HGF Endogenously Produced by Pancreatic Pericytes Regulates β-Cell Function

Hepatocyte growth factor (HGF)/c-Met signaling is a well-established pathway through which external signals regulate β-cell resilience and function. Yet the endogenous source of HGF in the islets and its physiological role in this context remain unclear. Here, we combined human islet single-cell transcriptomics with mouse pancreatic-cell profiling to show that pericytes, rather than endothelial cells, are the primary source of HGF in healthy islets. Using transgenic mouse tools and culture systems, we found that pericyte-derived HGF is required for β-cell function and glucose homeostasis. Adult mice lacking pericytic HGF in their pancreata developed glucose intolerance while maintaining β-cell mass and insulin sensitivity. Mechanistically, HGF secreted by pancreatic pericytes is required for proper insulin production and secretion by regulating the expression of key β-cell genes, including Pdx1, Slc2a2, and Ins1. In addition, neonatal and pregnant mice lacking mesenchymal/pericytic HGF had lower β-cell mass, indicating its context-dependent requirement for β-cell expansion. Thus, we suggest that pericytic HGF is required for insulin production and secretion during homeostasis and for supporting β-cell expansion during embryogenesis and pregnancy. Together, our findings establish pericytes as a significant endogenous source of HGF, coupling the islet microvasculature to insulin production and glucose homeostasis.