Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome
Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome
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DOI：
10.2119/molmed.2014.00104
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发表时间：
2014-07-01
影响因子：
5.7
通讯作者：
Su, Dongming
中科院分区：
文献类型：
--
作者：
Ding, Ying;Xu, Yuemei;Su, Dongming
用于治疗1型糖尿病的胰岛移植的过程受到高水平的移植失败的限制。这可以通过局部递送营养因子以增强植入来克服。再生胰岛衍生蛋白3 α（Reg 3 α）是胰腺分泌蛋白，其作为控制炎症和细胞增殖的抗微生物肽起作用。在这项研究中，为了研究Reg 3 α是否可以改善胰岛移植，将用表达Reg 3 α的腺病毒或对照EGFP预转导的同基因胰岛的边缘质量移植到链脲佐菌素诱导的糖尿病小鼠的肾包膜下。接受具有升高的Reg 3 α产生的胰岛的小鼠表现出显著较低的血糖水平（9.057 +/- 0.59 mmol/L vs 13.48 +/- 0.35 mmol/L，P < 0.05），并改善葡萄糖刺激的胰岛素分泌（1.80 +/- 0.17 ng/mL vs 1.16 +/- 0.16 ng/mL，P < 0.05）与对照组相比。通过形态学分析证实了在过度表达Reg 3 α的胰岛移植物中凋亡事件的减少（0.57% +/- 0.15%对1.06% +/-0.07%，P < 0.05）和α细胞增殖的增加（0.70% +/-0.10%对0.36% +/-0.14%，P < 0.05）。进一步的实验表明，Reg 3 α的产生显著地保护培养的胰岛和胰腺α细胞免受奎宁诱导的细胞凋亡和葡萄糖刺激的胰岛素分泌的损害。此外，与对照组相比，暴露于细胞因子导致胰腺β细胞中MAPK的活化，这被Reg 3 α过表达逆转。这些结果有力地表明，Reg 3 α可以通过其细胞保护作用增强胰岛植入，并提高胰岛移植的治疗效果。
The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure. This may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3 alpha (Reg3 alpha) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3 alpha could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3 alpha or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3 alpha production exhibited significantly lower blood glucose levels (9.057 +/- 0.59 mmol/L versus 13.48 +/- 0.35 mmol/L, P < 0.05) and improved glucose-stimulated insulin secretion (1.80 +/- 0.17 ng/mL versus 1.16 +/- 0.16 ng/mL, P < 0.05) compared with the control group. The decline of apoptotic events (0.57% +/- 0.15% versus 1.06% +/- 0.07%, P < 0.05) and increased alpha-cell proliferation (0.70% +/- 0.10% versus 0.36% +/- 0.14%, P < 0.05) were confirmed in islet grafts overexpressing Reg3 alpha by morphometric analysis. Further experiments showed that Reg3 alpha production dramatically protected cultured islets and pancreatic alpha cells from cytokine-induced apoptosis and the impairment of glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to the activation of MAPKs in pancreatic beta cells, which was reversed by Reg3 alpha overexpression in contrast to control group. These results strongly suggest that Reg3 alpha could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.