Self—Renewal, Stem Cell

Mechanisms of Self—Renewal

In steady—state conditions, the main molecular mechanism through which stem cells can achieve self—renewal is asymmetric division, which entails the division of a stem cell to give rise to two cells with different fates: one stem cell and one committed progenitor. This mechanism ensures that the stem cell pool (number of stem cells) remains constant during the lifetime of an organism. Self—renewal must be tightly regulated, requiring the coordination of both intracellular and extracellular factors. Intracellular asymmetry is achieved during cell division through the segregation of specific cellular components such as proteins and RNA to only one daughter cell and not to the other. Although still somewhat controversial, recent evidence suggests that the DNA itself can be distributed asymmetrically. Upon cell division, the original DNA strands are retained in the daughter stem cell, and the newly synthesized DNA is partitioned to the committed progenitor. This mechanism is thought to protect stem cells from the accumulation of mutations resulting from DNA synthesis and guarantees stem cells the exact same genome forever (immortal DNA). As a result, together with DNA, the epigenetic signature of a stem cell is inherited, including modifications to the DNA itself, as well as associated proteins (chromatin factors). This ensures that stem cell gene expression and function will be maintained over future cell generations. Extracellular asymmetry is provided by the microenvironment surrounding the stem cells (stem cell niche). The distribution of extracellular matrix components, secreted proteins, and other cells in the vicinity of the stem cells is critical to controlling the stem cell pool. For example, in the Drosophila ovary, the orientation of stem cell division is dictated by the niche. The mitotic spindle is perpendicular to the niche, so that after division, one cell remains in close contact with the [Page 494]niche and maintains stem cell function, and the other loses this contact and begins to differentiate into more committed progeny. Thus, the polarity of both intracellular and extracellular signals plays a crucial role in self—renewal.

Muscle stem cells lie beneath a thin basement membrane on top of a single contractile, multinucleated muscle fiber

Although asymmetric division occurs in homeo—static conditions and is necessary to maintain a constant stem cell pool, symmetric division is required during embryonic development and to meet the demands of tissue stress and injury. This mechanism ensures that when an acute damage severely impairs tissue function, stem cells can start dividing very rapidly to give rise to committed progenitors to guarantee the restoration of tissue function in a relatively short period of time. This leads to exhaustion of the stem cell pool (depletion). Conversely, stem cells can also divide symmetrically to give rise to more stem cells, thus expanding the stem cell pool (expansion). A third mechanism has been recently observed in mouse spermato—genesis—reversion—in which a stem cell initially divides, giving rise to two committed daughter cells (transient amplifying cells) and then, subsequently, these transient amplifying cells, when again in contact with the niche, revert to a stem cell state, thus expanding the stem cell pool. These studies underscore the importance of the niche in regulating cell fate and demonstrate the critical role of extrinsic factors in instructing cell function.

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