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. ARTICLE HIGHLIGHTS: Despite extensive research on the role of the hepatocyte growth factor (HGF)/c-Met pathway in β-cells and glucose homeostasis, the endogenous source of HGF in islets remains unclear. This study characterizes the pancreatic source of HGF and its physiological requirement in vivo. Pericytes were identified as the primary endogenous source of HGF in human and mouse islets. Pericytic HGF loss causes glucose intolerance by impairing insulin production through the regulation of key β-cell genes. Establishing β-cell mass during embryogenesis and pregnancy depends on mesenchymal/pericytic HGF. This study establishes the islet vasculature as a source of trophic factors required for glycemic control.