title: Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state.
abstract: Direct reprogramming of adult somatic cells into alternative cell types has been shown for several lineages. We previously showed that GATA4, MEF2C, and TBX5 (GMT) directly reprogrammed nonmyocyte mouse heart cells into induced cardiomyocyte-like cells (iCMs) in vitro and in vivo. However, GMT alone appears insufficient in human fibroblasts, at least in vitro. Here, we show that GMT plus ESRRG and MESP1 induced global cardiac gene-expression and phenotypic shifts in human fibroblasts derived from embryonic stem cells, fetal heart, and neonatal skin. Adding Myocardin and ZFPM2 enhanced reprogramming, including sarcomere formation, calcium transients, and action potentials, although the efficiency remained low. Human iCM reprogramming was epigenetically stable. Furthermore, we found that transforming growth factor β signaling was important for, and improved the efficiency of, human iCM reprogramming. These findings demonstrate that human fibroblasts can be directly reprogrammed toward the cardiac lineage, and lay the foundation for future refinements in vitro and in vivo.
authors: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA ; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA ; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA ; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
authors: Ji-Dong
authors: JD
authors: Fu
authors: Nicole R
authors: NR
authors: Stone
authors: Lei
authors: L
authors: Liu
authors: C Ian
authors: CI
authors: Spencer
authors: Li
authors: L
authors: Qian
authors: Yohei
authors: Y
authors: Hayashi
authors: Paul
authors: P
authors: Delgado-Olguin
authors: Sheng
authors: S
authors: Ding
authors: Benoit G
authors: BG
authors: Bruneau
authors: Deepak
authors: D
authors: Srivastava
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D065150:Cellular Reprogramming / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006801:Humans; D064326:MEF2 Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099251:Myocardin
chemical_list: D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; D009687:Nuclear Proteins; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000099251:Myocardin; C578040:MEF2C protein, human; C103172:T-box transcription factor 5; C117427:ZFPM2 protein, human