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

Summary 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.
Graphical Abstract
Highlights • Cardiomyocytes and fibroblast-like cells can be purified separately from EBs • BRAF-mutant cardiomyocytes display hypertrophy and intrinsic Ca2+-handling defects • BRAF-mutant fibroblast-like cells influence cardiomyocyte hypertrophy through TGFβ • The hypertrophic phenotype can be rescued by TGFβ or RAS/MAPK inhibition
To better understand the role of RAS/MAPK signaling in the pathogenesis of hypertrophic cardiomyopathy (HCM), Gelb and colleagues purified cardiomyocytes and fibroblast-like cells from hiPSCs derived from patients with BRAF mutations causing RASopathy-associated HCM. While mutant cardiomyocytes were pro-hypertrophic with altered Ca2+ handling, mutant fibroblast-like cells critically modulated cardiomyocyte hypertrophy through increased TGFβ signaling.