RT Journal Article
T1 Differentiation of Mouse Embryonic Stem Cells toward Functional Pancreatic ß-Cell Surrogates through Epigenetic Regulation of Pdx1 by Nitric Oxide
A1 Bedoya, Francisco J.
A1 Tejedo, JR
A1 Martin, Franz
A1 Salguero-Aranda, Carmen
A1 Tapia-Limonchi, Rafael
A1 Hitos, Ana Belen
A1 Diez, Irene
A1 Hmadcha, Abdelkrim
A1 Fraga, Mario
A1 Soria, Bernat
A1 Cahuana Macedo, Gladys M
K1 Embryonic stem cells (ESCs)
K1 Nitric oxide (NO)
K1 Cell differentiation
K1 Insulin-producing cells
K1 Diabetes
AB Pancreatic and duodenal homeobox 1 (Pdx1) is a transcription factor that regulates the embryonic development of the pancreas and the differentiation toward ß 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 molecule-based protocol succeeds in obtaining cells that express pancreatic ß-cell markers such as PDX1, INS1, GCK, and GLUT2 and respond in vitro to high glucose and KCl
PB SAGE Journals
SN 0963-6897
YR 2016
FD 2016-10
LK http://hdl.handle.net/10433/4132
UL http://hdl.handle.net/10433/4132
LA en
NO Cell Transplantation vol 25 nº 10, p 1879-1892
NO Centro Andaluz de Biología Molecular y Medicina Regenerativa (CABIMER)
DS RIO
RD Apr 23, 2026