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Abstract：
Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in FBN1, which encodes the extracellular matrix protein fibrillin-1. To investigate the pathogenesis of aortic aneurysms in MFS, we generated a vascular model derived from human induced pluripotent stem cells (MFS-hiPSCs). Our MFS-hiPSC-derived smooth muscle cells (SMCs) recapitulated the pathology seen in Marfan aortas, including defects in fibrillin-1 accumulation, extracellular matrix degradation, transforming growth factor-β (TGF-β) signaling, contraction and apoptosis; abnormalities were corrected by CRISPR-based editing of the FBN1 mutation. TGF-β inhibition rescued abnormalities in fibrillin-1 accumulation and matrix metalloproteinase expression. However, only the noncanonical p38 pathway regulated SMC apoptosis, a pathological mechanism also governed by Krüppel-like factor 4 (KLF4). This model has enabled us to dissect the molecular mechanisms of MFS, identify novel targets for treatment (such as p38 and KLF4) and provided an innovative human platform for the testing of new drugs.
摘要：
马凡综合征（MFS）是由FBN1突变引起的遗传性结缔组织疾病，FBN1编码细胞外基质原纤维蛋白-1。探讨MFS中主动脉瘤的发病机制,我们建立了一个来源于人诱导多能干细胞(MFS-hiPSCs)的血管模型.我们的MFS-hiPSC衍生的平滑肌细胞（SMC）概括了在马凡氏主动脉中看到的病理，包括纤丝蛋白-1积累的缺陷，细胞外基质降解，转化生长因子-β（TGF-β）信号，收缩和凋亡;异常通过基于CRISPR的FBN1突变编辑得到纠正。TGF-β抑制挽救了原纤维蛋白-1积累和基质金属蛋白酶表达的异常。然而,只有非典型的p38通路调节SMC凋亡，病理机制也受Krüppel样因子4（KLF4）控制。该模型使我们能够剖析MFS的分子机制，确定新的治疗靶点（如p38和KLF4），并为新药测试提供创新的人类平台。
