A CCR2+ myeloid cell niche required for pancreatic β cell growth
Kristin Mussar, … , Vincenzo Cirulli, Laura Crisa
Kristin Mussar, … , Vincenzo Cirulli, Laura Crisa
Published August 3, 2017
Citation Information: JCI Insight. 2017;2(15):e93834. https://doi.org/10.1172/jci.insight.93834.
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Research Article Development Endocrinology

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

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.

Authors

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

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Figure 7

Effects of CCR2+ cell depletion on body size and glycemic homeostatic control.

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Effects of CCR2+ cell depletion on body size and glycemic homeostatic co...
(A) Decreased body size of DT-treated CCR2DTR/+ mice compared with WT littermates at P10. (B) Body weight of untreated or DT-treated CCR2DTR/+ mice and WT littermates at P10 (n = 27–71). (C) Mild basal hypoglycemia detected in DT-treated CCR2DTR/+ mice at P10 (n = 9–16). (D) Tissue sections of liver and skeletal muscle stained by periodic acid–Schiff, showing decreased glycogen storages in DT-treated CCR2DTR/+ P10 pups. Scale bar: 50 μm. Representative of n = 4. (E and F) Basal plasma insulin (E) (n = 4–5) and glucose tolerance tests (F) (n = 7–9) in P10 DT-treated CCR2DTR/+ mice and WT littermates. **P < 0.01, ***P < 0.001, 1-way ANOVA nonparametric test, followed by Bonferroni post-hoc test. (G–I) Pancreatic sections from P10 DT-treated WT and CCR2DTR/+ mice stained for the islet markers NCAM and NKX6.1 (G); islet transcription factor MafA and E-cadherin (H); and islet transcription factors PDX1 and MafB (I). Insets in G and H show NKX6.1 and MafA localization to the islets’ nuclei, whereas insets in I show aberrant persistence of MafB in PDX+ cells in DT-treated CCR2DTR/+ mice (arrowheads). Representative of at least n = 6 per group. (J) Western blotting of NKX6.1 and MafA expressed in total protein lysates of P10 pancreatic islets. Membranes were stripped and reprobed for E-cadherin and Hsp90 as loading controls (n = 3). (K) Representative qPCR analysis of islet transcription factors mRNAs in pancreatic islets of DT-treated WT and CCR2DTR/+ mice at P10 (n = 2) (mean ± SD of triplicates). (L) Insulin content and glucose-stimulated insulin secretion of islets isolated from DT-treated WT and CCR2DTR/+ mice at P10 (n = 3–4). *P < 0.05, ***P < 0.001 by 2-tailed Student’s t test used for insulin content and by 1-way ANOVA nonparametric test for multiple comparisons of insulin secretion.