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

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Hakonen , E , Chandra , V , Fogarty , C L , Yu , N Y-L , Ustinov , J , Katayama , S , Galli , E , Danilova , T , Lindholm , P , Vartiainen , A , Einarsdottir , E , Krjutskov , K , Kere , J , Saarma , M , Lindahl , M & Otonkoski , T 2018 , ' MANF protects human pancreatic beta cells against stress-induced cell death ' , Diabetologia , vol. 61 , no. 10 , pp. 2202-2214 .

Title: MANF protects human pancreatic beta cells against stress-induced cell death
Author: Hakonen, Elina; Chandra, Vikash; Fogarty, Christopher L.; Yu, Nancy Yiu-Lin; Ustinov, Jarkko; Katayama, Shintaro; Galli, Emilia; Danilova, Tatiana; Lindholm, Paivi; Vartiainen, Aki; Einarsdottir, Elisabet; Krjutskov, Kaarel; Kere, Juha; Saarma, Mart; Lindahl, Maria; Otonkoski, Timo
Contributor organization: Research Programs Unit
Research Programme for Molecular Neurology
Children's Hospital
Institute of Biotechnology
Juha Kere / Principal Investigator
Mart Saarma / Principal Investigator
Timo Pyry Juhani Otonkoski / Principal Investigator
Lastentautien yksikkö
HUS Children and Adolescents
HUS Internal Medicine and Rehabilitation
HUS Abdominal Center
Date: 2018-10
Language: eng
Number of pages: 13
Belongs to series: Diabetologia
ISSN: 0012-186X
Abstract: There 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. Primary 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-beta H1. There 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-beta H1 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-kappa B signalling pathway and amelioration of ER stress. MANF also increased the proliferation of primary human beta cells twofold when TGF-beta signalling was inhibited (p <0.01). Our 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.
Subject: Beta cell proliferation
Beta cell protection
Endoplasmic reticulum stress
Mesencephalic astrocyte-derived neurotrophic factor (MANF)
NF-kappa B
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: other
Usage restriction: openAccess
Self-archived version: publishedVersion

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