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 | |
| State | Published - Sep 13 2016 |
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ASJC Scopus subject areas
- Biochemistry
- Genetics
- Developmental Biology
- Cell Biology
Cite this
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
}
TY - JOUR
T1 - Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes
AU - Josowitz, Rebecca
AU - Mulero-Navarro, Sonia
AU - Rodriguez, Nelson A.
AU - Falce, Christine
AU - Cohen, Ninette
AU - Ullian, Erik M.
AU - Weiss, Lauren A.
AU - Rauen, Katherine A
AU - Sobie, Eric A.
AU - Gelb, Bruce D.
PY - 2016/9/13
Y1 - 2016/9/13
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=84990036865&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84990036865&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2016.07.018
DO - 10.1016/j.stemcr.2016.07.018
M3 - Article
C2 - 27569062
AN - SCOPUS:84990036865
VL - 7
SP - 355
EP - 369
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 3
ER -