Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes

Rebecca Josowitz, Sonia Mulero-Navarro, Nelson A. Rodriguez, Christine Falce, Ninette Cohen, Erik M. Ullian, Lauren A. Weiss, Katherine A Rauen, Eric A. Sobie, Bruce D. Gelb

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)355-369
Number of pages15
JournalStem Cell Reports
Volume7
Issue number3
DOIs
StatePublished - Sep 13 2016

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes'. Together they form a unique fingerprint.

  • Cite this

    Josowitz, R., Mulero-Navarro, S., Rodriguez, N. A., Falce, C., Cohen, N., Ullian, E. M., Weiss, L. A., Rauen, K. A., Sobie, E. A., & Gelb, B. D. (2016). Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes. Stem Cell Reports, 7(3), 355-369. https://doi.org/10.1016/j.stemcr.2016.07.018