Building tissues to understand how tissues build themselves

Successful construction of tissues and organs requires an engineering-level understanding of the cell dynamics and forces that drive tissue morphogenesis. In vertebrates, the morphogenesis of epithelial sheets is often coupled to cell dynamics in the underlying mesenchyme, where cells dispersed in a loose ECM aggregate to mark the site of epithelial morphogenesis. Theoretical studies suggest that forces generated during these mesenchymal condensations could directly fold overlying tissue by producing stresses at the epithelial-mesenchyme interface. We test this idea using a reconstitution approach. We find that the mesenchyme compacts loose and fibrous ECM at tissue interfaces, aligns ECM fibers towards the center of condensation, and increases tension along aligned fibers. Tensions drive folding of interfaces along trajectories that can be predicted by finite element modeling. To demonstrate the robustness and versatility of this strategy for sculpting local tissue shape, we build a variety of folded tissue forms by engineering the pattern of mesenchymal condensates. These studies provide insight into the active mechanical properties of the embryonic mesenchyme and establish strategies for more reproducibly directing tissue morphogenesis ex vivo.