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Critical Roles for Macrophages in Islet Angiogenesis and Maintenance During Pancreatic Degeneration

¹ Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, Integrated Department of Immunology, University of Colorado Denver School of Medicine, Aurora, Colorado
² Barbara Davis Center for Childhood Diabetes, University of Colorado Denver School of Medicine, Aurora, Colorado
³ Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York

Corresponding author: James DeGregori, Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, Integrated Department of Immunology, University of Colorado Denver School of Medicine, Aurora, CO 80045-6511. E-mail: james.degregori{at}uchsc.edu

Abbreviations: BM, bone marrow; BMT, bone marrow transplant; BrdU, bromodeoxyuridine; CSF, colony-stimulating factor; IL, interleukin; MMP, matrix metalloproteinase; TAM, tumor associated macrophage; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; WT, wild type

OBJECTIVE— Chronic pancreatitis, characterized by pancreatic exocrine tissue destruction with initial maintenance of islets, eventually leads to insulin-dependent diabetes in most patients. Mice deficient for the transcription factors E2F1 and E2F2 suffer from a chronic pancreatitis-like syndrome and become diabetic. Surprisingly, onset of diabetes can be prevented through bone marrow transplantation. The goal of the described studies was to determine the hematopoietic cell type responsible for maintaining islets and the associated mechanism of this protection.

RESEARCH DESIGN AND METHODS— Mouse models of acute and chronic pancreatitis, together with mice genetically deficient for macrophage production, were used to determine roles for macrophages in islet angiogenesis and maintenance.

RESULTS— We demonstrate that macrophages are essential for preventing endocrine cell loss and diabetes. Macrophages expressing matrix metalloproteinase-9 migrate to the deteriorating pancreas. E2f1/E2f2 mutant mice transplanted with wild-type, but not macrophage-deficient colony stimulating factor 1 receptor mutant (Csf1r^–/–), bone marrow exhibit increased angiogenesis and proliferation within islets, coinciding with increased islet mass. A similar macrophage dependency for islet and islet vasculature maintenance is observed during caerulein-induced pancreatitis.

CONCLUSIONS— These findings demonstrate that macrophages promote islet angiogenesis and protect against islet loss during exocrine degeneration, could explain why most patients with chronic pancreatitis develop diabetes, and suggest an avenue for preventing pancreatitis-associated diabetes.

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