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

作者：Josowitz Rebecca; Mulero Navarro Sonia; Rodriguez Nelson A; Falce Christine; Cohen Ninette; Ullian Erik M; Weiss Lauren A; Rauen Katherine A; Sobie Eric A; Gelb Bruce D^*

来源：Stem Cell Reports, 2016, 7(3): 355-369.

DOI：10.1016/j.stemcr.2016.07.018

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 SIRP alpha and CD90, we generated a method to examine hiPSC-derived cell type-specific phenotypes and cellular interactions underpinning HCM. BRAF-mutant SIRP alpha(+)/CD90(-) cardiomyocytes displayed cellular hypertrophy, pro-hypertrophic gene expression, and intrinsic calcium-handling defects. BRAF-mutant SIRP alpha(-)/CD90(+) cells, which were fibroblast-like, exhibited a pro-fibrotic phenotype and partially modulated cardiomyocyte hypertrophy through transforming growth factor beta (TGF beta) paracrine signaling. Inhibition of TGFb or RAS/MAPK signaling rescued the hypertrophic phenotype. Thus, cell autonomous and non-autonomous defects underlie HCM due to BRAF mutations. TGFb inhibition may be a useful therapeutic option for patients with HCM due to RASopathies or other etiologies.

• 出版日期2016-9-13