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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)355-369
Number of pages15
JournalStem Cell Reports
Volume7
Issue number3
DOIs
StatePublished - Sep 13 2016

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Induced Pluripotent Stem Cells
Hypertrophic Cardiomyopathy
Transforming Growth Factors
Stem cells
Cardiac Myocytes
Defects
Phenotype
Hypertrophy
Fibroblasts
Sorting
Gene expression
Paracrine Communication
Cells
Mutation
Germ-Line Mutation
Calcium
Gene Expression

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Josowitz, R., Mulero-Navarro, S., Rodriguez, N. A., Falce, C., Cohen, N., Ullian, E. M., ... Gelb, B. D. (2016). Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes. Stem Cell Reports, 7(3), 355-369. https://doi.org/10.1016/j.stemcr.2016.07.018

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 journalArticle

Josowitz, R, Mulero-Navarro, S, Rodriguez, NA, Falce, C, Cohen, N, Ullian, EM, Weiss, LA, Rauen, KA, Sobie, EA & Gelb, BD 2016, 'Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes', Stem Cell Reports, vol. 7, no. 3, pp. 355-369. https://doi.org/10.1016/j.stemcr.2016.07.018
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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