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

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• 作者：Wataru Nishimura (1) (2)
  Satoru Takahashi (3)
  Kazuki Yasuda (1)
  
  1. Department of Metabolic Disorders ; Diabetes Research Center ; Research Institute ; National Center for Global Health and Medicine ; 1-21-1 Toyama ; Shinjuku-ku ; Tokyo ; 162-8655 ; Japan
  2. Division of Anatomy ; Bio-imaging and Neuro-cell Science ; Jichi Medical University ; Shimotsuke ; Tochigi ; Japan
  3. Department of Anatomy and Embryology ; University of Tsukuba ; Tsukuba ; Ibaraki ; Japan
  
• 关键词：Beta cells ; Cell plasticity ; Dedifferentiation ; Lineage tracing ; MafA
• 刊名：Diabetologia
• 出版年：2015
• 出版时间：March 2015
• 年：2015
• 卷：58
• 期：3
• 页码：566-574
• 全文大小：1,747 KB
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• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Internal Medicine
  Metabolic Diseases
  Human Physiology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0428

文摘

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.