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Intrinsic Extracellular Matrix Properties Regulate Embryonic Stem Cell Fate

Epigenetic regulation of cell fate by intrinsic properties of the surrounding extracellular matrix (ECM) appears to be an important but underappreciated contributor in development. Here we will show that undifferentiated embryonic stem cells (ESCs) can mature into an endoderm phenotype based on the 1) organization of the ECM protein fibronectin within the niche as well as 2) ECM elasticity, in a manner which is as sensitive as more canonical growth factor‐induced endoderm differentiation. Both intrinsic fibronectin‐based cues are time‐dependent, with matrix organization first pushing cells into a mesendoderm state and subsequently matrix elasticity of ~ 5kPa inducing definitive endoderm formation. The combination of both growth factors and ECM, however, does not appear to be additive and is suggestive of a more complex coupling via different signaling pathways. Endoderm induction via intrinsic matrix properties appears dependent on the appropriate ligation of α5β1 integrins which induce SRC kinase pathways and lead to endoderm expression.