Renewal of the intestinal epithelium requires a balance between progenitor cell divisions and differentiated cell loss. Maintaining division-loss balance is essential for digestive health, while its disruption characterizes numerous intestinal pathologies. Division-loss balance involves feedback signals that act within the epithelium; however, the molecular nature of these signals is largely unknown. Our long-range goal is to understand the processes that give rise to the spatiotemporal dynamics of intestinal cells in vivo. Supporting this goal, the objective of this proposal is to investigate mechano-sensitive mechanisms that coordinate stem cell divisions with the epithelium's need for new cells. These studies will exploit the tractability of the adult Drosophila intestine, whose simple stem cell lineage and advanced genetic tools enable precise mechanistic investigation. We have previously shown that the Drosophila intestine exhibits a stem cell driven, reversible growth response to increased dietary load (O'Brien et al., Cell 2011). Preliminary evidence from our lab suggests a correlation between stem cell division rate and the degree of intestinal distention. This correlation is reminiscent of density-sensitive proliferation in epithelial culture, a collectve cell behavior controlled by mechanotransduction through the adhesion receptor E-cadherin and the transcription factor YAP. Here, we will examine the hypothesis that analogous mechano-sensitive signals stimulate intestinal stem cell divisions when enterocytes are sparse. Specifically, we will (1) determine the mechano-sensitivity of E-cadherin and YAP in niche and non-niche cells during intestinal distention, and (2) elucidate the niche- and non-niche roles of E-cadherin and YAP in density-sensitive division control. Accomplishment of these aims may identify a mechano-sensitive pathway that links enterocyte density to stem cell divisions, providing basic insight into homeostatic control of intestinal renewal. Our proposed work is significant because knowledge of how cell loss and production are coordinated may engender future therapeutic strategies to enhance intestinal repair and regeneration. Our approach is innovative because it draws a novel conceptual link between density-sensitive proliferation and homeostatic tissue renewal, and because it exploits the unique attributes of an emerging experimental system. Finally, data from these studies will provide the foundation for a detailed, R01-level investigation of the mechanobiology of intestinal renewal and remodeling.
The ability of the intestine to renew itself can be overwhelmed by injury and disease, leading to impaired nutrient absorption and long-term intravenous feeding. To develop better therapies, we need to know more about the basic genes and processes that control intestinal renewal. Studying intestinal renewal in fruit flies, a simple animal model, will generate new leads for therapies to explore further in mammals.
| Liang, Jackson; Balachandra, Shruthi; Ngo, Sang et al. (2017) Feedback regulation of steady-state epithelial turnover and organ size. Nature 548:588-591 |
