Extracellular matrix flow guides emergent morphogenesis

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. We further validate ECM flow in 3D gastruloids and in quail embryos during primitive streak formation. 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. Overall design: Human pluripotent stemcell cultures were culture to confluence then exposed to media containing 10% Matrigel for 24 h. Along with Matrigel-free media condition, both samples were dissociated using TrypLE and analyzed separately using scRNA-seq