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

Kristin Mussar, Stephanie Pardike, Tobias M. Hohl, Gary Hardiman, Vincenzo Cirulli, Laura Crisa

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Abstract

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 β 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.

Original languageEnglish
Article numbere93834
Number of pages22
JournalJCI insight
Volume2
Issue number15
DOIs
Publication statusPublished - 03 Aug 2017

Keywords

  • Development
  • Endocrinology

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    Mussar, K., Pardike, S., Hohl, T. M., Hardiman, G., Cirulli, V., & Crisa, L. (2017). A CCR2+ myeloid cell niche required for pancreatic β cell growth. JCI insight, 2(15), [e93834]. https://doi.org/10.1172/jci.insight.93834