New Perspectives on Intestinal Morphogenesis: The Role of Cell Division and Intraepithelial Forces in Villus Formation

[摘要] Finger-like projections called villi convolute the intestinal surface, maximizing the area for nutrient absorption. Villi are rapidly formed and patterned during embryonic development; in the mouse, beginning at embryonic day (E)14.5, one new villus is defined approximately every 15 minutes. In this thesis, we worked at the interface of advanced in vivo imaging and in silico mechanical modeling to understand the transformation from a flat intestinal surface into a field of domed villi.For decades, villus morphogenesis was thought to involve formation of isolated lumens in a stratified epithelium. However, recent studies have shown that the pre-villus epithelium is a single pseudostratified layer and its surface remains connected throughout development. Here, we develop a new model that offers insight into how this dramatic lumenal surface expansion occurs within these parameters.We determined that initial villus demarcation occurs by patterned invaginations in the intestinal surface. Their location is controlled by mesenchymal clusters, patterned structures that signal to cause the adjacent epithelium to shorten and widen. This shape change compresses the intervening epithelium. Within these regions, cell division-associated invaginations occur. These in vivo observations informed an in silico mechanical model of the epithelium, which demonstrates that both compressive forces and cellular changes during mitosis can drive villus demarcation. We also utilized the Ezrin null mouse model to define other cell behavior essential for villus morphogenesis; this model exhibits both ectopic lumens and villus fusions. We show that loss of EZRIN impairs mitotic spindle orientation control and transforms the epithelium into a stratified structure. In this context, ectopic lumens form between cell layers. Additionally, we establish that Ezrin plays a critical role in maintenance of the intestinal epithelium throughout life, and provide functional evidence of impaired junctional remodeling in the absence of EZRIN. Finally, we offer a unified model of how fused villi develop embryonically and postnatally.Working at the interface between in vivo observations and in silico modeling will inform future studies on the biological and physical characteristics required for the dramatic epithelial convolution associated with villus development, potentially providing new avenues for the targeted engineering of intestinal surface.

[发布机构] University of Michigan

[效力级别] cell division

[关键词] small intestine;cell division;intestinal development;Molecular;Cellular and Developmental Biology;Health Sciences;Science;Cell & Developmental Biol PhD