A CCR2+ myeloid cell niche required for pancreatic β cell growth

Organ-specific patterns of myeloid cells may contribute tissue-specific growth and/ or regenerative potentials. The perinatal stage of pancreas development marks a time characterized by maximal proliferation of pancreatic islets, ensuring the maintenance of glucose homeostasis throughout life. Ontogenically distinct CX3CR1(+) and CCR2(+) macrophage populations have been reported in the adult pancreas, but their functional contribution to islet cell growth at birth remains unknown. Here, we uncovered a temporally restricted requirement for CCR2(+) myeloid cells in the perinatal proliferation of the endocrine pancreatic epithelium. CCR2(+) macrophages are transiently enriched over CX3CR1(+) subsets in the neonatal pancreas through both local expansion and recruitment of immature precursors. Using CCR2-specific depletion models, we show that loss of this myeloid population leads to a striking reduction in beta cell proliferation, dysfunctional islet phenotypes, and glucose intolerance in newborns. Replenishment of pancreatic CCR2(+) myeloid compartments by adoptive transfer rescues these defects. Gene profiling identifies pancreatic CCR2(+) myeloid cells as a prominent source of IGF2, which contributes to IGF1R-mediated islet proliferation. These findings uncover proproliferative functions of CCR2(+) myeloid subsets and identify myeloid-dependent regulation of IGF signaling as a local cue supporting pancreatic proliferation.