title: M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7.
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.
authors.affiliation: Division of Pediatric Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
authors.forename: Xiangwei
authors.initials: X
authors.lastname: Xiao
authors.forename: Iljana
authors.initials: I
authors.lastname: Gaffar
authors.forename: Ping
authors.initials: P
authors.lastname: Guo
authors.forename: John
authors.initials: J
authors.lastname: Wiersch
authors.forename: Shane
authors.initials: S
authors.lastname: Fischbach
authors.forename: Lauren
authors.initials: L
authors.lastname: Peirish
authors.forename: Zewen
authors.initials: Z
authors.lastname: Song
authors.forename: Yousef
authors.initials: Y
authors.lastname: El-Gohary
authors.forename: Krishna
authors.initials: K
authors.lastname: Prasadan
authors.forename: Chiyo
authors.initials: C
authors.lastname: Shiota
authors.forename: George K
authors.initials: GK
authors.lastname: Gittes
mesh_terms: D000818:Animals; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D008026:Ligation; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D066246:ErbB Receptors
keywords: TGFβ superfamily signaling pathway; epidermal growth factor receptor signaling pathway