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Published on: August 8, 2022
Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived
Rebecca Josowitz1, Sonia Mulero-Navarro1, Nelson A Rodriguez1
1The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Insights
Cardio-facio-cutaneous syndrome (CFCS) patients with BRAF mutations develop hypertrophic cardiomyopathy (HCM). This study used stem cells to reveal that both heart muscle cell defects and fibroblast signaling contribute to HCM, suggesting TGFβ inhibition as a therapy.
Area of Science:
- Genetics and Molecular Biology
- Cardiology
- Stem Cell Biology
Background:
- Germline BRAF mutations cause cardio-facio-cutaneous syndrome (CFCS).
- Approximately 40% of CFCS patients develop hypertrophic cardiomyopathy (HCM).
- The RAS/MAPK pathway's role in HCM pathogenesis remains unclear.
Purpose of the Study:
- To investigate the cellular mechanisms underlying HCM in CFCS using a human induced pluripotent stem cell (hiPSC) model.
- To elucidate the cell type-specific contributions of BRAF mutations to HCM.
- To identify potential therapeutic targets for HCM in RASopathies.
Main Methods:
- Generated hiPSC models from three CFCS patients with activating BRAF mutations.
- Developed a cell sorting method using SIRPα and CD90 to isolate distinct cell populations.
- Analyzed hiPSC-derived cardiomyocyte and fibroblast phenotypes, gene expression, and intercellular signaling.
Main Results:
- BRAF-mutant cardiomyocytes exhibited hypertrophy, altered gene expression, and calcium-handling defects.
- BRAF-mutant fibroblast-like cells displayed a pro-fibrotic phenotype and modulated cardiomyocyte hypertrophy via TGFβ signaling.
- Inhibition of TGFβ or RAS/MAPK signaling rescued the hypertrophic phenotype in the hiPSC model.
Conclusions:
- HCM in CFCS arises from both cell-autonomous defects in cardiomyocytes and non-autonomous signaling from fibroblasts.
- TGFβ paracrine signaling plays a significant role in mediating HCM.
- TGFβ inhibition presents a potential therapeutic strategy for HCM in RASopathies and other conditions.
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.
