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Presentation

MANF IS ESSENTIAL FOR THE PROLIFERATION AND SURVIVAL OF PANCREATIC Β-CELLS

Time: 10:10 am - 10:35 am Stream: MANF: Wolfram Syndrome, Type-1 Diabetes and Inflammation
All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β-cell mass, leading to insufficient insulin secretion. Thus one of the main strategies in improving current DM therapy is to define and validate novel approaches to protect and restore β-cells.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) was originally identified as a secreted trophic factor for dopaminergic neurons, but has been shown to be an endoplasmic reticulum (ER) stress inducible protein for many types of cells, and a maintenance factor for neurons and cardiac myocytes in vivo. Importantly, ER stress and unfolded protein response (UPR), a cellular defense mechanism to combat ER stress have been found to be involved in the pathogenesis of neurodegenerative diseases and DM.

To elucidate the biological role of MANF, we have developed MANF knockout mice (MANF KO). Strikingly, MANF KO mice display development of insulin-dependent diabetes due to progressive postnatal reduction of β-cell mass, caused by decreased β-cell proliferation and increased β-cell apoptosis. In line with the role of MANF in ER stress in vitro, pancreatic islets of MANF KO mice displayed activation of UPR genes and sustained activation of ER stress marker eIF2α, implicating unresolved ER stress as one possible cause of β-cell failure in these mice. Importantly, recombinant MANF protein enhanced β-cell proliferation in vitro. In multiple low dose streptozotocin (MLD-STZ) induced mouse model of diabetes, we found enhanced β-cell proliferation and decreased β-cell death in regions showing MANF overexpression induced by AAV6-mediated transduction. Our results demonstrate that MANF specifically promotes β-cell proliferation and survival thereby constituting a novel promising therapeutic candidate for β-cell protection and regeneration.

Supported by: Juvenile Diabetes Research Foundation (17-2013-410), Academy of Finland, the Commission of the European Union, Collaborative project MOLPARK, nr 400752, Sigrid Jusélius Foundation nr 4701537.

Maria Lindahl, Ph.D.
Senior researcher, Institute of Biotechnology
University of Helsinki, Finland

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