Suberoylanilide hydroxamic acid promotes cardiomyocyte differentiation of rat mesenchymal stem cells.
This study was to investigate the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on cardiomyocyte differentiation of bone marrow mesenchymal stem cells (MSCs) in vitro. Rat MSCs were isolated and induced to differentiate into cardiomyocyte with SAHA or 5-azacytidine (5-aza, a DNA methylation inhibitor) or their combination. Following 7 days of SAHA treatment, the transcriptional expression of the cardiomyocyte-specific genes GATA4, NKx2.5, and Mef2c was dose-dependently increased in the cells with up to 15-fold increase in their mRNA levels over baseline. However, the mRNA levels of these genes were only increased by 2-4 fold in 5-aza-treated cells. After 4 weeks of induction with SAHA, cTnT protein content was substantially increased dose-dependently by up to 8-fold in the cells over the baseline. In contrast, only minimal cTnT protein was found in 5-aza-treated cells. When MSCs were treated with both SAHA and 5-aza, the mRNA levels of GATA4, NKx2.5, and Mef2c and cTnT protein content were the same as those in the cells treated with SAHA alone. These results indicate that SAHA effectively promotes cardiomyocyte differentiation of rat MSCs in vitro. SAHA was a much more potent inducer for cardiac differentiation of MSCs then 5-aza. Our data also indicate that no synergistic or antagonistic effect between SAHA and 5-aza on cardiomyocyte differentiation of MSCs is present, and histone acetylation, not DNA demethylation, may be the dominant mechanism that determines the cardiac differentiation of rat MSCs.
Feng
Chuan
C
Department of Cardiology, Children's Hospital of Chongqing Medical University, People's Republic of China.
Zhu
Jing
J
Zhao
Lili
L
Lu
Tiewei
T
Zhang
Wen
W
Liu
Zhenguo
Z
Tian
Jie
J
D000818:Animals; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects*; D050991:GATA4 Transcription Factor / Q000235:genetics; D056572:Histone Deacetylase Inhibitors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D006877:Hydroxamic Acids / Q000494:pharmacology*; D064326:MEF2 Transcription Factors; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000187:drug effects; D018006:Myogenic Regulatory Factors / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D000077337:Vorinostat
D050991:GATA4 Transcription Factor; D056572:Histone Deacetylase Inhibitors; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D006877:Hydroxamic Acids; D064326:MEF2 Transcription Factors; C578042:MEF2C protein, rat; D018006:Myogenic Regulatory Factors; C524161:Nkx2-5 protein, rat; D012333:RNA, Messenger; D014157:Transcription Factors; D000077337:Vorinostat