MANF Is Required for the Postnatal Expansion and Maintenance of Pancreatic β-Cell Mass in Mice

Abstract

Global lack of mesencephalic astrocyte-derived neurotropic factor (MANF) leads to progressive postnatal loss of b-cell mass and insulin-dependent diabetes in mice. Similar to Manf 2/2 mice, embryonic ablation of MANF specifically from the pancreas results in diabetes. In this study, we assessed the importance of MANF for the postnatal expansion of pancreatic b-cell mass and for adult b-cell maintenance in mice. Detailed analysis of Pdx-1Cre +/2 ::Manf fl/fl mice revealed mosaic MANF expression in postnatal pancreata and a significant correlation between the number of MANF-positive b-cells and b-cell mass in individual mice. In vitro, recombinant MANF induced b-cell proliferation in islets from aged mice and protected from hyperglycemia-induced endoplasmic reticulum (ER) stress. Consequently, excision of MANF from b-cells of adult MIP-1Cre ERT ::Manf fl/fl mice resulted in reduced b-cell mass and diabetes caused largely by b-cell ER stress and apoptosis, possibly accompanied by b-cell dedifferentiation and reduced rates of b-cell proliferation. Thus, MANF expression in adult mouse b-cells is needed for their maintenance in vivo. We also revealed a mechanistic link between ER stress and inflammatory signaling pathways leading to b-cell death in the absence of MANF. Hence, MANF might be a potential target for regenerative therapy in diabetes.

Mesencephalic Astrocyte‐Derived Neurotrophic Factor Inhibits Liver Cancer Through Small Ubiquitin‐Related Modifier (SUMO)ylation‐Related Suppression of NF‐κB/Snail Signaling Pathway and Epithelial‐Mesenchymal Transition

“…We also have demonstrated that the ER stress inducer, tunicamycin, up‐regulates MANF expression in neurons and recombinant human MANF promotes the proliferation of neurons and prevents neurons from cerebral ischemia‐induced apoptosis . Meanwhile, MANF promotes the survival and proliferation of pancreatic β cells . Furthermore, MANF as an immune modulator mediates tissue repair in the mammalian retina and maintains liver metabolic homeostasis .…”

“…(8,9) Meanwhile, MANF promotes the survival and proliferation of pancreatic β cells. (10,11) Furthermore, MANF as an immune modulator mediates tissue repair in the mammalian retina and maintains liver metabolic homeostasis. (15,31) Additionally, MANF plays key roles in facilitating the survival of cardiac cells from ischemic injury, modulating myocardial hypertrophy and heart failure as well.…”

“…Recombinant human MANF promotes neuron proliferation and prevents neurons from apoptosis . ER stress‐related proteins are up‐regulated in pancreatic cell‐specific MANF deficiency mice, and recombinant MANF enhances pancreatic β cell proliferation in vivo and in vitro . Recombinant MANF protects mice from heart tissue damage in a mice myocardial infarction model .…”

“…(8,9) ER stress-related proteins are up-regulated in pancreatic cell-specific MANF deficiency mice, and recombinant MANF enhances pancreatic β cell proliferation in vivo and in vitro. (10,11) Recombinant MANF protects mice from heart tissue damage in a mice myocardial infarction model. (12) Meanwhile, our studies have indicated that inflammation triggers ER stress and promotes MANF nuclear translocation, which facilitates the interaction of MANF and nuclear factor kappa light chain enhancer of activated B cells (NF-κB) p65 and inhibits the transcriptional activity of NF-κB.…”

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

“…In nematodes, a mutation in the Manf homologue was suggested to result in the gradual degeneration of dopamine neurons (Richman et al, 2018), but a recent study implicated that MANF-depleted nematodes do not after all display any dopamine phenotype (Hartman et al, 2019). We have shown that conventional MANF knock-out (KO) mice and pancreas-specific conditional KO mice develop insulin-dependent diabetes due to prolonged ER stress in pancreatic b cells, leading to loss of the b cell mass and premature death (Lindahl et al, 2014;Danilova et al, 2019a). In MANF KO mice, it was also demonstrated that MANF regulates cortical development and migration of neuronal progenitor cells (Tseng et al, 2017).…”