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

Autor: Lauren A. Weiss, Katherine A. Rauen, Sonia Mulero-Navarro, Erik M. Ullian, Ninette Cohen, Bruce D. Gelb, Eric A. Sobie, Rebecca Josowitz, Nelson A. Rodriguez, Christine Falce
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Proto-Oncogene Proteins B-raf
0301 basic medicine
MAPK/ERK pathway
Cellular differentiation
Induced Pluripotent Stem Cells
macromolecular substances
Cell Separation
Biology
medicine.disease_cause
Biochemistry
Article
Transforming Growth Factor beta1
03 medical and health sciences
Paracrine signalling
Germline mutation
Paracrine Communication
Genetics
medicine
Humans
Myocytes
Cardiac
cardiovascular diseases
Induced pluripotent stem cell
lcsh:QH301-705.5
Mutation
lcsh:R5-920
Cell Differentiation
Cell Biology
Cardiomyopathy
Hypertrophic
Cellular Reprogramming
Phenotype
3. Good health
030104 developmental biology
lcsh:Biology (General)
cardiovascular system
ras Proteins
Cancer research
Calcium
Mitogen-Activated Protein Kinases
lcsh:Medicine (General)
Biomarkers
Signal Transduction
Developmental Biology
Transforming growth factor
Zdroj: Stem Cell Reports, Vol 7, Iss 3, Pp 355-369 (2016)
Stem Cell Reports
Weiss, Lauren; Josowitz, R; Mulero-Navarro, S; Rodriguez, NA; Falce, C; Cohen, N; et al.(2016). Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes. UC San Francisco: Retrieved from: http://www.escholarship.org/uc/item/6j48t8r4
ISSN: 2213-6711
Popis: 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.
Databáze: OpenAIRE
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