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Deprecated: Implicit conversion from float 263.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Stem+Cell+Reports 2016 ; 7 (3): 355-69 Nephropedia Template TP
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Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes #MMPMID27569062
Josowitz R; Mulero-Navarro S; Rodriguez N; Falce C; Cohen N; Ullian E; Weiss L; Rauen K; Sobie E; Gelb B
Stem Cell Reports 2016[Sep]; 7 (3): 355-69 PMID27569062show ga
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? and CD90, we generated a method to examine hiPSC-derived cell type-specific phenotypes and cellular interactions underpinning HCM. BRAF-mutant SIRP?+/CD90? cardiomyocytes displayed cellular hypertrophy, pro-hypertrophic gene expression, and intrinsic calcium-handling defects. BRAF-mutant SIRP??/CD90+ cells, which were fibroblast-like, exhibited a pro-fibrotic phenotype and partially modulated cardiomyocyte hypertrophy through transforming growth factor ? (TGF?) paracrine signaling. Inhibition of TGF? or RAS/MAPK signaling rescued the hypertrophic phenotype. Thus, cell autonomous and non-autonomous defects underlie HCM due to BRAF mutations. TGF? inhibition may be a useful therapeutic option for patients with HCM due to RASopathies or other etiologies.