Extracellular matrix-driven metabolic control of pancreatic endocrine lineage allocation

The mechanical and metabolic states of progenitor and stem cells are emerging as key regulators of cell fate decisions. Lineage specification of pancreatic endocrine cells is promoted by reduced mechanical tension in vitro, but the underlying mechanism is poorly understood. Here, we show that heterogeneously deposited low-adhesion extracellular matrix (ECM) components, such as the laminin isoform LN411, trigger a local "soft" environment by broadly reducing the expression of integrins. Mimicking this low-tension state by in vitro knockdown and in vivo gene targeting of the LN-binding integrins Itga3 and Itga6 reveal their importance in inducing endocrinogenesis. Unexpectedly, the cell responds to this change in tensile forces by engaging a major metabolic enzyme, PDK4, to execute the resulting cell fate decision. PDK4 achieves this through two distinct mechanisms: a non-canonical action controlling YAP activity and a canonical metabolic function maintaining PDX1 expression. In sum, we believe our findings have broad relevance for how local changes in mechanical tension governs cell behaviour in many developmental and disease contexts.