradable matrix scaffold and in vitro expansion of cells in defined culture conditions lead to formation of neuronal organoids, within three wks' time frame. These organoids structurally resemble brain tissue and consisted of neuroblasts (GFAP + , Nestin + , and Ki67 + ) and immature stem cells (OCT4 + and SOX2 + ). The neuroblasts of these organoids further can be differentiated into mature neurons (MAP2 + and TUJ1 + ) [ 66 ]. Administration of high dose of drugs in divesting neuroblastoma therapeutics requires immediate restoration of hematopoiesis. Although BMSCs had been promising in restoration of hematopoiesis UCSCs are sparely used in clinical settings. A case study demonstrates that neuroblastoma patients who received autologous UCSCs survive without any associated side effects [ 12 ]. During radiation therapy of neoplasm, spinal cord myelitis can occur, although occurrence of myelitis is a rare event and usually such neurodegenerative complication of spinal cord occurs 6–24 years after exposure to radiations. Transplantation of allogenic UC-MSCs in laryngeal patients undergoing radiation therapy restores myelination [ 102 ]. For treatment of neurodegenerative disease like Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), traumatic brain injuries (TBI), Parkinson's, SCI, stroke, and so forth, distribution of transplanted UCSCs is critical for therapeutic outcomes. In mice and rat, injection of UCSCs and subsequent MRI scanning show that transplanted UCSCs migrate to CNS and multiple peripheral organs [ 67 ]. For immunomodulation of tumor cells disease recovery, transplantation of allogenic DCs is required. The CD11c + DCs, derived from UCB, are morphologically and phenotypically similar to those of peripheral blood derived CTLs-DCs, suggesting that UCB-DCs can be used for personalized medicine of cancer patient, in need for DCs transplantation [ 103 ]. Coculture of UCSCs with radiation exposed human lung fibroblast stops their transdifferentiation, which suggests that factors secreted from UCSCs may restore niche identity of fibroblast, if they are transplanted to lung after radiation therapy [ 104 ]. Tearing of shoulder cuff tendon can cause severe pain and functional disability, whereas ultrasound guided transplantation of UCB-MSCs in rabbit regenerates subscapularis tendon in four wks' time frame, suggesting that UCB-MSCs are effective enough to treat tendons injuries when injected to focal points of tear-site [ 68 ]. Furthermore, transplantation of UCB-MSCs to chondral cartilage injuries site in pig knee along with HA hydrogel composite regenerates hyaline cartilage [ 69 ], suggesting that UCB-MSCs are effective regenerative medicine candidate for treating cartilage and ligament injuries. Physiologically circulatory systems of brain, placenta, and lungs are similar. Infusion of UCB-MSCs to preeclampsia (PE) induced hypertension mice reduces the endotoxic effect, suggesting that UC-MSCs are potential source for treatment of endotoxin induced hypertension during pregnancy, drug abuse, and other kinds of inflammatory shocks [ 105 ]. Transplantation of UCSCs to severe congenital neutropenia (SCN) patients restores neutrophils count from donor cells without any side effect, representing UCSCs as potential alternative for SCN therapy, when HLA matched bone marrow donors are not accessible [ 106 ]. In clinical settings, the success of myocardial infarction (MI) treatment depends on ageing, systemic inflammation in host, and processing of cells for infusion. Infusion of human hyaluronan hydrogel coaxed UCSCs in pigs induces angiogenesis, decreases scar area, improves cardiac function at preclinical level, and suggests that the same strategy might be effective for human [ 107 ]. In stem cells therapeutics, UCSCs transplantation can be either autologous or allogenic. Sometimes, the autologous UCSCs transplants cannot combat over tumor relapse, observed in Hodgkin's lymphoma (HL), which might require second dose transplantation of allogenic stem cells, but efficacy and tolerance of stem cells transplant need to be addressed, where tumor replace occurs. A case study demonstrates that second dose allogenic transplants of UCSCs effective for HL patients, who had heavy dose in prior transplant, increase the long term survival chances by 30% [ 10 ]. Patients undergoing long term peritoneal renal dialysis are prone to peritoneal fibrosis and can change peritoneal structure and failure of ultrafiltration processes. The intraperitoneal (IP) injection of WJ-MSCs prevents methylglyoxal induced programmed cell death and peritoneal wall thickening and fibrosis, suggesting that WJ-MSCs are effective in therapeutics of encapsulating peritoneal fibrosis [ 70 ]. In summary, UCB-HSCs, WJ-MSCs, perivascular MSCs, and UCB-MSCs have tissue regeneration potential.

6. BMSCs in Regenerative Medicine

Bone marrow found in soft spongy bones is responsible for formation of all peripheral blood and comprises hematopoietic stem cells (producing blood cells) and stromal cells (producing fat, cartilage, and bones) [ 108 ] ( Figure 6 ; Table 1 ). Visually bone marrow has two types, red marrow (myeloid tissue; producing RBC, platelets, and most of WBC) and yellow marrow (producing fat cells and some WBC) [ 108 ]. Imbalance in marrow composition can culminate to the diseased condition. Since 1980, bone marrow transplantation is widely accepted for cancer therapeutics [ 109 ]. In order to avoid graft rejection, HLA typing of donors is a must, but completely matched donors are limited to family members, which hampers allogenic transplantation applications. Since matching of all HLA antigens is not critically required, in that case defining the critical antigens for haploidentical allogenic donor for patients, who cannot find fully matched donor, might relieve from donor constraints. Two-step administration of lymphoid and myeloid BMSCs from haploidentical donor to the patients of aplastic anaemia and haematological malignancies reconstructs host immune system and the outcomes are almost similar to fully matched transplants, which recommends that profiling of critically important HLA is sufficient for successful outcomes of BMSCs transplantation. Haploidentical HLA matching protocol is the major process for minorities and others who do not have access to matched donor [ 71 ]. Furthermore, antigen profiling is not the sole concern for BMSCs based therapeutics. For example, restriction of HIV1 (human immune deficiency virus) infection is not feasible through BMSCs transplantation because HIV1 infection is mediated through CD4 + receptors, chemokine CXC motif receptor 4 (CXCR4), and chemokine receptor 5 (CCR5) for infecting and propagating into T helper (Th), monocytes, macrophages, and dendritic cells (DCs). Genetic variation in CCR2 and CCR5 receptors is also a contributory factor; mediating protection against infection has been reviewed elsewhere [ 110 ]. Engineering of hematopoietic stem and progenitor cells (HSPCs) derived CD4 + cells to express HIV1 antagonistic RNA, specifically designed for targeting HIV1 genome, can restrict HIV1 infection, through immune elimination of latently infected CD4 + cells. A single dose infusion of genetically modified (GM), HIV1 resistant HSPCs can be the alternative of HIV1 retroviral therapy. In the present scenario stem cells source, patient selection, transplantation-conditioning regimen, and postinfusion follow-up studies are the major factors, which can limit application of HIV1 resistant GM-HSPCs (CD4 + ) cells application in AIDS therapy [ 72 , 73 ]. Platelets, essential for blood clotting, are formed from megakaryocytes inside the bone marrow [ 74 ]. Due to infection, trauma, and cancer, there are chances of bone marrow failure. To an extent, spongy bone marrow microenvironment responsible for lineage commitment can be reconstructed ex vivo [ 75 ]. The ex vivo constructed 3D-scaffolds consisted of microtubule and silk sponge, flooded with chemically defined organ culture medium, which mimics bone marrow environment. The coculture of megakaryocytes and embryonic stem cells (ESCs) in this microenvironment leads to generation of functional platelets from megakaryocytes [ 75 ]. The ex vivo 3D-scaffolds of bone microenvironment can stride the path for generation of platelets in therapeutic quantities for regenerative medication of burns [ 75 ] and blood clotting associated defects. Accidents, traumatic injuries, and brain stroke can deplete neuronal stem cells (NSCs), responsible for generation of neurons, astrocytes, and oligodendrocytes. Brain does not repopulate NSCs and heal traumatic injuries itself and transplantation of BMSCs also can heal neurodegeneration alone. Lipoic acid (LA), a known pharmacological antioxidant compound used in treatment of diabetic and multiple sclerosis neuropathy when combined with BMSCs, induces neovascularisation at focal cerebral injuries, within 8 wks of transplantation. Vascularisation further attracts microglia and induces their colonization into scaffold, which leads to differentiation of BMSCs to become brain tissue, within 16 wks of transplantation. In this approach, healing of tissue directly depends on number of BMSCs in transplantation dose [ 76 ]. Dental caries and periodontal disease are common craniofacial disease, often requiring jaw bone reconstruction after removal of the teeth. Traditional therapy focuses on functional and structural restoration of oral tissue, bone, and teeth rather than biological restoration, but BMSCs based therapies promise for regeneration of craniofacial bone defects, enabling replacement of missing teeth in restored bones with dental implants. Bone marrow derived CD14 + and CD90 + stem and progenitor cells, termed as tissue repair cells (TRC), accelerate alveolar bone regeneration and reconstruction of jaw bone when transplanted in damaged craniofacial tissue, earlier to oral implants. Hence, TRC therapy reduces the need of secondary bone grafts, best suited for severe defects in oral bone, skin, and gum, resulting from trauma, disease, or birth defects [ 77 ]. Overall, HSCs have great value in regenerative medicine, where stem cells transplantation strategies explore importance of niche in tissue regeneration. Prior to transplantation of BMSCs, clearance of original niche from target tissue is necessary for generation of organoid and organs without host-versus-graft rejection events. Some genetic defects can lead to disorganization of niche, leading to developmental errors. Complementation with human blastocyst derived primary cells can restore niche function of pancreas in pigs and rats, which defines the concept for generation of clinical grade human pancreas in mice and pigs [ 111 ]. Similar to other organs, diaphragm also has its own niche. Congenital defects in diaphragm can affect diaphragm functions. In the present scenario functional restoration of congenital diaphragm defects by surgical repair has risk of reoccurrence of defects or incomplete restoration [ 8 ]. Decellularization of donor derived diaphragm offers a way for reconstruction of new and functionally compatible diaphragm through niche modulation. Tissue engineering technology based decellularization of diaphragm and simultaneous perfusion of bone marrow mesenchymal stem cells (BM-MSCs) facilitates regeneration of functional scaffolds of diaphragm tissues [ 8 ]. In vivo replacement of hemidiaphragm in rats with reseeded scaffolds possesses similar myography and spirometry as it has in vivo in donor rats. These scaffolds retaining natural architecture are devoid of immune cells, retaining intact extracellular matrix that supports adhesion, proliferation, and differentiation of seeded cells [ 8 ]. These findings suggest that cadaver obtained diaphragm, seeded with BM-MSCs, can be used for curing patients in need for restoration of diaphragm functions ( Figure 6 ; Table 1 ). However, BMSCs are heterogeneous population, which might result in differential outcomes in clinical settings; however clonal expansion of BMSCs yields homogenous cells population for therapeutic application [ 8 ]. One study also finds that intracavernous delivery of single clone BMSCs can restore erectile function in diabetic mice [ 112 ] and the same strategy might be explored for adult human individuals. The infection of hepatitis C virus (HCV) can cause liver cirrhosis and degeneration of hepatic tissue. The intraparenchymal transplantation of bone marrow mononuclear cells (BMMNCs) into liver tissue decreases aspartate aminotransferase (AST), alanine transaminase (ALT), bilirubin, CD34, and α -SMA, suggesting that transplanted BMSCs restore hepatic functions through regeneration of hepatic tissues [ 113 ]. In order to meet the growing demand for stem cells transplantation therapy, donor encouragement is always required [ 8 ]. The stem cells donation procedure is very simple; with consent donor gets an injection of granulocyte-colony stimulating factor (G-CSF) that increases BMSCs population. Bone marrow collection is done from hip bone using syringe in 4-5 hrs, requiring local anaesthesia and within a wk time frame donor gets recovered donation associated weakness.

7. iPSCs in Regenerative Medicine

The field of iPSCs technology and research is new to all other stem cells research, emerging in 2006 when, for the first time, Takahashi and Yamanaka generated ESCs-like cells through genetic incorporation of four factors, Sox2, Oct3/4, Klf4, and c-Myc, into skin fibroblast [ 3 ]. Due to extensive nuclear reprogramming, generated iPSCs are indistinguishable from ESCs, for their transcriptome profiling, epigenetic markings, and functional competence [ 3 ], but use of retrovirus in transdifferentiation approach has questioned iPSCs technology. Technological advancement has enabled generation of iPSCs from various kinds of adult cells phasing through ESCs or direct transdifferentiation. This section of review outlines most recent advancement in iPSC technology and regenerative applications ( Figure 7 ; Table 1 ). Using the new edge of iPSCs technology, terminally differentiated skin cells directly can be transformed into kidney organoids [ 114 ], which are functionally and structurally similar to those of kidney tissue in vivo. Up to certain extent kidneys heal themselves; however natural regeneration potential cannot meet healing for severe injuries. During kidneys healing process, a progenitor stem cell needs to become 20 types of cells, required for waste excretion, pH regulation, and restoration of water and electrolytic ions. The procedure for generation of kidney organoids ex vivo, containing functional nephrons, has been identified for human. These ex vivo kidney organoids are similar to fetal first-trimester kidneys for their structure and physiology. Such kidney organoids can serve as model for nephrotoxicity screening of drugs, disease modelling, and organ transplantation. However generation of fully functional kidneys is a far seen event with today's scientific technologies [ 114 ]. Loss of neurons in age-related macular degeneration (ARMD) is the common cause of blindness. At preclinical level, transplantation of iPSCs derived neuronal progenitor cells (NPCs) in rat limits progression of disease through generation of 5-6 layers of photoreceptor nuclei, restoring visual acuity [ 78 ]. The various approaches of iPSCs mediated retinal regeneration including ARMD have been reviewed elsewhere [ 79 ]. Placenta, the cordial connection between mother and developing fetus, gets degenerated in certain pathophysiological conditions. Nuclear programming of OCT4 knock-out (KO) and wild type (WT) mice fibroblast through transient expression of GATA3, EOMES, TFAP2C, and +/− cMYC generates transgene independent trophoblast stem-like cells (iTSCs), which are highly similar to blastocyst derived TSCs for DNA methylation, H3K7ac, nucleosome deposition of H2A.X, and other epigenetic markings. Chimeric differentiation of iTSCs specifically gives rise to haemorrhagic lineages and placental tissue, bypassing pluripotency phase, opening an avenue for generation of fully functional placenta for human [ 115 ]. Neurodegenerative disease like Alzheimer's and obstinate epilepsies can degenerate cerebrum, controlling excitatory and inhibitory signals of the brain. The inhibitory tones in cerebral cortex and hippocampus are accounted by γ -amino butyric acid secreting (GABAergic) interneurons (INs). Loss of these neurons often leads to progressive neurodegeneration. Genomic integration of Ascl1, Dlx5, Foxg1, and Lhx6 to mice and human fibroblast transforms these adult cells into GABAergic-INs (iGABA-INs). These cells have molecular signature of telencephalic INs, release GABA, and show inhibition to host granule neuronal activity [ 81 ]. Transplantation of these INs in developing embryo cures from genetic and acquired seizures, where transplanted cells disperse and mature into functional neuronal circuits as local INs [ 82 ]. Dorsomorphin and SB-431542 mediated inhibition of TGF- β and BMP signalling direct transformation of human iPSCs into cortical spheroids. These cortical spheroids consisted of both peripheral and cortical neurons, surrounded by astrocytes, displaying transcription profiling and electrophysiology similarity with developing fetal brain and mature neurons, respectively [ 83 ]. The underlying complex biology and lack of clear etiology and genetic reprogramming and difficulty in recapitulation of brain development have barred understanding of pathophysiology of autism spectrum disorder (ASD) and schizophrenia. 3D organoid cultures of ASD patient derived iPSC generate miniature brain organoid, resembling fetal brain few months after gestation. The idiopathic conditions of these organoids are similar with brain of ASD patients; both possess higher inhibitory GABAergic neurons with imbalanced neuronal connection. Furthermore these organoids express forkhead Box G1 (FOXG1) much higher than normal brain tissue, which explains that FOXG1 might be the leading cause of ASD [ 84 ]. Degeneration of other organs and tissues also has been reported, like degeneration of lungs which might occur due to tuberculosis infection, fibrosis, and cancer. The underlying etiology for lung degeneration can be explained through organoid culture. Coaxing of iPSC into inert biomaterial and defined culture leads to formation of lung organoids that consisted of epithelial and mesenchymal cells, which can survive in culture for months. These organoids are miniature lung, resemble tissues of large airways and alveoli, and can be used for lung developmental studies and screening of antituberculosis and anticancer drugs [ 87 ]. The conventional multistep reprogramming for iPSCs consumes months of time, while CRISPER-Cas9 system based episomal reprogramming system that combines two steps together enables generation of ESCs-like cells in less than two wks, reducing the chances of culture associated genetic abrasions and unwanted epigenetic [ 80 ]. This approach can yield single step ESCs-like cells in more personalized way from adults with retinal degradation and infants with severe immunodeficiency, involving correction for genetic mutation of OCT4 and DNMT3B [ 80 ]. The iPSCs expressing anti-CCR5-RNA, which can be differentiated into HIV1 resistant macrophages, have applications in AIDS therapeutics [ 88 ]. The diversified immunotherapeutic application of iPSCs has been reviewed elsewhere [ 89 ]. The α -1 antitrypsin deficiency (A1AD) encoded by serpin peptidase inhibitor clade A member 1 (SERPINA1) protein synthesized in liver protects lungs from neutrophils elastase, the enzyme causing disruption of lungs connective tissue. A1AD deficiency is common cause of both lung and liver disease like chronic obstructive pulmonary disease (COPD) and liver cirrhosis. Patient specific iPSCs from lung and liver cells might explain pathophysiology of A1AD deficiency. COPD patient derived iPSCs show sensitivity to toxic drugs which explains that actual patient might be sensitive in similar fashion. It is known that A1AD deficiency is caused by single base pair mutation and correction of this mutation fixes the A1AD deficiency in hepatic-iPSCs [ 85 ]. The high order brain functions, like emotions, anxiety, sleep, depression, appetite, breathing heartbeats, and so forth, are regulated by serotonin neurons. Generation of serotonin neurons occurs prior to birth, which are postmitotic in their nature. Any sort of developmental defect and degeneration of serotonin neurons might lead to neuronal disorders like bipolar disorder, depression, and schizophrenia-like psychiatric conditions. Manipulation of Wnt signalling in human iPSCs in defined culture conditions leads to an in vitro differentiation of iPSCs to serotonin-like neurons. These iPSCs-neurons primarily localize to rhombomere 2-3 segment of rostral raphe nucleus, exhibit electrophysiological properties similar to serotonin neurons, express hydroxylase 2, the developmental marker, and release serotonin in dose and time dependent manner. Transplantation of these neurons might cure from schizophrenia, bipolar disorder, and other neuropathological conditions [ 116 ]. The iPSCs technology mediated somatic cell reprogramming of ventricular monocytes results in generation of cells, similar in morphology and functionality with PCs. SA note transplantation of PCs to large animals improves rhythmic heart functions. Pacemaker needs very reliable and robust performance so understanding of transformation process and site of transplantation are the critical aspect for therapeutic validation of iPSCs derived PCs [ 28 ]. Diabetes is a major health concern in modern world, and generation of β -cells from adult tissue is challenging. Direct reprogramming of skin cells into pancreatic cells, bypassing pluripotency phase, can yield clinical grade β -cells. This reprogramming strategy involves transformation of skin cells into definitive endodermal progenitors (cDE) and foregut like progenitor cells (cPF) intermediates and subsequent in vitro expansion of these intermediates to become pancreatic β -cells (cPB). The first step is chemically complex and can be understood as nonepisomal reprogramming on day one with pluripotency factors (OCT4, SOX2, KLF4, and hair pin RNA against p53), then supplementation with GFs and chemical supplements on day seven (EGF, bFGF, CHIR, NECA, NaB, Par, and RG), and two weeks later (Activin-A, CHIR, NECA, NaB, and RG) yielding DE and cPF [ 86 ]. Transplantation of cPB yields into glucose stimulated secretion of insulin in diabetic mice defines that such cells can be explored for treatment of T1DM and T2DM in more personalized manner [ 86 ]. iPSCs represent underrated opportunities for drug industries and clinical research laboratories for development of therapeutics, but safety concerns might limit transplantation applications ( Figure 7 ; Table 1 ) [ 117 ]. Transplantation of human iPSCs into mice gastrula leads to colonization and differentiation of cells into three germ layers, evidenced with clinical developmental fat measurements. The acceptance of human iPSCs by mice gastrula suggests that correct timing and appropriate reprogramming regime might delimit human mice species barrier. Using this fact of species barrier, generation of human organs in closely associated primates might be possible, which can be used for treatment of genetic factors governed disease at embryo level itself [ 118 ]. In summary, iPSCs are safe and effective for treatment of regenerative medicine.

8. Stem Cells in Wildlife Conservation

The unstable growth of human population threatens the existence of wildlife, through overexploitation of natural habitats and illegal killing of wild animals, leading many species to face the fate of being endangered and go for extinction. For wildlife conservation, the concept of creation of frozen zoo involves preservation of gene pool and germ plasm from threatened and endangered species ( Figure 8 ). The frozen zoo tissue samples collection from dead or live animal can be DNA, sperms, eggs, embryos, gonads, skin, or any other tissue of the body [ 119 ]. Preserved tissue can be reprogrammed or transdifferentiated to become other types of tissues and cells, which opens an avenue for conservation of endangered species and resurrection of life ( Figure 8 ). The gonadal tissue from young individuals harbouring immature tissue can be matured in vivo and ex vivo for generation of functional gametes. Transplantation of SSCs to testis of male from the same different species can give rise to spermatozoa of donor cells [ 120 ], which might be used for IVF based captive breeding of wild animals. The most dangerous fact in wildlife conservation is low genetic diversity, too few reproductively capable animals which cannot maintain adequate genetic diversity in wild or captivity. Using the edge of iPSC technology, pluripotent stem cells can be generated from skin cells. For endangered drill, Mandrillus leucophaeus, and nearly extinct white rhinoceros, Ceratotherium simum cottoni , iPSC has been generated in 2011 [ 121 ]. The endangered animal drill ( Mandrillus leucophaeus ) is genetically very close to human and often suffers from diabetes, while rhinos are genetically far removed from other primates. The progress in iPSCs, from the human point of view, might be transformed for animal research for recapturing reproductive potential and health in wild animals. However, stem cells based interventions in wild animals are much more complex than classical conservation planning and biomedical research has to face. Conversion of iPSC into egg or sperm can open the door for generation of IVF based embryo; those might be transplanted in womb of live counterparts for propagation of population. Recently, iPSCs have been generated for snow leopard ( Panthera uncia ), native to mountain ranges of central Asia, which belongs to cat family; this breakthrough has raised the possibilities for cryopreservation of genetic material for future cloning and other assisted reproductive technology (ART) applications, for the conservation of cat species and biodiversity. Generation of leopard iPSCs has been achieved through retroviral-system based genomic integration of OCT4, SOX2, KLF4, cMYC, and NANOG. These iPSCs from snow leopard also open an avenue for further transformation of iPSCs into gametes [ 122 ]. The in vivo maturation of grafted tissue depends both on age and on hormonal status of donor tissue. These facts are equally applicable to accepting host. Ectopic xenografts of cryopreserved testis tissue from Indian spotted deer ( Moschiola indica ) to nude mice yielded generation of spermatocytes [ 123 ], suggesting that one-day procurement of functional sperm from premature tissue might become a general technique in wildlife conservation. In summary, tissue biopsies from dead or live animals can be used for generation of iPSCs and functional gametes; those can be used in assisted reproductive technology (ART) for wildlife conservation.

9. Future Perspectives

The spectacular progress in the field of stem cells research represents great scope of stem cells regenerative therapeutics. It can be estimated that by 2020 or so we will be able to produce wide array of tissue, organoid, and organs from adult stem cells. Inductions of pluripotency phenotypes in terminally differentiated adult cells have better therapeutic future than ESCs, due to least ethical constraints with adult cells. In the coming future, there might be new pharmaceutical compounds; those can activate tissue specific stem cells, promote stem cells to migrate to the side of tissue injury, and promote their differentiation to tissue specific cells. Except few countries, the ongoing financial and ethical hindrance on ESCs application in regenerative medicine have more chance for funding agencies to distribute funding for the least risky projects on UCSCs, BMSCs, and TSPSCs from biopsies. The existing stem cells therapeutics advancements are more experimental and high in cost; due to that application on broad scale is not feasible in current scenario. In the near future, the advancements of medical science presume using stem cells to treat cancer, muscles damage, autoimmune disease, and spinal cord injuries among a number of impairments and diseases. It is expected that stem cells therapies will bring considerable benefits to the patients suffering from wide range of injuries and disease. There is high optimism for use of BMSCs, TSPSCs, and iPSCs for treatment of various diseases to overcome the contradictions associated with ESCs. For advancement of translational application of stem cells, there is a need of clinical trials, which needs funding rejoinder from both public and private organizations. The critical evaluation of regulatory guidelines at each phase of clinical trial is a must to comprehend the success and efficacy in time frame.

Acknowledgments

Dr. Anuradha Reddy from Centre for Cellular and Molecular Biology Hyderabad and Mrs. Sarita Kumari from Department of Yoga Science, BU, Bhopal, India, are acknowledged for their critical suggestions and comments on paper.

Abbreviations

Competing Interests

There are no competing interests associated with this paper.

• Open access
• Published: 09 September 2024

Stem cell-derived extracellular vesicles in premature ovarian failure: an up-to-date meta-analysis of animal studies

• Yan Luo 1 , 4   na1 ,
• Jingjing Chen 1 , 2   na1 ,
• Jinyao Ning 1 , 4 ,
• Yuanyuan Sun 1 , 2 ,
• Yitong Chai 1 , 4 ,
• Fen Xiao 5 ,
• Bixia Huang 1 , 2 ,
• Ge Li 1 , 2 ,
• Fen Tian 1 , 2 ,
• Jie Hao 1 , 2 ,
• Qiong Zhang 1 , 2 ,
• Jing Zhao 1 , 2 ,
• Yanping Li 1 , 2 &
• Hui Li 1 , 2 , 3  

Journal of Ovarian Research volume  17 , Article number:  182 ( 2024 ) Cite this article

Metrics details

There has been a significant surge in animal studies of stem cell-derived extracellular vesicles (EVs) therapy for the treatment of premature ovarian failure (POF) but its efficacy remains unknown and a comprehensive and up-to-date meta-analysis is lacking. Before clinical translation, it is crucial to thoroughly understand the overall impact of stem cell-derived EVs on POF.

PubMed, EMBASE, Cochrane Library, Web of Science were searched up to February 18, 2024. The risk of bias was evaluated according to Cochrane Handbook criteria, while quality of evidence was assessed using the SYRCLE system. The PRISMA guidance was followed. Trial sequential analysis was conducted to assess outcomes, and sensitivity analysis and publication bias analysis were performed using Stata 14.

Data from 25 studies involving 339 animals were extracted and analyzed. The analysis revealed significant findings: stem cell-derived EVs increase ovary weight (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P  < 0.00001; I 2  = 70%), pregnancy rate (RR = 3.88; 95% CI: 1.94 ~ 7.79; P  = 0.0001; I 2  = 0%), count of births (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P  < 0.00001; I 2  = 69%) and counts of different types of follicles. In addition, it elevates the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P  < 0.00001; I 2  = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P  < 0.00001; I 2  = 80%) expression, while reducing FSH expression (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P  < 0.00001; I 2  = 90%). Subgroup analysis indicates that the source of EVs, animal species, modeling method, administration route, and test timepoint affected efficacy. Trial sequential analysis showed that there was sufficient evidence to confirm the effects of stem cell-derived EVs on birth counts, ovarian weights, and follicle counts. However, the impact of stem cell-derived EVs on pregnancy rates needs to be further demonstrated through more animal experimental evidence.

Conclusions

Stem cell-derived EVs demonstrate safety and efficacy in treating POF animal models, with potential improvements in fertility outcomes.

Trial registration

PROSPERO registration number: CRD42024509699.

Graphical Abstract

Premature ovarian failure (POF), or premature ovarian insufficiency (POI), is the cessation of ovarian function before the age of 40, affecting approximately 1% of women within this age group. More recently, a global incidence of about 3.7% of women of reproductive age were reported diagnosed with POF/POI [ 1 , 2 , 3 , 4 ]. POF is among the leading causes of female infertility prior to 40 years of age, and is characterized by lack of mature follicle, amenorrhea, hypogonadotropic hypogonadism [ 5 ]. Additionally, it is associated with an increased risk of long-term complications such as cardiovascular disease, osteoporosis, sexual dysfunction and psychological distress. While the etiology of POF remains unidentified in most cases, it has been linked to genetic disorders [ 6 , 7 ], autoimmunity [ 8 , 9 ], chemotherapy and radiotherapy [ 10 , 11 ], and environmental factors. POF is a devastating diagnosis for reproductive-aged women, and currently, preventive and therapeutic options are limited. Although hormone replacement therapy (HRT) remains the mainstay of management, it primarily alleviates symptoms without effectively restoring ovarian function [ 12 ]. Consequently, there is an urgent need for novel and effective therapeutics for POF.

In recent years, stem cell therapy has shown great promise in wide-ranging clinical applications and regenerative medicine, showing potential in restoring ovarian function in numerous pre-clinical studies [ 13 , 14 ]. However, it has been suggested that stem cells do not directly differentiate into granulosa cells but instead exert their effects through paracrine mechanisms, at least in part by secretion of extracellular vesicles (EVs), representing a more robust therapeutic product than intact cells [ 15 , 16 , 17 , 18 , 19 ]. EVs are nano-sized, lipid bilayer-enclosed structures capable of carrying and transferring proteins, lipids, RNAs, metabolites, growth factors and cytokines, playing a critical role in cell–cell communication [ 20 , 21 ]. Compared with their parental cells, stem cell-derived EVs not only retain similar functions but also exert higher biological stability, lower immunogenicity and are easier to obtain, making them a promising alternative therapeutic option [ 22 , 23 , 24 ].

Over the past decade, the growing interest in EVs therapies has brought them to the forefront of medical research, however accompanied by challenges and unanswered questions. There exists high heterogeneity in the source of EVs (embryonic stem cell, mesenchymal stem cell, etc.), EVs isolation methods, administration routes, and treating methods, etc., all of which influence therapeutic outcomes [ 25 , 26 ]. Particularly in 2023, a notable surge in studies within this the field has been observed, yet a comprehensive and up-to-dated meta-analysis is currently lacking. The diverse research landscape, with its numerous variables, requires a detailed exploration of experimental nuances. A thorough understanding the overall impact of stem cell-derived EVs on POF are essential prior to clinical translation.

In the clinical realm, rigorous meta-analysis is considered a gold standard for the objective and comprehensive evaluation of intervention efficacy. By applying systematical meta-research methods in preclinical EVs research, our study aims to assess the effectiveness of stem cell-derived EVs in treating POF across diverse literature. We conducted subgroup analyses to uncover specific EV characteristics and methodology influencing treatment outcomes, aiming to identify knowledge gaps. Notably, we utilized trial sequential analysis (TSA) to enhance control over random errors in cumulative meta-analyses, thereby assessing the reliability of current evidence. Our work aligns with the growing number of evidence from preclinical animal research, assessing the efficacy of EVs in POF and providing insights into the prospects of clinical translation.

Materials and methods

This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and PRISMA 2020 [ 27 , 28 ]. This meta-analysis has been registered on the PROSPERO website (CRD42024509699). Our study strictly adhered to the protocol without deviations, and it did not involve patients or the public.

Search strategy

Two authors (Yan Luo and Jinyao Ning) independently conducted literature searches in PubMed, the Cochrane Library, Web of Science, and EMBASE database from inception to February 18, 2024. The search utilized Medical Subject Headings (MeSH) terms “extracellular vesicles” or “exosomes” and “premature ovarian failure”, alone with corresponding free words and Boolean operators to construct a comprehensive literature search strategy (Please refer to the Supplementary Materials for detailed search strategies).

Criteria for inclusion and exclusion

The inclusion criteria are as follows: (1) Studies using animal models of POF and providing detailed modeling methods to investigate the efficacy of stem cell-derived EVs therapy; (2) The treatment/experimental group receiving EVs therapy alone or in combination with adjuvants, while the control/untreated group receiving phosphate buffered saline (PBS), physiological saline, no treatment or the same adjuvant as treatment group; (3) Provided detailed methods for the extraction and identification of EVs; (4) Reporting one or more of the following results: ovary weight, pregnancy rate, birth count, follicle count, levels of anti-Müllerian hormone (AMH), estradiol (E2) or follicle-stimulating hormone (FSH).

The exclusion criteria are as follows: (1) Studies have been published repeatedly or contain duplicated or redundant data; (2) Document types including letters, case reports, reviews, conference abstracts, etc.; (3) Studies where data are not provided or cannot be obtained from the original author; (4) EVs originating from non-stem cells.

Study selection and data extraction

Two researchers (Yan Luo and Jinyao Ning) independently conducted the study selection process after the literature search. Duplicates were firstly removed, followed by a first round of screening involving browsing titles and abstracts. A second round of screening involved evaluating the full text of all eligible articles. Subsequently, two researchers (Jingjing Chen and Jinyao Ning) extracted data from the retained studies, including first author, publication year, country, animal model characteristics, disease model, EVs therapy characteristics, experimental design, and outcome evaluation indicators. In case where key research data and information were not mentioned in the paper, the corresponding author was contacted for details via email. The extracted data were then collated and checked. In instances of disagreement, a third author (Hui Li) conduct a discussion with all author together for the final decision.

Outcome evaluation indicators

The primary outcome evaluation indicators extracted in this meta-analysis include ovary weight, pregnancy rate, birth count, and follicle count, which serve as the measures of animal fertility and regenerative potential of the ovary. Secondary outcomes encompassed serum levels of AMH, E2, and FSH, which indicate ovarian reserve capacity.

Quality assessment and statistical analysis

Two authors (Jingjing Chen and Jinyao Ning) independently assessed the risk of bias using the Systematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool (a 10-item risk assessment tool for preclinical studies) [ 29 ]. In cases of discrepancies, a third author (Yan Luo) participated in the discussion and collaborated on reaching a final decision. Dichotomous variables were evaluated with risk ratios (RRs) and 95% confidence intervals (CIs), while continuous variables were presented as standardized mean differences (SMDs) with 95% CI. A significance level of p  < 0.05 was applied to determine significant difference. Heterogeneity among selected studies was evaluated using the I 2 statistic. Given the methodological variation across studies leading to significant heterogeneity, a random effects model was utilized [ 30 ]. Sensitivity analyses was conducted by sequentially excluding one article at a time to assess the impact on the overall effect. Egger’s test was employed to detect publication bias, with a significance threshold set at p  < 0.05. In case where publication bias was detected and sufficient data were available, the trim-fill method developed by Duval and Tweedie was used to adjust for bias [ 31 ]. Data analysis was performed using RevMan software (Version 5.4) and Stata 14.0.

• Trial sequential analysis

We employed TSA to evaluate the risk of random error and determine the conclusiveness of cumulative results in the meta-analysis [ 32 , 33 ]. For continuous results, we set alpha value to 5% and the beta value to 20% (80% power), utilizing the heterogeneity correction method based on model variance. For dichotomous outcomes, a predefined relative risk reduction of 20% was applied, with alpha set to 5% and beta set to 20% (80% power). Control event rates were calculated from either the placebo or control group. TSA Viewer version 0.9 beta software was used for analysis ( http://www.ctu.dk/tsa ).

Bibliometric analysis

The Bibliometrics method is usually used to study the development of a field and predict future hot spots. In this study, we use the Web of Science database, which is the one that is most frequently utilized in bibliometrics, as the source of relevant literature. Please refer to Sect. "  Search strategy " for specific search strategies. VOSviewers (Leiden University, Leiden, Netherlands) software was used for keyword analysis and citation tracking.

Study selection

The literature search yielded a total of 1521 potentially relevant publications. Among them, 606 studies were removed due to duplication. Subsequently, 356 articles were excluded based on the initial screening. Upon examination of the full text of 534 research articles, 25 studies [ 22 , 25 , 26 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 ] met the inclusion criteria and were finally included in this meta-analysis. The literature screening flow chart is shown in Fig. 1 .

Study flow diagram. (Abbreviation: POF: premature ovarian failure)

Connection between keywords

The visual mapping showed that keywords were divided into 3 clusters: “Stem cell therapy for POF”, “Ovaries and oocytes-related organismal processes”, “EVs and ovarian cancers” (Fig.  2 A). Research focuses include studying the pathophysiological mechanisms of POF and exploring stem cell-based EV therapies and innovative bioengineering methods. The citation track map in Web of Science database depicts the citation between important works of the research field (Fig.  2 B). This field experienced an outburst between the year 2015–2020. We also found that in the PubMed database, published documents related to EVs and POF are gradually increasing (Fig.  2 C). It indicates that research in this field has developed rapidly and is in a rapid rising stage, highlighting the necessity of such meta-studies.

Bibliometric analysis. A Connection between keywords map. Cluster 1 (blue): “Stem cell therapy for POF”. Cluster 2 (green): “Ovaries and oocytes-related organismal processes”. Cluster 3 (red): “EVs and ovarian cancers”. B Citation track map. Each circle represents documents (including DOI numbers) that have been cited more than 20 times, and are defined as representative documents in the field. The larger the circle, the more times it has been cited. C Analysis of annual publishing trends in PubMed database. (Abbreviation: EVs: extracellular vesicles; POF: premature ovarian failure; DOI: digital object identifier)

Study characteristics

The characteristics of the included studies are shown in Supplementary Table 1. The 25 studies spanned from 2016 to 2023 (Fig. 3 A), with the majority (21 trials) conducted in China [ 25 , 26 , 34 , 35 , 36 , 37 , 38 , 39 , 41 , 42 , 43 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 53 , 54 , 55 ], followed by 2 trials in Iran [ 45 , 52 ], one in the United States [ 22 ], and one in Egypt [ 40 ] (Fig. 3 B). The total sample size across studies was 339 animals, with 173 allocated to the EVs treatment group and the remaining to the control group. Seventeen studies utilized mice as the animal model, while the remainder employed rats (Fig. 3 C). Various methods were employed for disease modeling, include cyclophosphamide (CTX), CTX + busulfan (BUS), cisplatin, 4-vinylcyclohexene diepoxide (VCD), and D-galactose (D-gal) (Fig. 3 D). The EVs utilized in the trials were derived from different stem cells sources, including umbilical cord mesenchymal stem cells (UC-MSCs), bone marrow mesenchymal stem cells (BMSCs) and adipose tissue mesenchymal stem cells (ADSCs), etc. Despite EVs being derived from cells of different species, each study independently demonstrated their effectiveness against POF in animal models. The route of drug administration primarily involved intravenous injection, although ovary and intraperitoneal injections were also used (Fig. 3 E).

An overview of studies characteristics, including distribution of ( A ) publications by year ( B ) region ( C ) animal model ( D ) disease model ( E ) route of administration

Risk of bias in the eligible studies

The included articles did not specify whether animal groups were randomly generated, nor did they provide details on randomization and allocation concealment methods, resulting in an unclear risk of selection bias (Fig.  4 ). While these studies did not extensively discuss blinding of personnel, it is evident that the animals were unaware of the group assignment, thus ensuring blinding of participants. Overall, the risk of reporting bias in these articles was low. Thirteen studies demonstrated a low risk of attrition bias, while one study had incomplete outcome data, resulting in a high risk of attrition bias.

Risk of bias summary

Outcomes of the meta-analysis

Ovary weight.

Eight studies reported the effect of stem cell-derived EVs on ovary weight [ 34 , 38 , 42 , 44 , 48 , 51 , 52 , 54 ]. The meta-analysis revealed a significant increase in ovary weight following the administration of stem cell-derived EVs (SMD = 3.88; 95% CI: 2.50 ~ 5.25; P  < 0.00001; I 2  = 70%, P  = 0.0007) (Fig. 5 A).

Forest plots depicting the comparison between the stem cell-derived EVs and control groups: A Ovary weight; B Pregnancy rate; C Count of births. (Abbreviation: EVs: extracellular vesicles)

Pregnancy rate

Four studies, encompassing 6 trials, examined the efficacy of stem cell-derived EVs on pregnancy rate, demonstrating a significantly improvement with EV administration (RR = 3.88; 95% CI: 1.94 ~ 7.79; P  = 0.0001; I2 = 0%) (Fig. 5 B) [ 22 , 48 , 49 , 52 ].

Count of births

Analysis of data from 12 trials revealed that administration of stem cell-derived EVs significantly increased the count of births in POF animals (SMD = 2.17; 95% CI: 1.31 ~ 3.04; P  < 0.00001; I2 = 69%) (Fig. 5 C) [ 22 , 25 , 34 , 40 , 44 , 45 , 48 , 49 , 52 , 54 ].

Follicle count

The effects of stem cell-derived EVs on primordial, primary, secondary, and antral follicle counts were assessed across 16, 14, 14, and 15 included trials, respectively. The results demonstrate that administration of stem cell-derived EVs significantly increased primordial follicle count (SMD = 3.75; 95% CI: 2.30 ~ 5.19; P  < 0.00001; I2 = 86%), primary follicle count (SMD = 2.99; 95% CI: 1.83 ~ 4.14; P  < 0.00001; I2 = 78%), secondary follicle count (SMD = 3.21; 95% CI: 2.03 ~ 4.38; P  < 0.00001; I2 = 81%), antral follicle count (SMD = 3.41; 95% CI: 2.31 ~ 4.51; P  < 0.00001; I2 = 81%) (Fig.  6 ).

Forest plots depicting the comparison between the stem cell-derived EVs and control groups: A Primordial follicle count; B Primary follicle count; C Secondary follicle count; D Antral follicle count. (Abbreviation: EVs: extracellular vesicles)

The serum levels of FSH, E2 and AMH

We analyzed data from 18, 22 and 21 trials, respectively, to evaluate the effect of stem cell-derived EVs on the serum level of AMH, E2, and FSH. All studies employed enzyme-linked immunosorbent assay (ELISA) for detection. The analysis showed that administration of stem cell-derived EVs significantly increased the level of AMH (SMD = 4.15; 95% CI: 2.75 ~ 5.54; P  < 0.00001; I2 = 88%) and E2 (SMD = 2.88; 95% CI: 2.02 ~ 3.73; P  < 0.00001; I2 = 80%), while reducing the level of FSH (SMD = -5.05; 95% CI: -6.60 ~ -3.50; P  < 0.00001; I2 = 90%) (Fig.  7 ).

Forest plots depicting the comparison between the stem cell-derived EVs and control groups: A AMH; B E2; C FSH. (Abbreviation: EVs: extracellular vesicles; AMH: anti-Müllerian hormone; E2: estradiol; FSH: follicle-stimulating hormone)

Subgroup analysis results

The efficacy of EVs and heterogeneity in meta-analysis may be influenced by various factors including the source of EVs, animal species, disease model, EVs administration route, and test timepoint. Therefore, we conducted a series of subgroup analyses on the primary outcome indicators based on these conditions (Supplementary Table 2).

Based on the source of EVs, the main subgroups included UC-MSCs, clonal mesenchymal stromal cells (cMSCs), BMSCs, amniotic fluid mesenchymal stem cells (AFSCs), ADSCs. UC-MSCs, and cMSCs were found to significantly increase ovary weight, count of births and pregnancy rate. Additionally, UC-MSCs demonstrated an increase in the follicle count. However, the effects of BMSCs, cMSCs, and AFSCs on different types of follicles showed unstable statistical differences.

The animal species utilized in the study comprised mice and rats. Subgroup analyses indicated statistical differences in all outcome indicators, except for the rat subgroups of primordial follicles and antral follicles, which showed no statistical difference ( p  > 0.05). Furthermore, the heterogeneity was reduced in these analyses.

The disease models of POF primarily involved CTX and CTX + BUS. Subgroup analyses based on disease models showed statistical differences in all outcome indicators. However, heterogeneity was not consistently reduced across the analyses.

The main methods of EVs administration route include ovary injection, tail vein injection, and intraperitoneal injection. The results of subgroup analysis showed that there was no statistically significant difference between ovarian injection + tail vein injection on primary follicle and antral follicle count, and there was also no statistical difference on the effect of tail vein injection on primary follicle count. Additionally, the EVs administration route showed statistical differences in increasing ovary weight and count of births, accompanied by reduced heterogeneity.

The follow-up period and testing timepoint, mainly ranging from 1 day to 12 weeks after the last transplantation, was analyzed in subgroup analyses. Results indicated that when the test timepoint was 1 day, subgroup analysis outcomes were not statistically significant ( p  > 0.05), whereas significant statistical differences were observed for the remaining timepoints.

Sensitivity analysis and publication bias

Table 1 summarizes the sensitivity analysis and publication bias of this meta-analysis. Each study was individually excluded to assess its impact on the final effect, with results remaining consistent with those of all included studies, indicating the stability and reliability (Supplementary Fig. 1). However, in Egger’s test, only primary follicle count did not exhibit publication bias ( p  > 0.05). Subsequent trim and fill method analysis showed that ovary weight, count of births, primary follicle count, secondary follicle count, level of FSH were not trimmed, and the data in the funnel plot remained unchanged, suggesting no significant publication bias (Supplementary Fig. 2–4). Pregnancy rate, antral follicle count, level of AMH and E2 were trimmed using the trim and fill method (Supplementary Fig. 4 and Supplementary Table 3).

TSA can assess whether results are supported by sufficient data. The TSA results indicate that there is enough data to draw definite conclusions about the count of births, ovary weight, as well as primordial, primary, secondary, and antral follicle counts. However, regarding pregnancy rate, the evidence is inconclusive according to TSA. This uncertainty may result in false negative or false positive conclusions due to the small number of experimental animals. Therefore, more animal experiments are warranted in the future to further validate these findings (Fig.  8 ).

Trial sequential analysis results depicting the comparison between the stem cell-derived EVs and control groups. A Ovary weight. The cumulative Z curve crossed the conventional line, but did not reach the RIS. B Pregnancy rate. The cumulative Z curve crossed the conventional line, but did not reach the RIS. C Count of births. The cumulative Z curve crossed the conventional and reached the RIS. D Primordial follicle count. The cumulative Z curve crossed the conventional, but did not reach the RIS. E Primary follicle count. The cumulative Z curve crossed the conventional, but did not reach the RIS. F Secondary follicle count. The cumulative Z curve crossed the conventional and reached the RIS. G Antral follicle count. The cumulative Z curve crossed the conventional, but did not reach the RIS. (Abbreviation: EVs: extracellular vesicles; RIS, required information size)

Safety of stem cell-derived EVs

In the 25 studies included, the safety of EVs is mentioned in 6 of them [ 22 , 34 , 40 , 48 , 50 , 55 ]. Two studies explicitly mention experiments on the safety of EVs, reporting safety outcomes, and indicating that none of the participants treated with EVs during the study period experienced EVs-related adverse events or complications [ 22 , 48 ]. In the other 4 studies, EVs are generally accepted as safe [ 34 , 40 , 50 , 55 ]. The incidence of serious adverse drug reactions was not recorded or reported.

Principal findings

This meta-analysis comprised 25 studies involving a total of 368 experimental animals. The analysis demonstrates that administration of EVs can improve the ovary function of POF rat/mouse model. Specifically, it increases ovary weight, pregnancy rate, count of births, and follicle count. In addition, it elevates the serum level of AMH and E2 while reducing the expression of FSH. The source of EVs, animal species, disease model, EVs administration route and test timepoint are identified as important factors influencing the efficacy of EVs in POF.

As stem cell-derived EVs are increasingly recognized for their therapeutic potential in treating POF, their intricate mechanism of action, demonstrated in preclinical mouse models, involves attenuating fibrotic changes [ 45 ], reducing oxidative injury and apoptosis in granulosa cells [ 38 , 46 ], inhibiting autophagy [ 42 ], and promoting angiogenesis [ 43 ]. The actions effectively prevent follicular atresia and normalize sex-related hormones, contributing to the restoration of ovarian function. The identified effects are mediated through the activation of specific pathways, including PI3K/Akt pathway [ 26 ], TGF-β/Smad signaling pathway [ 50 ], Hippo pathway [ 49 ] and AMPK/mTOR pathway [ 42 ]. Additionally, key miRNAs have been identified as playing crucial roles in the above processes. Both miRNA-145-5p [46], carried by hUC-MSC-EVs, and miR-369-3p [52], carried by AFSC-EVs, specifically attenuated GC apoptosis, while knockdown these miRNAs partly abolished the therapeutic effects. Furthermore, transfection of parental stem cells with specific miRNA mimics/inhibitors effectively regulated the expression in cell-derived EVs. Delivery of circLRRC8A-enriched exosomes [38] and miR-144-5p [37] overexpressed in BMSCs-EVs enhanced efficacy in protecting cellular senescence and POF. These findings demonstrate modified EVs as effective carriers and pave the way for establishing of a cell-free therapeutic approach for POF.

Comparison with existing literature

Instead of performing a meta-analysis, Liao et al. [ 56 ] conducted a review focusing on the therapeutic role of mesenchymal stem cell-derived EVs (MSC-EVs) in female reproductive diseases, such as intrauterine adhesions (IUA), POF, and polycystic ovary syndrome (PCOS). They highlighted various therapeutic effects, include repairing damaged endometrium, inhibiting endometrial fibrosis, regulating immune response, and resisting inflammation, as well as inhibiting apoptosis of granulosa cells in the ovary. Additionally, they summarized the potential mechanism of action. On the other hand, Zhou et al. [ 57 ] performed a meta-analysis specifically exploring the impact of MSC-EVs in the animal model of female reproductive diseases (IUA, POF, PCOS). Their analysis, involving 15 studies, demonstrated that treatment with MSC-EVs significantly improved AMH at 2 and 4 weeks compared with control. Subgroup analysis indicated that factors such as animal type, modeling method, MSC source, EVs isolation method, number of injections, route of administration, and outcome measurement unit did not contribute to heterogeneity. It is worth noticing that our meta-analysis centered on the effect of whole stem cell-derived EVs on POF, encompassing not only MSC-EVs but also other sources of EVs. We conducted detailed subgroup analyses on factors such as animal types, modeling methods, stem cell sources, administration routes, etc. Additionally, we employed sensitivity analysis, assessed publication bias and conducted TSA to evaluate the stability and reliability of the results.

Strengths of this meta-analysis

(1) We conducted a comprehensive and systematic literature search, rigorous screening and data extraction, ultimately including 25 animal studies, with the majority published within the past two years (12 of 25). This resulted in relatively abundant number of documents, with most publications being recent. (2) Detailed subgroup analyses were performed to explore the heterogeneous sources and role factors of EVs in POF animal models. Factors examined included the source of EVs, animal species, disease model, EVs administration route and test timepoint, etc. (3) Various methods, including sensitivity analysis, egger’s test, SYRCLE’s risk of bias tool, and TSA, were employed to assess the quality and accuracy of the results, enhancing the credibility and convincingness of our finding.

Limitations

(1) Although we included a lot of literature, the overall quality of the included literature was deemed low due to numerous risks of bias being unclear, and the presence of some publication. (2) The data of our meta-analysis is derived from animal experiments, primarily utilizing mice and rats as experimental subjects. It’s important to acknowledge that there are inherent differences between animal models and humans, which may impact the translation of findings to clinical practice. (3) The number of animals in the included studies was relatively small, and there was considerable variation in experimental protocols, including the source of EVs, EVs injection dose, number of injections, EVs isolation methods, etc. Consequently, we were unable to determine an optimal EVs treatment option. (4) Due to differences in EVs composition between human-derived and animal-derived stem cells, as well as species differences, there may be some differences in therapeutic efficacy which require more experimental research to prove in the future.

Implications for clinical practice and research

Collectively, our study rigorously evaluated the evidence and scrutinized the risks associated with the current studies, providing a solid foundation for future research and subsequent clinical translation. However, because existing studies provide limited data on fertility status (such as pregnancy rates, number of births, etc.), the results of the analysis are therefore limited. Future studies would benefit from providing comprehensive data on pregnancy status, hormone levels, and follicle counts to better evaluate the efficacy of EVs in POF. While there are unresolved issues that necessitate further investigation, stem cell-derived EVs holds significant promise as a cell-free therapeutic approach capable of enhancing ovarian function and fertility. Continued research in this area has the potential to significantly impact clinical practice and improve outcomes for patients with POF.

This meta-analysis compared the efficacy of stem cell-derived EVs in POF animal models using indicators such as pregnancy rate, ovary weight, count of births, counts of different types of follicles, serum level of AMH, E2, FSH. The overall results indicate that stem cell-derived EVs therapy has beneficial effects in the treatment of POF animal models. However, the potential use of stem cell-derived EVs to treat human POF remains to be explored in larger, more biologically relevant animal models or clinical trials.

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files.

Data availability 

No datasets were generated or analysed during the current study.

Abbreviations

• Premature ovarian failure

Premature ovarian insufficiency

Hormone replacement therapy

• Extracellular vesicles

Preferred Reporting Items for Systematic Reviews and Meta-analyses

Medical Subject Headings

Phosphate buffered saline

Anti-Müllerian hormone

Follicle-stimulating hormone

Systematic Review Centre for Laboratory animal Experimentation

Risk ratios

Confidence intervals

Standardized mean differences

Cyclophosphamide

4-Vinylcyclohexene diepoxide

D-galactose

Umbilical cord mesenchymal stem cells

Bone marrow mesenchymal stem cells

Adipose tissue mesenchymal stem cells

Enzyme-linked immunosorbent assay

Clonal mesenchymal stromal cells

Amniotic fluid mesenchymal stem cells

Mesenchymal stem cell-derived EVs

Intrauterine adhesions

Polycystic ovary syndrome

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Acknowledgements

This work was supported by the Department of Reproductive Medicine, Xiangya Hospital, Central South University. We would like to thank the China Postdoctoral Science Foundation, the Hunan Provincial Natural Science Foundation, the National Natural Science Foundation, and the Xiangya Hospital Foundation for their support.

This project was supported by the Science Foundation For Excellent Young Scholars of Hunan Province, China (No. 2024JJ4091); Young Scientists Fund of the National Natural Science Foundation of China (No. 82301835); Science Foundation for Young Scholars of Hunan Province, China (No. 2023JJ40956); China Postdoctoral Science Foundation(General Program) (No. 2022M713522); China Postdoctoral Foundation (No. 2021TQ0372); Young Investigator Grant of Xiangya Hospital, Central South University (No.2021Q03); National Natural Science Foundation of China(General Program) (No. 82371682); Fundamental Research Funds for the Central Universities of Central South University (1053320222496).

Author information

Yan Luo and Jingjing Chen contributed equally to this work and share first authorship.

Authors and Affiliations

Department of Reproductive Medicine, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan Province, 410008, China

Yan Luo, Jingjing Chen, Jinyao Ning, Yuanyuan Sun, Yitong Chai, Bixia Huang, Ge Li, Fen Tian, Jie Hao, Qiong Zhang, Jing Zhao, Yanping Li & Hui Li

Clinical Research Center for Women’s, Reproductive Health in Hunan Province, Hunan Province, Changsha, 410008, China

Jingjing Chen, Yuanyuan Sun, Bixia Huang, Ge Li, Fen Tian, Jie Hao, Qiong Zhang, Jing Zhao, Yanping Li & Hui Li

Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China

Clinical Medicine Eight-Year Program, Xiangya Hospital, Central South University, Changsha, China

Yan Luo, Jinyao Ning & Yitong Chai

Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China

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Contributions

YL: Conceptualization, project administration, data curation, formal analysis, investigation, methodology, visualization, writing—original draft, writing- review and editing. JC: Conceptualization, project administration, data curation, formal analysis, investigation, methodology, visualization, writing—original draft, writing- review and editing. JN: Supervision, methodology, resources, writing—review and editing. YS: Methodology, formal analysis, software, writing—review and editing. YC: Supervision, resources, methodology, software, writing—review and editing. FX: Data curation, formal analysis, writing—review and editing. BH: Data curation, formal analysis, writing—review and editing. GL: Data curation, formal analysis, writing—review and editing. FT: Supervision, formal analysis, writing—review and editing. JH: Supervision, formal analysis, writing—review and editing. HS: Supervision, formal analysis, writing—review and editing. QZ: Supervision, formal analysis, writing—review and editing. JZ: Supervision, formal analysis, writing—review and editing. YLi: Supervision, formal analysis, writing—review and editing. HL: Conceptualization, financial acquisition, data curation, supervision, writing—review and editing.

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Correspondence to Hui Li .

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Luo, Y., Chen, J., Ning, J. et al. Stem cell-derived extracellular vesicles in premature ovarian failure: an up-to-date meta-analysis of animal studies. J Ovarian Res 17 , 182 (2024). https://doi.org/10.1186/s13048-024-01489-y

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Received : 14 May 2024

Accepted : 07 August 2024

Published : 09 September 2024

DOI : https://doi.org/10.1186/s13048-024-01489-y

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