Pluripotent stem cells potentialities and differentiation abilities

Updated: May 25

Human body contains approximately 30 trillons of cells. While mature cells exert a specific function in organism (bone structure, muscle contraction, pain sensing, …), stem cells allow renewal of mature cells lost by aging or following any type of stress. Mature cells are arising from stem cells through a process termed differentiation. For purists, cell differentiation consists in the loose of potentialities or plasticity abilities of a stem cell, to specialize in a given function in organism (1).


Let’s take a closer look at the potentialities and the abilities of pluripotent stem cells.

 

Pluripotent stem cells potentialities

Pluripotent stem cells can give rise to any type of cell of the organism, excepting placental cells on the contrary to totipotent stem cells. Because pluripotent stem cells have high plasticity abilities, their epigenome show global DNA hypomethylation and is considered as highly open and freed of lineage specification (2, 3). Indeed, stem cells express constantly at low level most part of their genome, while mature cells express at high level a specific part of their genome (1).

Thus, pluripotent stem cells are constantly stimulated by various microenvironmental molecular factors, including :

  • FGFs

  • WNTs

  • TGFb superfamily

  • and their respective antagonists (4)


An imbalance in those factors due to cellular microenvironment variation, engage pluripotent stem cells to differentiate. Then, pluripotent stem cells meet the first branching of differentiation toward :

  • ectoderm (skin and nerves)

  • mesoderm (bones and muscles)

  • or endoderm (most of internal organs).



Differentiation can be accompanied by chemoattraction and cellular migration. To note, a cell lineage resumes all the cell states crossed by a differentiated/mature cell from the stem cell which it arises.


Lineage specification of pluripotent stem cells

Along lineage, molecular factors from cellular environment orient and specialize cells across various differentiation branching, while loosing potentialities. So, pluripotent stem cells are becoming multipotential stem cells, then progenitor cells, then precursor cells (or unipotent), and finally mature cells.

While mature cells do not proliferate, pluripotent stem cells can self-renew, thus allowing theoretically maintenance of a pool of immature stem cells along life. However, nowadays the presence of pluripotent stem cells in adult tissues is mired with controversies (5, 6). It is admitted that pluripotent stem cells are found in embryo, but that most of adult stem cells passed at least the first branching of differentiation to become multipotential.


While keeping some potentialities, multipotential stem cells are considered tissue-specific stem cells. Problem is that in vivo multipotential stem cells are not fully characterized, heterogenous, and can be difficult to be purely isolated from native tissues, and to be maintained in long-term cultures (7, 8). Progenitor cells are the most proliferative cells in the organism, thus permitting a rapid increase in cell number during tissue development or following tissue damage. Yet, progenitor cells show high specialization and are difficult to keep in long-term cultures.


Plasticity of mature cells

While scientific community thought that differentiation process was sequential, unidirectional, and irreversible, some evidence of plastic abilities of mature cells were given. Indeed, adipocytes can convert between a white UCP1- (storing fatty acids) and a beige UCP1+ (consuming fatty acids) phenotype in response to cold/warm, catecholamines, exercise, diet and others.


Moreover, vascular smooth muscle cells can switch between a synthetic and a contractile phenotype (10). Switch or conversion process was also described for Schwann cells between a myelinating and a non-myelinating phenotype following tissue damage (11). Otherwise, some processes of trans-differentiation were also described between a lineage and another. For example, adipocytic myofibroblasts were described showing a fatty vesicles-positive cellular pole, and a microfilaments-rich pole at the opposite side (12). Fibroblastic-adipocytic trans-differentiation was also artificially induced by NPC2 deletion in human dermal fibroblasts (13).


Yet, the indisputable proof of reversibility of differentiation process was demonstrated in 2007. Yamanaka’s team demonstrated for the first time that the mature state of a human cell can be reverted to a pluripotent state by inducing four key molecular factors (14). Yamanaka named the resulted cells induced-pluripotent stem cells. This work was awarded by a Nobel Prize of medicine in 2012 and gave rising hopes in regenerative medicine.


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References

1. Zipori, D. The nature of stem cells: state rather than entity. Nat. Rev. Genet. 5, 873–878 (2004).

2. Yagi, M., Yamanaka, S. & Yamada, Y. Epigenetic foundations of pluripotent stem cells that recapitulate in vivo pluripotency. Lab. Investig. J. Tech. Methods Pathol. 97, 1133–1141 (2017).

3. Leitch, H. G. et al. Naive pluripotency is associated with global DNA hypomethylation. Nat. Struct. Mol. Biol. 20, 311–316 (2013).

4. Li, L. & Xie, T. Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005).

5. Gao, L., Thilakavathy, K. & Nordin, N. A plethora of human pluripotent stem cells. Cell Biol. Int. 37, 875–887 (2013).

6. Bhartiya, D. Pluripotent Stem Cells in Adult Tissues: Struggling To Be Acknowledged Over Two Decades. Stem Cell Rev. Rep. 13, 713–724 (2017).

7. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

8. Merrick, D. et al. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science 364, eaav2501 (2019).

9. Rosenwald, M., Perdikari, A., Rülicke, T. & Wolfrum, C. Bi-directional interconversion of brite and white adipocytes. Nat. Cell Biol. 15, 659–667 (2013).

10. Alexander, M. R. & Owens, G. K. Epigenetic control of smooth muscle cell differentiation and phenotypic switching in vascular development and disease. Annu. Rev. Physiol. 74, 13–40 (2012).

11. Jessen, K. R. & Mirsky, R. The repair Schwann cell and its function in regenerating nerves. J. Physiol. 594, 3521–3531 (2016).

12. Dennis, J. E., Carbillet, J.-P., Caplan, A. I. & Charbord, P. The STRO-1+ marrow cell population is multipotential. Cells Tissues Organs 170, 73–82 (2002).

13. Csepeggi, C., Jiang, M. & Frolov, A. Somatic cell plasticity and Niemann-pick type C2 protein: adipocyte differentiation and function. J. Biol. Chem. 285, 30347–30354 (2010).

14. Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).



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