title: 5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase.
abstract: 5-Azacytidine (5-Aza) induces differentiation of mesenchymal stem cells (MSCs) into cardiomyocytes. However, the underlying mechanisms are not well understood. Our previous work showed that 5-Aza induces human bone marrow-derived MSCs to differentiate into cardiomyocytes. Here, we demonstrated that 5-Aza induced cardiac differentiation of human umbilical cord-derived MSCs (hucMSCs) and explored the potential signaling pathway. Our results showed that hucMSCs had cardiomyocyte phenotypes after 5-Aza treatment. In addition, myogenic cells differentiated from hucMSCs were positive for mRNA and protein of desmin, β-myosin heavy chain, cardiac troponin T, A-type natriuretic peptide, and Nkx2.5. Human diploid lung fibroblasts treated with 5-Aza expressed no cardiac-specific genes. 5-Aza did not induce hucMSCs to differentiate into osteoblasts. Further study revealed that 5-Aza treatment activated extracellular signal related kinases (ERK) in hucMSCs, but protein kinase C showed no response to 5-Aza administration. U0126, a specific inhibitor of ERK, could inhibit 5-Aza-induced expression of cardiac-specific genes and proteins in hucMSCs. Increased phosphorylation of signal transducers and activators of transcription 3, and up-regulation of myocyte enhancer-binding factor-2c and myogenic differentiation antigen in 5-Aza-treated hucMSCs were also suppressed by U0126. Taken together, these results suggested that sustained activation of ERK by 5-Aza contributed to the induction of the differentiation of hucMSCs into cardiomyocytes in vitro.
authors.affiliation: School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, People's Republic of China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Qian
authors.forename: Hui
authors.initials: H
authors.lastname: Qian
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Yongmin
authors.initials: Y
authors.lastname: Yan
authors.forename: Shengqin
authors.initials: S
authors.lastname: Ye
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Peng
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Zhe
authors.initials: Z
authors.lastname: Xu
authors.forename: Lingyun
authors.initials: L
authors.lastname: Sun
authors.forename: Wenrong
authors.initials: W
authors.lastname: Xu
mesh_terms: D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D001374:Azacitidine / Q000494:pharmacology*; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology*
chemical_list: D000943:Antigens, Differentiation; D002070:Butadienes; D020536:Enzyme Activators; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D009570:Nitriles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D001374:Azacitidine