Last Reviewed on November 12, 2021 by Alice Pien, MD & Asher Milgrom, PhD
Every cell in our body comes from the original stem cells that comprised the embryo we once were.
Everything starts with a sperm and egg, which fertilize each other by merging into a single cell thereby becoming the first stem cell from which our entire body will be created. At that point the merged cell starts dividing into 2 cells, then 4, 8, 16, 32 cells etc.
In these early stages, every one of these cells can become any cell in the human body. These are called “Totipotent” stem cells.
Stem Cell Differentiation Process
As the original stem cells continue to divide, they start changing, a process called “Cell Differentiation” by following three different developmental pathways or “lineages”.
Embryonic Stem Cell Lineages
In fact, in the adult human body there are approximately 200 different types of cells all of which fall under these three major categories: Cells that emanate from the endoderm lineage, mesoderm lineage and the ectoderm lineage. Each of these lineages can be identified in the very young embryo, within just a few days of conception.
At this stage all the cells of the embryo are still stem cells, but these cells are limited to developing into the tissues associated with their specific lineage. Thus they are no longer defined as “totipotent” but rather as stem cells with a limited potential of differentiation and are called “pluripotent” stem cells.
Eventually as these “pluripotent” stem cells undergo further differentiation, they will lose even more potential of differentiation and become “multipotent”.
As the embryo continues to develop, its cells choose a path of development down one of those three lineages that lead to specific organs with specific functions. This is called cell “differentiation” that leads to the creation of specific tissues with specific functions, such a nerve tissue, or skin, bone or blood tissue etc. As these early stem cells choose a lineage, they lose their ability to become any tissue, and retain the ability to become just those tissues associated with that specific lineage.
Eventually, every organ and tissue in the adult human will contain a certain percentage of stem cells that are responsible for simply replacing the cells of only that organ that die and need to be replaced.
Unique Characteristics of Stem Cells
Stem cells differ from the other adult kinds of cells that make up all the organs and tissues of the body. All stem cells, regardless of their lineage, have two general properties:
- They are capable of dividing and renewing themselves for long periods, called “self-renewal”
- They are unspecialized in that they do not YET have a specific function… However, when called upon they divide and differentiate into a specific organ cell that does have specific physiological functions.
Stem cells are capable of dividing and renewing themselves for long periods. In contrast adult organ cells – also known as Somatic Cells, such as muscle cells, blood cells, or nerve cells— have a limited number of times they can replicate themselves.
Eventually every adult somatic cell will age and lose its ability to function at peak efficiency. When this happens, it will undergo “programmed cell death” or “apoptosis”. At this point the dying cell will be replaced from a new cell generated from a local stem cell.
Proliferation (Long-term Self Renewal)
Conversely, stem cells may replicate themselves essentially throughout a human’s entire lifetime, (proliferate).
In a laboratory under the correct nourishing conditions, a handful of stem cells can proliferate and generate millions of identical stem cells in just a few short weeks, and can essentially continue proliferating for years. This is called long-term self-renewal.
It is also evident that embryonic stem cells have a much more robust ability to self-renew, in comparison to adult stem-cells. The fact is, as we age, the amount of stem cells we have dramatically diminishes. Therefore, our adult stem cells have a limited capacity of long-term self-renewal, and they do eventually die.
Scientists are trying to understand two fundamental properties of stem cells that relate to their long-term self-renewal:
- Why can embryonic stem cells proliferate in laboratory conditions for a year or more without differentiating, but most adult stem cells cannot; and
- What are the factors in living organisms that normally regulate stem cell proliferation and self-renewal?
The hope is that discovering the answers to these questions may reveal two important things:
- Understand how to keep our adult stem cell population large and active.
- What goes wrong with cell proliferation when abnormal cell division occurs that leads to cancer?
Stem Cells are Unspecialized
One of the fundamental properties of a stem cell is that it does not have tissue-specific structures that allow it to perform specialized physiological functions. For example, a stem cell cannot work with its neighbors to cleanse blood (like a liver cell), and it cannot transport oxygen (O2) like a red blood cell.
However, under the right condition, specific physiological signals will stimulate unspecialized stem cells to “differentiate” into specialized cells, including liver, heart muscle cells, blood cells, or any adult organ cells (somatic cells).
The specific factors and conditions that stimulate stem cells to remain unspecialized as well as those factors that stimulate them to undergo Cell-differentiation are of great interest to physicians and scientists. After all, given the fact that human embryonic stem cells give rise to every cell in the adult human, maybe we can learn how to grow entire new and healthy organs in a laboratory as a replacement to a diseased organ.
When called upon by specific physiological signals and conditions, Stem cells which are unspecialized can give rise to specialized cells (Fig. 4). This process is called cellular differentiation. Cellular differentiation usually requires several stages, during which the cell becomes more specialized at each step.
The Process of Cellular Differentiation
Both internal signals and external conditions contribute to the conditions that give rise to cellular differentiation. Of course many of the internal signals are controlled by the genes of each cells, which are encoded in the cell’s DNA. This is called Gene-Expression.
The external signals that influence cell differentiation include chemicals secreted by other cells such as growth factors, cytokines and lymphokines, as well as physical contact with neighboring cells. All of these influences are inherent properties of the microenvironment in which cells live.
To the extent that these internal and external influences effect Gene-Expression during stem cell differentiation, has given rise to a new science of Epigenetics. Epigenetics studies how environmental factors, both internal and external control which genes are expressed.
Basically, we now know that cells can acquire epigenetic marks that control DNA expression in the cell and that can be passed on through multiple generations of cells.
There are still many questions about stem cell differentiation that are unanswered.
For example, are the external and internal signals for cell differentiation similar for all kinds of stem cells?
For instance, can we take a lipid stem cell and a bone stem cell (hematopoietic stem cell) and make them both differentiate into a nerve cell?
Can any adult stem cell become any kind of organ cells?
What are the specific signals that promote differentiation into specific tissue types?
The answers to these questions might lead stem cell researchers to develop novel ways to control stem cell differentiation under laboratory conditions, whereby we can grow cells or tissues that are used for stem cell therapies in treating diseased or damaged organs.
About the Authors
Doctors Alice Pien, MD and Asher Milgrom, Phd are established pioneers in the fields of Regenerative Medicine and Skincare. Their expertise ranges from advanced laser systems to HCT/P – Stem Cell medicine. Their medical education and advanced certifications span from medical schools of NY State University, the University of Chicago, to Johns Hopkins, Harvard and UCLA. They approach medicine with the clinical expertise of over 85,000 successful treatments over the past 20 years and significant scientific research resulting in proprietary protocols that they customize for each individual patient.
- Anzalone R, Opatrilova R, Kruzliak P, Gerbino A and La Rocca G. Mesenchymal Stromal Cells From Wharton’s Jelly (WJ-MSCs): Coupling Their Hidden Differentiative Program to Their Frank Immunomodulatory Phenotype. 2018;20:271-279.
- Vangsness CT Jr, Sternberg H, Harris L. Umbilical Cord Tissue Offers the Greatest Number of Harvestable Mesenchymal Stem Cells for Research and Clinical Application: A Literature Review of Different Harvest Sites. 2015 Sep;31(9):1836-43.
- Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan M, Borlongan C. Discarded Wharton’s Jelly of the Human Umbilical Cord: A Viable Source for Mesenchymal Stem Cells. 2015 Jan;17(1):18–24.
- Kalaszczynska I, Ferdyn K. Wharton’s Jelly Derived Mesenchymal Stem Cells: Future of Regenerative Medicine? Recent Findings and Clinical Significance. 2015, Article ID 430847, 11 pages.
- Davies J, Walker J, Keating A. Concise Review: Wharton’s Jelly: The Rich, but Enigmatic, Source of Mesenchymal Stromal Cells. 2017 Jul;6(7):1620–1630.
- Weiss M, Troyer D. Stem Cells in the Umbilical Cord. 2006;2(2):155–162.
- Erices A, Conget P, Minguell J. Mesenchymal Progenitor Cells in Human Umbilical Cord Blood. 2000 Apr;109(1):235-42.
- Shawki S, Gaafar T, Erfan H, El Khateeb E, El Sheikhah A, El Hawary R. Immunomodulatory Effects of Umbilical Cord‐Derived Mesenchymal Stem Cells. 2015 Jun;59(6):348-56.
- Arutyunyan I, Elchaninov A, Makarov A, Fatkhudinov T. Umbilical Cord as Prospective Source for Mesenchymal Stem Cell-Based Therapy. 2016;2016:6901286.
- SubramanianA, Fong C, Biswas A, Bongso A. Comparative Characterization of Cells from the Various Compartments of the Human Umbilical Cord Shows that the Wharton’s Jelly Compartment Provides the Best Source of Clinically Utilizable Mesenchymal Stem Cells. 2015 Jun;10(6):e0127992
- Ilic D, Polak JM. Stem Cells in Regenerative Medicine: Introduction. 2011;98:117-26.
- Sanchez-Ramos J. Stem Cells from Umbilical Cord Blood. 2006 Nov;24(5):358-69.
- Low CB, Liou YC, Tang BL. Neural Differentiation and Potential use of Stem Cells from the Human Umbilical Cord for Central Nervous System Transplantation Therapy. 2008 Jun;86(8):1670-9.
- Herranz AS, Gonzalo-Gobernado R, Reimers D, Asensio MJ, Rodríguez-Serrano M, Bazán E. Applications of Human Umbilical Cord Blood Cells in Central Nervous System Regeneration. 2010 Mar;5(1):17-22.
- Zarrabi M, Mousavi SH, Abroun S, Sadeghi B. Potential uses for Cord Blood Mesenchymal Stem Cells. 2014 Winter;15(4):274-81.
- Kabataş S, Civelek E, İnci Ç, Yalçınkaya EY, Günel G, Kır G, Albayrak E, Öztürk E, Adaş G, Karaöz E. Wharton’s Jelly-Derived Mesenchymal Stem Cell Transplantation in a Patient with Hypoxic-Ischemic Encephalopathy: A Pilot Study. 2018 Oct;27(10):1425-1433.
- Sadlik B, Jaroslawski G, Puszkarz M, Blasiak A, Oldak T, Gladysz D, Whyte G. Cartilage Repair in the Knee Using Umbilical Cord Wharton’s Jelly–Derived Mesenchymal Stem Cells Embedded Onto Collagen Scaffolding and Implanted Under Dry Arthroscopy. 2018 Jan;7(1):e57–e63.
- Kim DW, Staples M, Shinozuka K, Pantcheva P, Kang SD, Borlongan CV. Wharton’s Jelly-Derived Mesenchymal Stem Cells: Phenotypic Characterization and Optimizing Their Therapeutic Potential for Clinical Applications. 2013 May 31;14(6):11692-712.
- Nagamura-Inoue T, He H. Umbilical Cord-Derived Mesenchymal Stem Cells: Their Advantages and Potential Clinical Utility. 2014 Apr 26;6(2):195–202.
- Kalaszczynska I and Ferdyn K. Wharton’s Jelly Derived Mesenchymal Stem Cells: Future of Regenerative Medicine? Recent Findings and Clinical Significance. 2014 Dec.