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Title

Differentiation of mouse embryonic stem cells toward functional pancreatic β-cell surrogates through epigenetic regulation of Pdx1 by nitric oxide

AuthorsSalguero-Aranda, Carmen ; Tapia-Limonchi, Rafael ; Cahuana, Gladys M. ; Hitos, Ana B. ; Díaz, Irene ; Hmadcha, Abdelkrim ; Fraga, Mario F.; Martín, Franz ; Soria Escoms, Bernat ; Tejedo Huamán, Juan Rigoberto ; Bedoya Bergua, Francisco Javier
KeywordsDiabetes
Insulin-producing cells
Cell differentiation
Nitric oxide (NO)
Embryonic stem cells (ESCs)
Issue Date2016
PublisherCognizant Communication Corporation
CitationCell Transplantation 25(10): 1879-1892 (2016)
AbstractPancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic development of the pancreas and the differentiation toward β cells. Previously, we have shown that exposure of mouse embryonic stem cells (mESCs) to high concentrations of diethylenetriamine nitric oxide adduct (DETA-NO) triggers differentiation events and promotes the expression of Pdx1. Here we report evidence that Pdx1 expression is associated with release of polycomb repressive complex 2 (PRC2) and P300 from its promoter region. These events are accompanied by epigenetic changes in bivalent markers of histones trimethylated histone H3 lysine 27 (H3K27me3) and H3K4me3, site-specific changes in DNA methylation, and no change in H3 acetylation. On the basis of these findings, we developed a protocol to differentiate mESCs toward insulin-producing cells consisting of sequential exposure to DETA-NO, valproic acid, and P300 inhibitor (C646) to enhance Pdx1 expression and a final maturation step of culture in suspension to form cell aggregates. This small moleculebased protocol succeeds in obtaining cells that express pancreatic b-cell markers such as PDX1, INS1, GCK, and GLUT2 and respond in vitro to high glucose and KCl.
Publisher version (URL)https://doi.org/10.3727/096368916X691178
URIhttp://hdl.handle.net/10261/165166
Identifiersdoi: 10.3727/096368916X691178
issn: 0963-6897
e-issn: 1555-3892
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