Self renewal

Self-renewal is the ability of stem cells to divide in order to make more stem cells, growing the stem cell pool throughout the lifespan of the living organism. Self-renewal is the division of the stem cell along with the maintenance of the undifferentiated state so that the body does not run out of the essential stem cells. Any defects in the mechanisms of self-renewal can cause developmental disorders, premature aging phenotypes, and/or cancer. understanding the complexities of self-renewal mechanisms provides the potential for fundamental insights into development, cancer, and aging. Stem cells remain quiescent unless there great physiological need at which point they divide to create daughter cells that have the same developmental potential as their mother cell. In this way, it is different in nature to general cell proliferation.

This requires control of the cell cycle and often the maintenance of potency (the capacity of the stem cell to divide into different cell types), depending on the stem cell.

The balance of proto-oncogenes (that promote self-renewal), gate-keeping tumor suppressor genes (that limit self-renewal), and care-taking tumor suppressor genes (that maintain genomic integrity) is crucial in the self-renewal of stem cells.
These intrinsic mechanisms of the cell are regulated by signals originating from the niche, which is the microenvironment surrounding the stem cells that maintains and regulates their function in tissues.

In response to the dynamic tissue demands, stem cells can undergo changes in their cell cycle condition and developmental potential over time, necessitating particular self-renewal programs at different stages of life.

During aging, the stem cell function and tissue regenerative capacity are reduced. This is caused by changes in self-renewal programs that amplify tumor suppression. Cancer can arise from mutations that inappropriately activate self-renewal programs.

Regulation of Self-renewal in Pluripotent Stem Cells

Embryonic Stem cells (ESC) have unique transcriptional and cell cycle regulation which leads to properties of unlimited self-renewal potential and pluripotency. Oct4, the POU domain transcription factor is critical for the pluripotency of the inner cell mass of the blastocyst as well as ESCs in culture. Sox2, the SRY-related HMG-box transcription factor is also needed in order to maintain the pluripotency of the embryo and of ESCs in culture. Both these factors coordinate in order to activate the expression of a group of genes whose role is to regulate pluripotency. Nanog is a homeodomain protein that is also required for the maintenance of pluripotency. This Oct4-Sox2-Nanog network is finely regulated by positive and negative signals because even the slightest hyper- or hypoactivation of some of these factors can disrupt pluripotency. Besides these factors, there are epigenetic regulators as well that also promote the maintenance of pluripotency.

Diagram depicting the Oct4-Sox2-Nanog regulatory network. This also shows that ESCs inhibit differentiation in order to self-renew.


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