Extracellular matrix flow guides emergent in-vitro morphogenesis

Abstract Morphogenesis of vertebrate embryos requires extracellular matrix (ECM) in multiple developmental contexts1. Symmetry-breaking events in initially homogenous tissues trigger collective cellular dynamics which follow fluid-like behaviors, and the ECM, which is in constant engagement with morphing tissues, also undergoes fluid-like motion2–4. Cell and ECM deformations require coordination, however the interplay between them at cellular and tissue-scale remains largely unexplored. Here, we reveal a novel mechanism coupling morphogenetic events and epithelia-driven ECM flow. We show that exposure to ECM components triggers periodic morphogenesis of dome-shaped structures in human pluripotent stem cell monolayers, driven by directional ECM flow towards the sites of morphogenesis. We show that this flow is initiated by local symmetry-breaking events, is driven by microvilli and requires unperturbed flow conditions and cytoskeletal contractility. A theoretical model shows that a reaction-diffusion-like mechanism is responsible for organizing local morphogenesis into global tissue-wide events. The cell patterning landscape predicted by the model is experimentally recapitulated during mesoderm differentiation. These results uncover a new role for the ECM: in addition to being a site of cell adhesion, structural support and mechanical force generation5, as is currently established, we show that directional transport of ECM, termed ECM flow, is a major contributor in sustaining epithelial morphogenesis and differentiation.