Compartment specific responses to contractility in the small intestinal epithelium

Abstract

Tissues are subject to multiple mechanical inputs at the cellular level that influence their overall shape and function. In the small intestine, actomyosin contractility can be induced by many physiological and pathological inputs. However, we have little understanding of how contractility impacts the intestinal epithelium on a cellular and tissue level. In this study, we probed the cell and tissue-level effects of contractility by using mouse models to genetically increase the level of myosin activity in the two distinct morphologic compartments of the intestinal epithelium, the crypts and villi. We found that increased contractility in the villar compartment caused shape changes in the cells that expressed the transgene and their immediate neighbors. While there were no discernable effects on villar architecture, even low levels of transgene induction in the villi caused non-cell autonomous hyperproliferation of the transit amplifying cells in the crypt, driving increased cell flux through the crypt-villar axis. In contrast, induction of increased contractility in the proliferating cells of the crypts resulted in nuclear deformations, DNA damage, and apoptosis. This study reveals the complex and diverse responses of different intestinal epithelial cells to contractility and provides important insight into mechanical regulation of intestinal physiology. Author SummaryThe small intestine epithelium is comprised of two main compartments: the villi which contain differentiated cells that function in nutrient absorption, and the crypts which are made up of undifferentiated cells which serve to replenish cells of the villi. Because of their physical location within the tissue, villi and crypts are subjected to different types of insults and mechanical forces. We sought to directly test how villi and crypts respond to mechanical changes in the epithelia by genetically inducing actomyosin contraction. Increasing contractility in villar cells resulted in cell shape changes without affecting their overall polarity or organization. However, it led to a non-autonomous increase in proliferation of the undifferentiated cells of the intestine. In contrast, increased contractility in the proliferative cells of the crypt resulted in nuclear shape changes, DNA damage and ultimately a rapid cell death. Thus, our work demonstrates that the crypt and villi epithelia respond differently to mechanical changes and highlights long-range regulation between villi and crypt compartments.