title: Reg3α Overexpression Protects Pancreatic β Cells from Cytokine-Induced Damage and Improves Islet Transplant Outcome.
abstract: 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 3α (Reg3α) is a pancreatic secretory protein which functions as an antimicrobial peptide in control of inflammation and cell proliferation. In this study, to investigate whether Reg3α could improve islet engraftment, a marginal mass of syngeneic islets pretransduced with adenoviruses expressing Reg3α or control EGFP were transplanted under the renal capsule of streptozotocin-induced diabetic mice. Mice receiving islets with elevated Reg3α 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 β-cell proliferation (0.70% ± 0.10% versus 0.36% ± 0.14%,P< 0.05) were confirmed in islet grafts overexpressing Reg3α by morphometric analysis. Further experiments showed that Reg3α production dramatically protected cultured islets and pancreatic β 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 β cells, which was reversed by Reg3α overexpression in contrast to control group. These results strongly suggest that Reg3α could enhance islet engraftments through its cytoprotective effect and advance the therapeutic efficacy of islet transplantation.
authors.affiliation: Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.|Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Yuemei
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Xuanyu
authors.initials: X
authors.lastname: Shuai
authors.affiliation: Department of Pathology, Nanjing Medical University, Nanjing, China.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Shi
authors.affiliation: Center of Cellular Therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Nanjing First Hospital, Nanjing, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Center of Metabolic Research, Nanjing Medical University, Nanjing, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center of Metabolic Research, Nanjing Medical University, Nanjing, China.
authors.forename: Xiubin
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Nanjing Medical University, Nanjing, China.|Center of Cellular Therapy, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.|Center of Metabolic Research, Nanjing Medical University, Nanjing, China.
authors.forename: Dongming
authors.initials: D
authors.lastname: Su
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