title: Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes.
abstract: Germline mutations in BRAF cause cardio-facio-cutaneous syndrome (CFCS), whereby 40% of patients develop hypertrophic cardiomyopathy (HCM). As the role of the RAS/MAPK pathway in HCM pathogenesis is unclear, we generated a human induced pluripotent stem cell (hiPSC) model for CFCS from three patients with activating BRAF mutations. By cell sorting for SIRPα and CD90, we generated a method to examine hiPSC-derived cell type-specific phenotypes and cellular interactions underpinning HCM. BRAF-mutant SIRPα(+)/CD90(-) cardiomyocytes displayed cellular hypertrophy, pro-hypertrophic gene expression, and intrinsic calcium-handling defects. BRAF-mutant SIRPα(-)/CD90(+) cells, which were fibroblast-like, exhibited a pro-fibrotic phenotype and partially modulated cardiomyocyte hypertrophy through transforming growth factor β (TGFβ) paracrine signaling. Inhibition of TGFβ or RAS/MAPK signaling rescued the hypertrophic phenotype. Thus, cell autonomous and non-autonomous defects underlie HCM due to BRAF mutations. TGFβ inhibition may be a useful therapeutic option for patients with HCM due to RASopathies or other etiologies.
authors: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Rebecca
authors: R
authors: Josowitz
authors: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Sonia
authors: S
authors: Mulero-Navarro
authors: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Nelson A
authors: NA
authors: Rodriguez
authors: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Christine
authors: C
authors: Falce
authors: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Ninette
authors: N
authors: Cohen
authors: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Erik M
authors: EM
authors: Ullian
authors: Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Lauren A
authors: LA
authors: Weiss
authors: Department of Pediatrics, University of California, Davis, Davis, CA 95616, USA.
authors: Katherine A
authors: KA
authors: Rauen
authors: Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors: Eric A
authors: EA
authors: Sobie
authors: The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: bruce.gelb@mssm.edu.
authors: Bruce D
authors: BD
authors: Gelb
mesh_terms: D015415:Biomarkers; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002469:Cell Separation; D065150:Cellular Reprogramming; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D010641:Phenotype; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D053773:Transforming Growth Factor beta1; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D002118:Calcium