Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration.
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.


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.
Tessem
Jeffery S
JS
Department of Biochemistry and Molecular Genetics, Program in Molecular Biology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045-6511, USA.
Jensen
Jan N
JN
Pelli
Hanna
H
Dai
Xu-Ming
XM
Zong
Xiao-Hua
XH
Stanley
E Richard
ER
Jensen
Jan
J
DeGregori
James
J
D000818:Animals; D016026:Bone Marrow Transplantation; D003920:Diabetes Mellitus / Q000473:pathology / Q000517:prevention & control*; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics; D050703:E2F2 Transcription Factor / Q000172:deficiency / Q000235:genetics; D007515:Islets of Langerhans / Q000098:blood supply*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics / Q000517:prevention & control; D019283:Pancreatitis, Acute Necrotizing / Q000235:genetics / Q000517:prevention & control; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000517:prevention & control
D050687:E2F1 Transcription Factor; D050703:E2F2 Transcription Factor; C493754:E2f1 protein, mouse; C484940:E2f2 protein, mouse