Intrinsic regulation of quiescence and radioresistance in intestinal stem cells

Intrinsic regulation of quiescence and radioresistance in intestinal stem cells Public Deposited

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Roche, Kyle
- Affiliation: School of Medicine, Department of Cell Biology and Physiology

Abstract

The intestinal epithelium regenerates every 5-7 days, a process that is facilitated by a pool of intestinal stem cells. Over the past decade, it has become apparent that the intestinal stem cell pool is diverse, containing at least two populations. Active stem cells (aISCs) are moderately proliferative and contribute to homeostatic regeneration, while reserve stem cells (rISCs) are slowly proliferative and facilitate regeneration following damage-induced loss of the aISC population. The genetic mechanisms required for the production and maintenance of rISCs are unknown. Sox9 is a transcription factor that has been shown to maintain stem cell populations in various tissues. In the intestinal epithelium, Sox9 is expressed in a gradient that negatively correlates with proliferative capacity. Transit-amplifying progenitors express the lowest levels of Sox9, while aISCs express intermediate levels, and cells expressing the highest levels of Sox9 are consistent with slowly cycling rISCs. In this dissertation, I will address the role that Sox9 plays in maintaining rISC function within the intestinal epithelium. I find that Sox9 is not only necessary for the production of a quiescent rISCs, but that it is also uniformly necessary for maintaining radioresistance within the rISC pool. This work identifies Sox9 as a novel intrinsic regulator of the rISC state.

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