Search

Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, initiated by the formation of an epithelial invagination - termed placode – that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions, and physical compartmentalization of the placode are unknown. Here, we identify a key role for coordinated mechanical forces stemming from contractile, proliferative, and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which in collaboration with polarized epithelial myosin activity promote elongation and local tissue thickening. These mechanical stresses further enhance and compartmentalize Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodeling locally softens the basement membrane to facilitate release of pressure on the placode, enabling localized cell divisions, tissue fluidification, and epithelial invagination into the underlying mesenchyme. Together, our experiments and modeling identify dynamic cell shape transformations and tissue-scale mechanical co-operation as key factors for orchestrating organ formation.

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. Here we map the three-dimensional cell-ECM and cell-cell forces in mouse intestinal organoids grown on soft hydrogels. We show 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 establish that the transit amplifying zone isolates mechanically the stem cell compartment and the villus-like domain. A 3D vertex model shows 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 show 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. Our study unveils how patterned forces enable folding and collective migration in the intestinal crypt.

There is growing evidence that the physical properties of the cellular environment can impact cell migration. However, it is not currently understood how active physical remodeling of the network by cells affects their migration dynamics. Here, we study collective migration of small clusters of cells on deformable collagen-1 networks. Combining theory and experiments, we find that cell clusters, despite displaying no apparent internal polarity, migrate persistently and generate asymmetric collagen gradients during migration. We find that persistent migration can arise from viscoelastic relaxation of collagen networks, and reducing the viscoelastic relaxation time by chemical crosslinking leads to a reduction in migration persistence. Single cells produce only short range network deformations that relax on shorter timescales, which leads to lower migration persistence. This physical model provides a mechanism for self-generated directional migration on viscoelastic substrates in the absence of internal biochemical cues.