Survivin Is Required for Beta-Cell Mass Expansion in the Pancreatic Duct-Ligated Mouse Model

Xiaohong Wu,Minna Woo,Jiayu Zhu,Hitoshi Okada,Qinfeng Zhang,Rennian Wang,Kuangfeng Xu,Xiaojing Wang

doi:10.1371/journal.pone.0041976

Abstract

Aims/HypothesisPancreatic beta-cell mass expands through adulthood under certain conditions. The related molecular mechanisms are elusive. This study was designed to determine whether surviving (also known as Birc5), which is transiently expressed perinatally in islets, was required for beta-cell mass expansion in the pancreatic duct-ligated mouse model.MethodsMice with beta cell–specific deletion of survivin (RIPCre+survivinfl/fl) and their control littermates (RIPCre+survivin+/+) were examined to determine the essential role of survivin in partial pancreatic duct ligation (PDL)-induced beta-cell proliferation, function and survival.ResultsResurgence of survivin expression occurred as early as day 3 post-PDL. By day 7 post-PDL, control mice showed significant expansion of beta-cell mass and increase in beta-cell proliferation and islet number in the ligated tail of the pancreas. However, mice deficient in beta-cell survivin showed a defect in beta-cell mass expansion and proliferation with a marked attenuation in the increase of total islet number, largely due to an impairment in the increase in number of larger islets while sparing the increase in number of small islets in the ligated tail of pancreas, resulting in insufficient insulin secretion and glucose intolerance. Importantly however, beta cell neogenesis and apoptosis were not affected by the absence of survivin in beta cells after PDL.Conclusions/InterpretationOur results indicate that survivin is essential for beta-cell mass expansion after PDL. Survivin appears to exhibit a preferential requirement for proliferation of preexisting beta cells.

Highlights

As type 1 and type 2 diabetes result from absolute or relative deficiencies in beta-cell mass, respectively, understanding how beta-cell mass is regulated can lead to new therapeutic options
We show that survivin, which was absent in adult pancreas was induced within beta cells in the ligated tail of pancreas following pancreatic duct ligation (PDL) during the period of peak regeneration, and that expansion of beta-cell mass following PDL was impaired in rat insulin promoter (RIP)-Cre+survivinfl/fl mice due to reduced beta-cell proliferation
PDL Induces Survivin Expression and Promotes Beta-cell Mass Expansion In C57BL/6 mice, the duct leading to the pancreatic tail was closed while the organ’s head located adjacent to the stomach and duodenum remained unaffected

Summary

Introduction

As type 1 and type 2 diabetes result from absolute or relative deficiencies in beta-cell mass, respectively, understanding how beta-cell mass is regulated can lead to new therapeutic options. Genetic lineage tracing studies provide evidence that pre-existing beta cells, rather than stem/progenitor cells, are the major source of new beta cells in adult mice both under normal physiological conditions and after 50% to 70% pancreatectomy [3,4]. A recent study [5] in mice has shown that new beta cells are generated from facultative adult progenitor cells (neogenesis) in response to pancreatic injury, in a manner reminiscent of embryonic endocrine cell differentiation. Tissue-specific knockout of survivin in thymocytes, neuronal precursors, endothelial cells or haematopoietic progenitors resulted in impaired cell proliferation, cell cycle arrest, apoptosis, or mitotic spindle formation, illustrating a complex physiological role for survivin in normal cell development [12,13,14,15]

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Results

Conclusion