title: Transcription factor-induced activation of cardiac gene expression in human c-kit+ cardiac progenitor cells.
abstract: Although transplantation of c-kit+ cardiac progenitor cells (CPCs) significantly alleviates post-myocardial infarction left ventricular dysfunction, generation of cardiomyocytes by exogenous CPCs in the recipient heart has often been limited. Inducing robust differentiation would be necessary for improving the efficacy of the regenerative cardiac cell therapy. We assessed the hypothesis that differentiation of human c-kit+ CPCs can be enhanced by priming them with cardiac transcription factors (TFs). We introduced five different TFs (Gata4, MEF2C, NKX2.5, TBX5, and BAF60C) into CPCs, either alone or in combination, and then examined the expression of marker genes associated with the major cardiac cell types using quantitative RT-PCR. When introduced individually, Gata4 and TBX5 induced a subset of myocyte markers. Moreover, Gata4 alone significantly induced smooth muscle cell and fibroblast markers. Interestingly, these gene expression changes brought by Gata4 were also accompanied by morphological changes. In contrast, MEF2C and NKX2.5 were largely ineffective in initiating cardiac gene expression in CPCs. Surprisingly, introduction of multiple TFs in different combinations mostly failed to act synergistically. Likewise, addition of BAF60C to Gata4 and/or TBX5 did not further potentiate their effects on cardiac gene expression. Based on our results, it appears that GATA4 is able to potentiate gene expression programs associated with multiple cardiovascular lineages in CPCs, suggesting that GATA4 may be effective in priming CPCs for enhanced differentiation in the setting of stem cell therapy.
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Tareq
authors.initials: T
authors.lastname: Al-Maqtari
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Bathri N
authors.initials: BN
authors.lastname: Vajravelu
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Afsoon
authors.initials: A
authors.lastname: Moktar
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Pengxiao
authors.initials: P
authors.lastname: Cao
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Moore
authors.affiliation: Institute of Molecular Cardiology, Department of Medicine, University of Louisville, Louisville, KY, United States of America.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002868:Chromosomal Proteins, Non-Histone; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D000072576:Homeobox Protein Nkx-2.5 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D061251:Primary Cell Culture; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic
chemical_list: D015415:Biomarkers; D002868:Chromosomal Proteins, Non-Histone; D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D000072576:Homeobox Protein Nkx-2.5; D064326:MEF2 Transcription Factors; C578040:MEF2C protein, human; C095552:NKX2-5 protein, human; C491649:SMARCD3 protein, human; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D014157:Transcription Factors; D019009:Proto-Oncogene Proteins c-kit