Pdx1 Maintains β Cell Identity and Function by Repressing an α Cell Program

Gao, Tao; McKenna, Brian D.; Li, Changhong; Reichert, Maximilian; Nguyen, James; Singh, Tarjinder; Yang, Chenghua; Pannikar, Archana; Doliba, Nicolai M.; Zhang, Tingting; Stoffers, Doris A.; Edlund, Helena; Matschinsky, Franz; Stein, Roland; Stanger, Ben Z.

doi:10.1016/j.cmet.2013.12.002

Cited by 354 publications

(340 citation statements)

References 39 publications

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“…Dedifferentiation of beta cells is a topic of current islet research, and important contributions have been published by several groups in recent years during the course of this study [8,13,14]. In addition, Hang et al showed that MafA is required in adult beta cells for the maintenance of their phenotype but not for their initial differentiation [31], which is consistent with our results.…”

Section: Discussionsupporting

confidence: 81%

“…This result is supported by the increased expression of factors such as MafB that are transiently expressed in endocrine progenitors of the embryonic pancreas. MafB is also upregulated in the dedifferentiated beta cells of beta cellspecific Foxo1 KO mice with metabolic stress and Pdx1 KO mice [8,14], and induces genome-wide changes in DNA methylation [39]. Thus, MafB may be responsible for the upregulation of molecules including those beta cell disallowed genes in dedifferentiated beta cells by inducing epigenetic changes, which have been shown to regulate Slc16a1 expression [35,40].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, recent studies have identified factors critical for the maintenance of a mature beta cell phenotype. The loss of a mature beta cell phenotype results in the dedifferentiation of beta cells [8,[12][13][14][15][16], which may be implicated in compromised beta cell function in diabetes, although the molecular mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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

2014

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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.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2014

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“…Several recent reports demonstrate that forced expression of lineageinappropriate transcription factors causes islet cells to switch identity (Collombat et al, 2007;Collombat et al, 2009;Gao et al, 2014;Papizan et al, 2011;, which has been attributed to the similar chromatin states of alpha and beta cells (Bramswig et al, 2013). This establishes that beta cells can arise from nonbeta endocrine cells in the islet via direct transdifferentiation.…”

Section: Introductionmentioning

confidence: 92%

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

et al. 2017

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“…These factors favour low grade tissue inflammation and insulin resistance [10][11][12][13][14]. The ultimate cause of hyperglycaemia, however, is insufficient insulin secretion as a consequence of impaired glucoseinduced insulin secretion (GIIS), dedifferentiated beta cells or beta cell apoptosis [15][16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

et al. 2017

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Aims/hypothesis Obesity-linked ectopic fat accumulation is associated with the development of type 2 diabetes. Whether pancreatic and liver steatosis impairs insulin secretion is controversial. We examined the crosstalk of human pancreatic fat cells with islets and the role of diabetogenic factors, i.e. palmitate and fetuin-A, a hepatokine released from fatty liver. Methods Human pancreatic resections were immunohistochemically stained for insulin, glucagon, somatostatin and the macrophage/monocyte marker CD68. Pancreatic adipocytes were identified by Oil Red O and adiponectin staining.Primary pancreatic pre-adipocytes and differentiated adipocytes were co-cultured with human islets isolated from organ donors and the metabolic crosstalk between fatty liver and fatty pancreas was mimicked by the addition of palmitate and fetuin-A. Insulin secretion was evaluated by ELISA and RIA. Cytokine expression and secretion were assessed by RT-PCR and multiplex assay, respectively. Subcellular distribution of proteins was examined by confocal microscopy and protein phosphorylation by western blotting. Results In human pancreatic parenchyma, highly differentiated adipocytes were detected in the proximity of islets with normal architecture and hormone distribution. Infiltration of adipocytes was associated with an increased number of CD68-positive cells within islets. In isolated primary pancreatic preadipocytes and differentiated adipocytes, palmitate and fetuin-A induced IL6, CXCL8 and CCL2 mRNA expression. Cytokine production was toll-like receptor 4 (TLR4)-dependent and further accentuated in pre-adipocytes when cocultured with islets. In islets, IL6 and CXCL8 mRNA levels were also increased by fetuin-A and palmitate. Only in macrophages within the isolated islets, palmitate and fetuin-A stimulated the production of the cytotoxic cytokine IL-1β. Palmitate, but not fetuin-A, exerted pro-apoptotic effects in islet cells. Instead, fetuin-A impaired glucose-induced insulin secretion in a TLR4-independent, but c-Jun N-terminal kinase-and Ca 2+ -dependent, manner. Conclusions/interpretation These results provide the first evidence that fetuin-A-mediated metabolic crosstalk of fatty liver with islets may contribute to obesity-linked glucose blindness of beta cells, while fatty pancreas may exacerbate local inflammation.

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Pdx1 Maintains β Cell Identity and Function by Repressing an α Cell Program

Cited by 354 publications

References 39 publications

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

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

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

Metabolic crosstalk between fatty pancreas and fatty liver: effects on local inflammation and insulin secretion

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