Reciprocal folding dynamics in cellular networks at the stroma-basement membrane interface

Epithelium layer stands on a membrane, called basement membrane (BM) which serves as a boundary with the underlying stroma. While most studies on morphogenesis have focused on the epithelium-BM complex, the role of the BM-stroma interface remains poorly understood. In this study, we demonstrate how forces originating from the stromal layer contribute to tissue morphogenesis. Folds focalization at the BM-stroma interface is driven by mechanical instability, which arises from the fluidity of the stroma and the polarized tractional forces acting on the rigid membrane of stromal cell condensates. Stromal cells move towards the folded region by topographic guidance, while the concentration of forces intensifies. Through this process, stromal cells and folds engage in recursive interactions, resulting in the formation of a cellular network. Our observation provides a rational mechanism for pattern formation in a multi-layered living tissue. STATEMENT OF SIGNIFICANCE: This study addresses a crucial gap in understanding how stromal cells interact with the basement membrane to lead tissue surface morphogenesis. By developing a collagen-based, nanometer-thick engineered basement membrane, we demonstrate that the stromal cells exert traction forces on the basement membrane to fold. The folding process guides stromal cell migration, which in turn induces further folding in a recursive manner. The direction of folding, invagination or evagination, is determined by the stiffness difference between the stroma and the basement membrane. This model offers better understanding about how the basement membrane interacts with stromal cells to make evaginated network structures on tissue surface.