Cellular proliferation in mouse and human pancreatic islets is regulated by serpin B13 inhibition and downstream targeting of E-cadherin by cathepsin L
We previously reported that exposure to antibodies neutralising serpin B13, a protease inhibitor expressed in exocrine pancreatic ducts, promotes beta cell proliferation, underscoring the importance of a functional relationship between exocrine and endocrine pancreas. The aim of the present study was to identify the molecular events that link inhibition of serpin B13 to islet cell proliferation.
We used an in vitro culture system consisting of isolated pancreatic islets, an extract of pancreatic ductal epithelium and a monoclonal antibody (mAb) to serpin B13 or IgG isotype control. In vivo studies involved treatment of mice with these mAbs.
The catalytic activity of cathepsin L (CatL), a cysteine protease target of serpin B13, was augmented in the pancreas of mice injected with serpin B13 mAb. Furthermore, the addition of serpin B13 mAb to the islets, together with the pancreatic ductal epithelium lysate, caused CatL-dependent cleavage of E-cadherin and concomitant upregulation of REG genes, ultimately leading to beta cell proliferation. Direct blockade of E-cadherin with mAb also markedly enhanced REG gene induction, while chemical inhibition of β-catenin, a binding target of E-cadherin, prevented the serpin B13 mAb-induced upregulation of REG genes.
Our work implicates the CatL–E-cadherin–REG pathway in the regulation of islet cell proliferation in response to signals generated in exocrine pancreatic tissue and demonstrates that protease activity may promote adaptive changes in the islets.
Microarray data that support the findings of this study have been deposited in Gene Expression Omnibus (GEO) with the accession no. GSE125151.
KeywordsBeta cell proliferation Pancreatic islets Proteases Serpins
Dolichos biflorus agglutinin
Some of the data were presented as an abstract at the ADA 77th Scientific Sessions meeting in 2017.
C-WL designed and performed experiments, analysed the data and helped to write, edit and review the manuscript. YK and T-JS helped to design experiments and interpret results. C-HC was responsible for analysing microarray data. JC designed experiments, interpreted results and wrote the manuscript. All authors participated in drafting the article and gave their final approval. JC is responsible for the integrity of the work as a whole.
This work was supported by the Juvenile Diabetes Research Foundation Grant no.17–2013-428 and the American Diabetes Association Grant no. 1–17-ICTS-083 (awarded to JC).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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