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M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2014 Apr 01; Vol. 111 (13), pp. E1211-20. Date of Electronic Publication: 2014 Mar 17. - Publication Year :
- 2014
-
Abstract
- Determination of signaling pathways that regulate beta-cell replication is critical for beta-cell therapy. Here, we show that blocking pancreatic macrophage infiltration after pancreatic duct ligation (PDL) completely inhibits beta-cell proliferation. The TGFβ superfamily signaling inhibitor SMAD7 was significantly up-regulated in beta cells after PDL. Beta cells failed to proliferate in response to PDL in beta-cell-specific SMAD7 mutant mice. Forced expression of SMAD7 in beta cells by itself was sufficient to promote beta-cell proliferation in vivo. M2, rather than M1 macrophages, seem to be the inducers of SMAD7-mediated beta-cell proliferation. M2 macrophages not only release TGFβ1 to directly induce up-regulation of SMAD7 in beta cells but also release EGF to activate EGF receptor signaling that inhibits TGFβ1-activated SMAD2 nuclear translocation, resulting in TGFβ signaling inhibition. SMAD7 promotes beta-cell proliferation by increasing CyclinD1 and CyclinD2, and by inducing nuclear exclusion of p27. Our study thus reveals a molecular pathway to potentially increase beta-cell mass through enhanced SMAD7 activity induced by extracellular stimuli.
- Subjects :
- Animals
Cell Movement
Cell Nucleus metabolism
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p27 metabolism
Disease Models, Animal
ErbB Receptors metabolism
Inflammation metabolism
Inflammation pathology
Ligation
Mice
Mice, Inbred C57BL
Models, Biological
Signal Transduction
Transforming Growth Factor beta metabolism
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells pathology
Macrophages metabolism
Smad7 Protein metabolism
Up-Regulation
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 111
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 24639504
- Full Text :
- https://doi.org/10.1073/pnas.1321347111