Embryonic stem cells

Introduction to the nature’s master builders

You may have noticed that more and more people are discussing the option of storing their newborns’ stem cells. By choosing to store these cells, parents are taking a proactive step to safeguard their child’s future, providing a valuable resource in case their child is ever diagnosed with a rare or life-threatening disease. The reason for this growing interest is that stem cells possess the remarkable ability to self-renew (able to make more cells like themselves) indefinitely and develop into any cell type under controlled conditions via the process of differentiation (1). This remarkable property enables its use in treating a wide range of serious health conditions such as immune disorders, heart diseases, and neurodegenerative conditions, among others. Embryonic stem cells (ESCs) are specialized stem cells that can give rise to all somatic (muscle, nerve, skin, bone, etc.) cell types in an embryo. They are derived from the inner cell mass of the blastocyst, an early stage of a developing embryo, approximately 4 days old (2). The indefinite self-renewal and long-term proliferation capacity of ESCs is an attribute of their high telomerase activity. A reverse transcriptase enzyme, telomerase, which is typically diminished after birth in somatic cells, is enhanced in ESCs, which maintains their cellular immortality and proliferative capacity (3). Similarly, the pluripotent characteristic of ESCs is suggested to be a direct contribution of the presence of high levels of cyclin dependent kinases, Cdk1 and Cdk2 which play a crucial role in cell cycle regulation (4).

You can be anything you want to be

The unspecialized embryonic stem cells can differentiate into any specialized cell type during the process of organogenesis. Organogenesis is a phase of embryonic development that gives rise to three different germ layers: ectoderm, mesoderm and endoderm. These germ layers further transform into various organs of the body. The fate or lineage of an ESC is largely dependent on the specific set of genes and markers (Oct-4, Nanog, Sox-2, etc.) that it demonstrates. For example, cells in the ectoderm (outermost layer) expressing skin specific genes will form into epidermal cells. Interestingly, some ectodermal cells become neuroectoderm eventually forming into the brain and spinal cord. Mesoderm, the middle layer, develops into a large variety of cells and tissues such as skeletal muscle, kidney, heart, and blood cells, to name a few. Endoderm depicts the innermost layer and represents the embryonic precursor of internal organs such as the stomach, lung, pancreas, and liver (5). ESCs can differentiate into more than 200 specialized cell types of the human body (6). This unique capability of ESCs to form into any cell type render them an invaluable tool for regenerative medicine. They have the potential to provide an unlimited supply of transplantable organs (7), addressing the shortage of donors for life-threatening diseases. Due to various technical, ethical and regulatory challenges, there are currently no specific studies documenting the transplantation of stem cell-derived organs into humans. However, the field of regenerative medicine is actively addressing these obstacles and making ongoing efforts to turn this possibility into a reality.

Discovery, innovation, and future directions

Mouse ESCs were cultured for the first time in a laboratory in 1981 by two biologists: Sir Martin John Evans and Matthew Kaufman, which subsequently got them a Nobel prize in physiology and medicine in 2007 along with Mario Capecchi and Oliver Smithies. The discovery of ESCs opened new horizons of research and therapy and resulted in the establishment of the first public and private stem cell bank in 1992. Soon after in 1998, James Thomson, a biologist, uncovered the existences of human ESCs from human blastocysts (8). While promising for disease modeling (9) and regenerative medicine (10), it came with its own set of hurdles and controversies. It raised a lot of religious and ethical issues with some questioning the moral status and dignity of early human life, while some believed in the potential of utilizing the surplus embryos for potentially life-saving research (11).

As it is said, science always finds a way through innovation! Despite all the challenges and issues, researchers unveiled the development of induced pluripotent stem cells (iPSCs)(12) from skin cells that offer close functional resemblance to ESCs without the need of exploiting human embryos. However, ESCs will always get an upper hand because of their inherent pluripotent nature and remain the gold standard for validating the properties of iPSCs (13). ESCs serve as powerful tools for studying early human development and modeling genetic diseases in the laboratory. As the field evolves, further intensive investigations and ethical oversight is required to fully understand the safe and responsible use of ESCs for therapeutic applications.

Recognizing and appreciating the labs working in this space

• Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. https://www.hsci.harvard.edu/research , Twitter: @harvardstemcell
• Ali H. Brivanlou, Laboratory of Synthetic Embryology. The Rockefeller University, New York, USA. https://xenopus.rockefeller.edu/ , Twitter: @RockefellerUniv
• Center for Embryonic Cell and Gene Therapy , Oregon Health and Science University, Oregon, USA. https://www.ohsu.edu/embryonic-cell-gene-therapy-center
• Center for Human Embryonic Stem Cell Research and Education, Stanford Medicine, California, USA. https://med.stanford.edu/hesc.html , Twitter: @StanfordMed
• Stem Cell Engineering CoRE, Icahn School of Medicine at Mount Sinai, New York, USA. https://icahn.mssm.edu/research/resources/deans-cores/stem-cell-engineering , Twitter: @IcahnMountSinai
• Shinya Yamanaka, Gladstone Institute of Cardiovascular Diseases. Gladstone Institutes, San Francisco, California, USA. ​​https://gladstone.org/people/shinya-yamanaka , Twitter: @GladstoneInst
• James Thomson, Morgridge Institute for Research, Madison, WIsconsin, USA. https://morgridge.org/profile/james-thomson/ , Twitter: @Morgridge_Inst
• Chris Mason, University College London, London, UK. https://profiles.ucl.ac.uk/7080-chris-mason , Twitter: @Prof_ChrisMason
• Robert Lanza, Chief Scientific Officer, Advanced Cell Technology. Massachusetts, USA. https://robertlanza.com/ , Twitter: @RobertLanza

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References

1. Zakrzewski, W., Dobrzyński, M., Szymonowicz, M., & Rybak, Z. (2019). Stem cells: past, present, and future. Stem cell research & therapy, 10(1), 68. https://doi.org/10.1186/s13287-019-1165-5
2. National Research Council (US) and Institute of Medicine (US) Committee on the Biological and Biomedical Applications of Stem Cell Research. Stem Cells and the Future of Regenerative Medicine. Washington (DC): National Academies Press (US); 2002. CHAPTER THREE, Embryonic Stem Cells. Available from: https://www.ncbi.nlm.nih.gov/books/NBK223690/
3. Hiyama, E., & Hiyama, K. (2007). Telomere and telomerase in stem cells. British journal of cancer, 96(7), 1020–1024. https://doi.org/10.1038/sj.bjc.6603671
4. Liu, L., Michowski, W., Kolodziejczyk, A., & Sicinski, P. (2019). The cell cycle in stem cell proliferation, pluripotency and differentiation. Nature cell biology, 21(9), 1060–1067. https://doi.org/10.1038/s41556-019-0384-4
5. Muhr J, Arbor TC, Ackerman KM. Embryology, Gastrulation. [Updated 2023 Apr 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK554394/
6. Bartold, M., & Ivanovski, S. (2022). Stem Cell Applications in Periodontal Regeneration. Dental clinics of North America, 66(1), 53–74. https://doi.org/10.1016/j.cden.2021.06.002
7. De Vos, J., & Assou, S. (2017). Induced pluripotent stem cells: An unlimited source of organs for transplantation. Clinics and research in hepatology and gastroenterology, 41(3), 249–253. https://doi.org/10.1016/j.clinre.2016.10.008
8. Charitos, I. A., Ballini, A., Cantore, S., Boccellino, M., Di Domenico, M., Borsani, E., Nocini, R., Di Cosola, M., Santacroce, L., & Bottalico, L. (2021). Stem Cells: A Historical Review about Biological, Religious, and Ethical Issues. Stem cells international, 2021, 9978837. https://doi.org/10.1155/2021/9978837
9. Avior, Y., Sagi, I., & Benvenisty, N. (2016). Pluripotent stem cells in disease modelling and drug discovery. Nature reviews. Molecular cell biology, 17(3), 170–182. https://doi.org/10.1038/nrm.2015.27
10. Carpentier, A., Nimgaonkar, I., Chu, V., Xia, Y., Hu, Z., & Liang, T. J. (2016). Hepatic differentiation of human pluripotent stem cells in miniaturized format suitable for high-throughput screen. Stem cell research, 16(3), 640–650. https://doi.org/10.1016/j.scr.2016.03.009
11. Greely H. T. (2006). Moving human embryonic stem cells from legislature to lab: remaining legal and ethical questions. PLoS medicine, 3(5), e143. https://doi.org/10.1371/journal.pmed.0030143
12. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science (New York, N.Y.), 282(5391), 1145–1147. https://doi.org/10.1126/science.282.5391.1145
13. Smith, K. P., Luong, M. X., & Stein, G. S. (2009). Pluripotency: toward a gold standard for human ES and iPS cells. Journal of cellular physiology, 220(1), 21–29. https://doi.org/10.1002/jcp.21681

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About the author:

DR. SURUCHI PODDAR

Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Poddar received a PhD in Biomedical Engineering from Indian Institute of Technology-Banaras Hindu University (IIT-BHU), Varanasi, India. She started her career as a postdoctoral researcher in 2020 with the Nanoscience Technology Center at the University of Central Florida, Orlando where she worked on a multi-organ human-on-a-chip system. Currently she is working on solid-state nanopore technology at Wake Forest University, North Carolina. When not working, she enjoys watching movies, cooking food and exploring new places, restaurants, attractions.

About the artist:

OLGA KURKINA

Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories

My passion for art and love for medicine led me to the field of medical illustration, a profession in which I have been dedicated for many years. Through my work, I have the privilege of meeting and collaborating with remarkable individuals — doctors and scientists who are at the forefront of global scientific advancements. Their dedication and discoveries continue to inspire me. As a medical illustrator at a medical communications agency, my primary role is to transform complex processes and concepts into visually appealing and easily understandable images that become part of an animation or publication. Additionally, my works have been featured in numerous scientific magazines and books. Now I live and work in Poland.

About the animator:

DR. EMANUELE PETRETTO

Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.

Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.

About the series:

The League of Extraordinary Cell types

The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.