| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Stem Cell Reports, Vol 7, Iss 3, Pp 355-369 (2016) |
| Druh dokumentu: |
article |
| ISSN: |
2213-6711 |
| DOI: |
10.1016/j.stemcr.2016.07.018 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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