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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

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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.

Authors

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

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Figure 1

Distribution and age-associated changes of myeloid subsets in distinct pancreatic tissue compartments.

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Distribution and age-associated changes of myeloid subsets in distinct p...
(A) Flow cytometric analysis of GR1+ and F480+ subsets in mesenchymal and epithelial fractions of E15.5 and newborn pancreas (n = 3). (B) F480+ gates showing enrichment of CCR2+ macrophages in the mesenchymal fraction of newborn pancreas, whereas CX3CR1+ subsets predominate within the epithelial fraction of E15.5 pancreas. (C) Contingency plots showing the number of F480+CX3CR1+ and CCR2+ subsets detected in E15.5 and newborn pancreas (mean ± SEM of 3 tissue samples). (D) Age-associated changes in the frequency of pancreatic F480+CCR2+ cells (mean ± SD of at least 2 tissue pools per time point). (E) qPCR of chemokine transcripts in mesenchymal fractions of E14.5, P1, and 4-week-old pancreas (mean ± SD of triplicates) (n = 2, using pools of 3–5 tissues per time point). (F) Myeloid CFU outgrowth from 100,000 cells/tissue (mean ± SD of n = 2 tissue pools, each run in duplicate cultures).

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