MANF protects human pancreatic beta cells against stress-induced cell death

Elina Hakonen,Maria Lindahl,Shintaro Katayama,Kaarel Krjutškov,Elisabet Einarsdottir,Tatiana Danilova,Emilia Galli,Nancy Yiu-Lin Yu,Christopher L Fogarty,Vikash Chandra,Päivi Lindholm,Juha Kere,Timo Otonkoski,Aki Vartiainen,Mart Saarma,Jarkko Ustinov

doi:10.1007/s00125-018-4687-y

Abstract

Aims/hypothesisThere is a great need to identify factors that could protect pancreatic beta cells against apoptosis or stimulate their replication and thus prevent or reverse the development of diabetes. One potential candidate is mesencephalic astrocyte-derived neurotrophic factor (MANF), an endoplasmic reticulum (ER) stress inducible protein. Manf knockout mice used as a model of diabetes develop the condition because of increased apoptosis and reduced proliferation of beta cells, apparently related to ER stress. Given this novel association between MANF and beta cell death, we studied the potential of MANF to protect human beta cells against experimentally induced ER stress.MethodsPrimary human islets were challenged with proinflammatory cytokines, with or without MANF. Cell viability was analysed and global transcriptomic analysis performed. Results were further validated using the human beta cell line EndoC-βH1.ResultsThere was increased expression and secretion of MANF in human beta cells in response to cytokines. Addition of recombinant human MANF reduced cytokine-induced cell death by 38% in human islets (p < 0.05). MANF knockdown in EndoC-βH1 cells led to increased ER stress after cytokine challenge. Mechanistic studies showed that the protective effect of MANF was associated with repression of the NF-κB signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-β signalling was inhibited (p < 0.01).Conclusions/interpretationOur studies show that exogenous MANF protein can provide protection to human beta cells against death induced by inflammatory stress. The antiapoptotic and mitogenic properties of MANF make it a potential therapeutic agent for beta cell protection.

Highlights

Insulin-secreting pancreatic beta cells are long-lived and vulnerable to various metabolic and cytotoxic assaults
We previously reported that Manf knockout mice used as a model of diabetes develop the condition owing to a progressive postnatal reduction of beta cell mass caused by reduced beta cell proliferation and increased beta cell apoptosis [11]
We previously showed that global knockout of Manf in mice results in early-onset diabetes owing to increased beta cell apoptosis and reduced proliferation via persistent activated endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) pathways [11]

Summary

Introduction

Insulin-secreting pancreatic beta cells are long-lived and vulnerable to various metabolic and cytotoxic assaults. In the case of type 1 diabetes, beta cells are selectively targeted by autoimmune attack and die mostly through apoptosis Proinflammatory cytokines such as IL-1β, IFN-γ, IL-17 and TNF-α have been shown to be crucial players in this process [1, 2]. We previously reported that Manf knockout mice used as a model of diabetes develop the condition owing to a progressive postnatal reduction of beta cell mass caused by reduced beta cell proliferation and increased beta cell apoptosis [11]. Both in vitro and in vivo, MANF was identified as a mitogen for mouse beta cells. A recent study by Cunha et al [12] showed that thrombospondin 1 protects rat, mouse and human beta cells against cytokine-induced cell death by maintaining the expression of MANF

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Results

Conclusion