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

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

doi:10.1016/j.stemcr.2016.07.018

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

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

General Pediatrics

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14 Scopus citations

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.

Original language	English (US)
Pages (from-to)	355-369
Number of pages	15
Journal	Stem Cell Reports
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.stemcr.2016.07.018
State	Published - Sep 13 2016

ASJC Scopus subject areas

Biochemistry
Genetics
Developmental Biology
Cell Biology

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

In: Stem Cell Reports, Vol. 7, No. 3, 13.09.2016, p. 355-369.

Research output: Contribution to journal › Article › peer-review

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. / Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes. In: Stem Cell Reports. 2016 ; Vol. 7, No. 3. pp. 355-369.

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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.",

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AB - 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.

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

Abstract

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