Coordination of signaling and tissue mechanics during morphogenesis of murine intestinal villi: a role for mitotic cell rounding

Abstract

Efficient digestion and absorption of nutrients by the intestine requires a very large apical surface area, a feature that is enhanced by the presence of villi, fingerlike epithelial projections that extend into the lumen. Prior to villus formation, the epithelium is a thick pseudostratified layer. In mice, villus formation begins at embryonic day (E)14.5, when clusters of mesenchymal cells form just beneath the thick epithelium. At this time, analysis of the flat lumenal surface reveals a regular pattern of short apical membrane invaginations that form in regions of the epithelium that lie in between the mesenchymal clusters. Apical invaginations begin in the proximal intestine and spread distally, deepening with time. Interestingly, mitotically rounded cells are frequently associated with these invaginations. These mitotic cells are located at the tips of the invaginating membrane (internalized within the epithelium), rather than adjacent to the apical surface. Further investigation of epithelial changes during membrane invagination reveals that epithelial cells located between mesenchymal clusters experience a circumferential compression, as epithelial cells above each cluster shorten and widen. Using a computational model, we examined whether such forces are sufficient to cause apical invaginations. Simulations and in vivo data reveal that proper apical membrane invagination involves intraepithelial compressive forces, mitotic cell rounding in the compressed regions and apico-basal contraction of the dividing cell. Together, these data establish a new model that explains how signaling events intersect with tissue forces to pattern apical membrane invaginations that define the villus boundaries.

Morphogenesis and maturation of the embryonic and postnatal intestine

“…On the other hand, it has been predicted that tension/force placed on the epithelium by the underlying mesenchymal clusters may instruct the overlying epithelium to start forming a villus [124]. Here, it has been proposed that nascent clusters deform the epithelium as they form on the basal side of the epithelium, placing compression forces on the epithelium and placing strain on the apical epithelial surface.…”

“…Here, it has been proposed that nascent clusters deform the epithelium as they form on the basal side of the epithelium, placing compression forces on the epithelium and placing strain on the apical epithelial surface. When coupled with reduced tension in the apical F-actin cortical network due to a mitotic event in the highly proliferative epithelium, sufficient strain from below the epithelium coupled with a local reduction in apical surface tension would lead the epithelium to deform and buckle in between the mesenchymal clusters, effectively forming nascent villi above the clusters [124]. …”

“…For example, epithelial Hh ligands are concentrated in the underlying mesenchyme after epithelial buckling to induce changes in the mesenchyme [110]. Collectively, these data suggest that the mechanisms driving villus development and regulating epithelial and mesenchymal differentiation in the two species are dramatically different, but also show the importance of both signaling molecules and biomechanical forces in tissue morphogenesis in both species [14,84,110,124]. …”

Bioengineering for intestinal organoid cultures

“…(Figure 3A) On the other hand, due to a thicker epithelium, it has been put forward that pattern formation in the mouse gut requires localized biochemical signals in addition to mechanical forces. [42–44]…”

Generating tissue topology through remodeling of cell-cell adhesions

“…The physical mechanisms underlying murine villus morphogenesis have recently been described by Freddo et al After mesenchymal clusters have formed, epithelial cells directly above them shorten and widen, generating compressive forces felt by cells between clusters. Mitotic cells in these compressed regions undergo internalized cell rounding and generate apical invaginations that spread and deepen over the course of intestinal development (Figure 1B) [10]. …”