Mechanisms of fetal intestinal stem cell regulation and maturation Regulation of embryonic progenitor cells and adult tissue-specific stem cells has been intensely studied. However, these populations (embryonic progenitor vs. adult stem cell) are often considered to be discrete entities existing within time and space. For example, it is uniformly accepted that fetal intestinal progenitor cells give rise to the adult intestinal epithelum, but some literature suggests that adult intestinal stem cells emerge de novo during crypt formation and are molecularly distinct from their embryonic predecessors. However, our preliminary observations suggest that in the fetal/embryonic intestine, adult intestinal stem cell genes are expressed and maintained in a subset of cells throughout development/differentiation. Based on these results, we hypothesize that the "adult stem cell" state is not a discrete event, but part of a developmental continuum. That is, a "stem/progenitor" state is established developmentally in a subset of embryonic intestinal cells that give rise to adult intestinal stem cells. To test our hypothesis we will take advantage of two model systems, the murine model system and human pluripotent stem cell derived intestinal tissue. Combined, these powerful in vivo and in vitro systems will allow us to investigate the genetic and epigenetic ontogeny of intestinal stem cell precursors and adult intestinal stem cells.
Our proposal will explore the idea that adult intestinal stem cells are set aside as a precursor population in the embryonic intestine and we will explore the possibility that an epigenomic and transcriptional signature is acquired early in the fetal intestie and maintained into adult life. These studies may help inform regenerative strategies for underdeveloped or damaged embryonic and neonatal disorders affecting the intestine, such as intestinal atresia and short bowel syndrome.
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