RT Journal Article
T1 Differentiation of Mouse Embryonic Stem Cells Toward Functional Pancreatic beta-Cell Surrogates Through Epigenetic Regulation of Pdx1 by Nitric Oxide
A1 Salguero-Aranda, Carmen
A1 Tapia-Limonchi, Rafael
A1 Margot Cahuana, Gladys
A1 Belen Hitos, Ana
A1 Diaz, Irene
A1 Hmadcha, Abdelkrim
A1 Fraga, Mario
A1 Martin, Franz
A1 Soria, Bernat
A1 Rigoberto Tejedo, Juan
A1 Javier Bedoya, Francisco
K1 Embryonic stem cells (ESCs)
K1 Nitric oxide (NO)
K1 Cell differentiation
K1 Insulin-producing cells
K1 Diabetes
K1 Insulin-producing cells
K1 In-vitro
K1 Developmental regulators
K1 Gene-expression
K1 Es cells
K1 Polycomb
K1 Repression
K1 Jarid2
K1 P300
K1 Prc2
AB Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic development of the pancreas and the differentiation toward beta 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 Pdxl. Here we report evidence that Pdxl 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 Pdxl expression and a final maturation step of culture in suspension to form cell aggregates. This small molecule based protocol succeeds in obtaining cells that express pancreatic beta-cell markers such as PDX1, INS1, GCK, and GLUT2 and respond in vitro to high glucose and KCl.
PB Cognizant communication corp
SN 0963-6897
YR 2016
FD 2016-01-01
LK http://hdl.handle.net/10668/19335
UL http://hdl.handle.net/10668/19335
LA en
DS RISalud
RD Apr 11, 2025