title: MANF is indispensable for the proliferation and survival of pancreatic β cells.
abstract: All forms of diabetes mellitus (DM) are characterized by the loss of functional pancreatic β cell mass, leading to insufficient insulin secretion. Thus, identification of novel approaches to protect and restore β cells is essential for the development of DM therapies. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-stress-inducible protein, but its physiological role in mammals has remained obscure. We generated MANF-deficient mice that strikingly develop severe diabetes due to progressive postnatal reduction of β cell mass, caused by decreased proliferation and increased apoptosis. Additionally, we show that lack of MANF in vivo in mouse leads to chronic unfolded protein response (UPR) activation in pancreatic islets. Importantly, MANF protein enhanced β cell proliferation in vitro and overexpression of MANF in the pancreas of diabetic mice enhanced β cell regeneration. We demonstrate that MANF specifically promotes β cell proliferation and survival, thereby constituting a therapeutic candidate for β cell protection and regeneration.
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland. Electronic address: maria.lindahl@helsinki.fi.
authors.forename: Maria
authors.initials: M
authors.lastname: Lindahl
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Danilova
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Erik
authors.initials: E
authors.lastname: Palm
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Lindholm
authors.affiliation: Neuroscience Center, University of Helsinki, Viikinkaari 4, 00014 Helsinki, Finland.
authors.forename: Vootele
authors.initials: V
authors.lastname: Võikar
authors.affiliation: Research Program for Molecular Neurology and Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Hakonen
authors.affiliation: Research Program for Molecular Neurology and Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Jarkko
authors.initials: J
authors.lastname: Ustinov
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Jaan-Olle
authors.initials: JO
authors.lastname: Andressoo
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.affiliation: Research Program for Molecular Neurology and Biomedicum Stem Cell Center, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, Haartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Timo
authors.initials: T
authors.lastname: Otonkoski
authors.affiliation: Institute of Biomedicine, Anatomy, University of Helsinki, Haartmaninkatu 8, 00014 Helsinki, Finland.
authors.forename: Jari
authors.initials: J
authors.lastname: Rossi
authors.affiliation: Institute of Biotechnology, University of Helsinki, Viikinkaari 9, 00014 Helsinki, Finland.
authors.forename: Mart
authors.initials: M
authors.lastname: Saarma
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D056811:Unfolded Protein Response
chemical_list: C534671:MANF protein, mouse; D009414:Nerve Growth Factors
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