Dataset Information

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

ABSTRACT:

Aims/hypothesis

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.

Methods

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-?H1.

Results

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?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.

SUBMITTER: Hakonen E

PROVIDER: S-EPMC6133171 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

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

Hakonen Elina E Chandra Vikash V Fogarty Christopher L CL Yu Nancy Yiu-Lin NY Ustinov Jarkko J Katayama Shintaro S Galli Emilia E Danilova Tatiana T Lindholm Päivi P Vartiainen Aki A Einarsdottir Elisabet E Krjutškov Kaarel K Kere Juha J Saarma Mart M Lindahl Maria M Otonkoski Timo T

Diabetologia 20180721 10

<h4>Aims/hypothesis</h4>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, app ...[more]

PMID: 30032427

Similar Datasets

Project description:BackgroundExtracellular accumulation of amyloid ?-peptide (A?) is one of pathological hallmarks of Alzheimer's disease (AD) and contributes to the neuronal loss. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-inducible neurotrophic factor. Many groups, including ours, have proved that MANF rescues neuronal loss in several neurological disorders, such as Parkinson's disease and cerebral ischemia. However, whether MANF exerts its protective effect against A? neurotoxicity in AD remains unknown.MethodsIn the present study, the characteristic expressions of MANF in A?1-42-treated neuronal cells as well as in the brains of APP/PS1 transgenic mice were analyzed by immunofluorescence staining, qPCR, and Western blot. The effects of MANF overexpression, MANF knockdown, or recombination human MANF protein (rhMANF) on neuron viability, apoptosis, and the expression of ER stress-related proteins following A?1-42 exposure were also investigated.ResultsThe results showed the increased expressions of MANF, as well as ER stress markers immunoglobulin-binding protein (BiP) and C/EBP homologous protein (CHOP), in the brains of the APP/PS1 transgenic mice and A?1-42-treated neuronal cells. MANF overexpression or rhMANF treatment partially protected against A?1-42-induced neuronal cell death, associated with marked decrease of cleaved caspase-3, whereas MANF knockdown with siRNA aggravated A?1-42 cytotoxicity including caspase-3 activation. Further study demonstrated that the expressions of BiP, ATF6, phosphorylated-IRE1, XBP1s, phosphorylated-eIF2?, ATF4, and CHOP were significantly downregulated by MANF overexpression or rhMANF treatment in neuronal cells following A?1-42 exposure, whereas knockdown of MANF has the opposite effect.ConclusionsThese findings demonstrate that MANF may exert neuroprotective effects against A?-induced neurotoxicity through attenuating ER stress, suggesting that an applicability of MANF as a therapeutic candidate for AD.

Dataset Information

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

Aims/hypothesis

Methods

Results

Publications

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

Similar Datasets

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