MafA is critical for maintenance of the mature beta cell phenotype in mice

Abstract

Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

Demethylation of the MafB promoter in a compromised β-cell model

“…adult mature b-cells at least in mice (Nishimura et al 2006, Artner et al 2010. Using MafB reporter mice (Moriguchi et al 2006), we previously reported that the MafB promoter was upregulated in b-cells of the diabetic model mice (Nishimura et al 2015). The present study suggests the possibility that MafB upregulation in compromised b-cells in vivo may also be at least in part due to lower methylation status of the MafB promoter.…”

“…1C). The increased transcriptional activity of MafB is also similar to the b-cells in diabetic model mice (Nishimura et al 2015).…”

“…Upregulation of genes that are normally repressed in mature b-cells, including the transcription factors transiently expressed in endocrine progenitors of the embryonic pancreas, was identified in these compromised b-cells as a hallmark of dedifferentiation (Thorrez et al 2011, Nishimura et al 2015 and may result in the impaired hallmark of dedifferentiation (Talchai et al 2012, Gao et al 2014, Nishimura et al 2015. We also reported that the promoter activity of MafB is increased in b-cells of diabetes model mice such as db/db mice and mice that have received low-dose streptozotocin (Nishimura et al 2015). Because MafB induces genome-wide changes in DNA methylation (Vicente-Dueñas et al 2012), we speculated the MafB may be a key molecule for the upregulation of b-cell disallowed genes in dedifferentiated b-cells.…”

β Cells led astray by transcription factors and the company they keep

“…This knowledge will pave the way toward the development of new therapeutic approaches to prevent or reverse the progressive loss of functional β cell mass in patients with type 2 diabetes (T2D). In this issue, studies from the laboratories of Sussel (8), Dor (9), and Stoffers (10) collectively reinforce the consensus view that the same TFs that direct β cell specification are also required to maintain the gene activation and repression programs that undergird mature β cell identity (11)(12)(13)(14)(15). This unexpected property of the murine and human β cell transcriptional network provides an additional explanation for the intrinsic fragility, sensitivity (16), and propensity of these cells to adopt alternate endocrine cell fates as a consequence of various stressors (2,4,17).…”

Pancreatic β-cell failure in type 2 diabetes mellitus

“…[3,4] It is noted that MafA and PDX-1 are very important transcription factors for insulin gene in mature β-cells. [3][4][5][6][7][8][9][10][11][12] Furthermore, antioxidant treatment protects β-cells from glucose toxicity in various diabetic model animals; β-cell mass and insulin content are preserved by antioxidant treatment. [13,14] In addition, expression levels of MafA and PDX-1 are decreased by oxidative stress and those expression levels are preserved by antioxidant treatment.…”