Ascorbic acid promotes cardiomyogenesis through SMAD1 signaling in differentiating mouse embryonic stem cells.

摘要: Numerous groups have documented that Ascorbic Acid (AA) promotes cardiomyocyte differentiation from both mouse and human ESCs iPSCs. AA is now considered indispensable for the routine production of hPSC-cardiomyocytes (CMs) using defined media; however, mechanisms involved with inductive process are poorly understood. Using a genetically modified embryonic stem cell (mESC) line containing dsRED transgene driven by cardiac-restricted portion ncx1 promoter, we show promoted mESCs to CMs in dose- time-dependent manner. Treatment mPSCs did not modulate total SMAD content; phosphorylated/active forms SMAD2 SMAD1/5/8 were significantly elevated. Co-administration SMAD2/3 activator Activin A had no significant effect, but addition nodal co-receptor TDGF1 (Cripto) antagonized AA's cardiomyogenic-promoting ability. could also reverse some inhibitory effects on cardiomyogenesis ALK/SMAD2 inhibition SB431542, TGFβ pathway inhibitor. BMP2 strongly amplified positive cardiomyogenic dose-dependent not, rescue dorsomorphin-mediated ALK/SMAD1 activity. an inducible model system, found SMAD1, SMAD2, was essential promote formation TNNT2+-CMs. These data firmly demonstrate BMP receptor-activated SMADs, preferential necessary stimulated cardiomyogenesis. AA-enhanced thus relies ability ratio signaling among TGFβ-superfamily receptor pathways.