The luminal surface of the gastrointestinal tract has distinct structures along the anatomical segments of the gut such as the gastric rugae, circular folds and villi in the midgut, and haustra and the colonic villi in the hindgut. The emergence of the endodermal topography coincides with the spatial restriction of proliferating cells into patterned arrays from which crypts and pits will later form. These epithelial stem cell zones maintain the luminal fold structure of the gut. Villous atrophy can lead to malnutrition and dehydration that are often refractory; disruption of the luminal stem cell zone architecture is an early sign of cancers. An understanding of how the patterning of the stem cell zones and luminal topography are related would give insight to these diseases. Recently, it has been demonstrated that the generation of luminal topography of the developing small intestine can be completely understood in terms of multi-axial buckling by mechanical forces. The timing of smooth muscle differentiation in different axis provide sufficient physical constraint to the growing mucosa to generate the villi. This finding suggests that the different shapes of folds along the alimentary canal may arise by variation of a few physical parameters as well. Moreover, the finding suggests that the folds by buckling may provide radially non-uniform positional cues for patterned, restricted epithelial stem cell zones in the gut. Lastly, it points o the possible role of mechanical processes in luminal regeneration conditions. To investigate this, following aims are proposed:
Specific Aim 1. Determine the role of physical forces in specifying the different endodermal topographies along the anterior-posterior (A-P) axis of the gut.
Specific Aim 2. Determine the role of topology on molecular signaling events in the formation and maintenance of stem cell zones in the developing small intestine.
Specific Aim 3. Determine the role of physical forces during the recovery of the adult gut epithelium following pathologic insult. These studies will combine the unique advantages afforded by both chick and mouse systems. They share close similarity to human anatomy and gut development. Measurement of mechanical properties and physical manipulation of gut explants will be combined with in silico modeling approaches to understand the role of mechanical forces in shaping the different luminal topographies of the gut. Pharmacological and genetic perturbations on explant cultures will be utilized to understand the relationship of shape and morphogen gradients to the patterning of the stem cell compartments. The work may give a fresh light on our understanding of pathological conditions such as villous atrophy, but may also contribute to a more comprehensive picture between the molecular and mechanical forces that underlie gut morphogenesis.
In all parts of the gut, the cells surrounding the inside of the gut have particular folds and projections such as villi that have essential functions and are maintained by regularly spaced stem cell compartments, that replace the epithelial structure lost by wear and tear. Malnutrition and dehydration happens when these folds are destroyed by many bowel diseases, which persists often even when the underlying cause is removed; the earliest marks of cancers arising from the gut are the disruption of these folds and the perturbation of the maintenance mechanism of the stem cells. The purpose of this study is to understand how these folds and stem cell compartments arise in the first place, to gain an understanding of the physical and molecular checks and signals responsible for the maintenance, as well as probe ways to efficiently regenerate these structures when they are destroyed.
|Shyer, Amy E; Huycke, Tyler R; Lee, ChangHee et al. (2015) Bending gradients: how the intestinal stem cell gets its home. Cell 161:569-580|