Reg3α Overexpression Protects Pancreatic Beta Cells From Cytokine-induced Damage And Improves Islet Transplant Outcome

The process of islet transplantation for treating type 1 diabetes has been limited by the high level of graft failure that may be overcome by locally delivering trophic factors to enhance engraftment. Regenerating islet-derived protein 3 alpha (Reg3a) is a pancreatic secretory protein, which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3a could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3a or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3a production exhibited significantly lower blood glucose levels (9.057 ± 0.59 mmol/1 vs 13.48 ± 0.35 mmol/1, P<.05) and improved glucose-stimulated insulin secretion (1.80 ± 0.17 ng/ml vs 1.16 ± 0.16 ng/ml, P<.05) compared with control group. The decline of apoptotic events (0.57% ±0.15% vs 1.06% ± 0.07%, P <.05) and increased beta cell proliferation (0.70% ± 0.10% vs 0.36% ± 0.14%, P <.05) were confirmed in islet grafts overexpressing Reg3a by morphometric analysis. Further experiments showed that Reg3a production dramatically protect cultured islets and pancreatic beta cells from cytokine-induced apoptosis and -injured glucose-stimulated insulin secretion. Moreover, exposure to cytokines led to an increase in the activation of p38 MAPKs in beta cells, which was reversed by Reg3a overexpression in contrast to control group. These results strongly suggest that Reg3a could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.