title: Conversion of human fibroblasts into functional cardiomyocytes by small molecules.
abstract: Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells into specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds that we term 9C. The chemically induced cardiomyocyte-like cells uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters and enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to chemically induced cardiomyocyte-like cells. This pharmacological approach to lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Nan
authors.initials: N
authors.lastname: Cao
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, CA 94158, USA. California Institute for Quantitative Biosciences, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Jiashun
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
authors.forename: C Ian
authors.initials: CI
authors.lastname: Spencer
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Heart and Vascular Research Center, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Fu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Baoming
authors.initials: B
authors.lastname: Nie
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Mingliang
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Ma
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Xu
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Guilai
authors.initials: G
authors.lastname: Shi
authors.affiliation: Gladstone Institute of Cardiovascular Disease, 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.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D054338:Cell Transdifferentiation; D065150:Cellular Reprogramming / Q000187:drug effects*; D000067470:Cellular Reprogramming Techniques; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006321:Heart / Q000196:embryology; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009203:Myocardial Infarction / Q000601:surgery; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D018995:Myosin Heavy Chains / Q000235:genetics; D038081:Organogenesis / Q000235:genetics; D011487:Protein Conformation; D012867:Skin / Q000166:cytology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D059467:Transcriptome; D014161:Transduction, Genetic
chemical_list: D002843:Chromatin; D054852:Small Molecule Libraries; D018995:Myosin Heavy Chains