title: Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors.
abstract: The reprogramming of fibroblasts to induced pluripotent stem cells (iPSCs) raises the possibility that a somatic cell could be reprogrammed to an alternative differentiated fate without first becoming a stem/progenitor cell. A large pool of fibroblasts exists in the postnatal heart, yet no single "master regulator" of direct cardiac reprogramming has been identified. Here, we report that a combination of three developmental transcription factors (i.e., Gata4, Mef2c, and Tbx5) rapidly and efficiently reprogrammed postnatal cardiac or dermal fibroblasts directly into differentiated cardiomyocyte-like cells. Induced cardiomyocytes expressed cardiac-specific markers, had a global gene expression profile similar to cardiomyocytes, and contracted spontaneously. Fibroblasts transplanted into mouse hearts one day after transduction of the three factors also differentiated into cardiomyocyte-like cells. We believe these findings demonstrate that functional cardiomyocytes can be directly reprogrammed from differentiated somatic cells by defined factors. Reprogramming of endogenous or explanted fibroblasts might provide a source of cardiomyocytes for regenerative approaches.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, CA 94158, USA. ieda@cpnet.med.keio.ac.jp
authors.forename: Masaki
authors.initials: M
authors.lastname: Ieda
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Fu
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguin
authors.forename: Vasanth
authors.initials: V
authors.lastname: Vedantham
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Benoit G
authors.initials: BG
authors.lastname: Bruneau
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020869:Gene Expression Profiling; D064326:MEF2 Transcription Factors; D051379:Mice; D009119:Muscle Contraction; D009206:Myocardium / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5