Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes.
Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes.
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DOI：
10.1016/j.stemcr.2016.07.018
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发表时间：
2016-09-13
影响因子：
5.9
通讯作者：
Gelb, Bruce D.
中科院分区：
文献类型：
--
作者：
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.
BRAF的种系突变引起心-面-皮综合征（CFCS），由此40%的患者发展为肥厚性心肌病（HCM）。由于RAS/MAPK通路在HCM发病机制中的作用尚不清楚，我们从3例激活BRAF突变的CFCS患者中建立了人诱导多能干细胞（hiPSC）模型。通过SIRPα和CD90的细胞分选，我们创建了一种方法来检测hipsc衍生的细胞类型特异性表型和支撑HCM的细胞相互作用。braf突变的SIRPα+/CD90−心肌细胞表现出细胞肥大、促肥大基因表达和内在的钙处理缺陷。braf突变的SIRPα−/CD90+细胞呈成纤维细胞样，表现出促纤维化表型，并通过转化生长因子β (TGFβ)旁分泌信号部分调节心肌细胞肥大。抑制TGFβ或RAS/MAPK信号可以挽救肥厚表型。因此，细胞自主和非自主缺陷是BRAF突变引起的HCM的基础。TGFβ抑制可能是由RASopathies或其他病因引起的HCM患者的一种有用的治疗选择。braf突变型心肌细胞表现出肥厚和内在Ca2+处理缺陷，braf突变型成纤维细胞样细胞通过TGFβ影响心肌细胞肥厚，肥厚表型可以通过TGFβ或RAS/MAPK抑制来挽救。Gelb和他的同事从BRAF突变导致ras病相关HCM的患者的hiPSCs中纯化了心肌细胞和成纤维细胞样细胞。突变型心肌细胞随着Ca2+处理的改变而促肥厚，突变型成纤维细胞样细胞通过增加tgf - β信号通路严重调节心肌细胞肥厚。
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. 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.
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