Periodic Reporting for period 2 - EpiFold (Engineering epithelial shape and mechanics: from synthetic morphogenesis to biohybrid devices)
Reporting period: 2022-07-01 to 2023-12-31
We have also applied these technologies to the study of the mechanics of intestinal organoids. Intestinal organoids capture essential features of the intestinal epithelium such as folding of the crypt, spatial compartmentalization of different cell types, and cellular movements from crypt to villus-like domains. Each of these processes and their coordination in time and space requires patterned physical forces that are currently unknown. Within EpiFold, we mapped the three-dimensional cell-matrix and cell-cell forces in mouse intestinal organoids grown on soft hydrogels. We showed that these organoids exhibit a non-monotonic stress distribution that defines mechanical and functional compartments. The stem cell compartment pushes the ECM and folds through apical constriction, whereas the transit amplifying zone pulls the ECM and elongates through basal constriction. Tension measurements established that the transit amplifying zone isolates mechanically the stem cell compartment and the villus-like domain. A 3D vertex model showed that the shape and force distribution of the crypt can be largely explained by cell surface tensions following the measured apical and basal actomyosin density. Finally, we showed that cells are pulled out of the crypt along a gradient of increasing tension, rather than pushed by a compressive stress downstream of mitotic pressure as previously assumed. Thus, EpiFold unveiled how patterned forces enable folding and collective migration in the intestinal crypt.