Bi-directional crosstalk between cells and extracellular matrix leads to network morphogenesis in multi-layered tissues.

Cell-generated mechanical forces drive many cellular and tissue-level movements and rearrangements required for the tissue or organ to develop its shape(1, 2, 3, 4, 5). The prevalent view of tissue morphogenesis relies on epithelial folding resulting in compressed epithelial monolayers, overlooking the involvement of stroma in morphogenesis(1, 4, 6, 7). Here, we report a giant web-like network formation of stromal cells in the epithelium-stroma interface, resulting from a multi-scale mechano-reciprocity between migrating cells and their extracellular environment. In multi-layered tissues, surface wrinkles form by a stromal cell-mediated tensional force exerted at the basement membrane. The topographical cue is transmitted to the stromal cell, directing its protrusion and migration along the wrinkles. This inductive movement of the cells conveys traction forces to its surrounding extracellular matrix, remodeling the local architectures of the stroma. In this manner, stromal cells and wrinkles communicate recursively to generate the cellular network. Our observation provides a rational mechanism for network formation in living tissues and a new understanding of the role of cellular-level tensional force in morphogenesis.