Division of Pediatric Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224.
Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):E1211-20. doi: 10.1073/pnas.1321347111. Epub 2014 Mar 17.
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.
确定调节β细胞复制的信号通路对于β细胞治疗至关重要。在这里，我们表明，在胰腺导管结扎（PDL）后阻断胰腺巨噬细胞浸润可完全抑制β细胞增殖。TGFβ超家族信号抑制剂 SMAD7 在 PDL 后β细胞中显著上调。在β细胞特异性 SMAD7 突变小鼠中，β细胞对 PDL 无反应而不能增殖。SMAD7 在β细胞中的强制表达本身足以促进体内β细胞增殖。M2 巨噬细胞，而不是 M1 巨噬细胞，似乎是 SMAD7 介导的β细胞增殖的诱导剂。M2 巨噬细胞不仅释放 TGFβ1 直接诱导β细胞中 SMAD7 的上调，还释放 EGF 激活 EGF 受体信号，抑制 TGFβ1 激活的 SMAD2 核易位，从而抑制 TGFβ 信号。SMAD7 通过增加细胞周期蛋白 D1 和 D2 并诱导 p27 的核排除来促进β细胞增殖。因此，我们的研究揭示了一种通过细胞外刺激诱导的增强的 SMAD7 活性来潜在增加β细胞质量的分子途径。
