Chen Yuhao, Zhu Yuankang, Ren Xiaoli, Ding Lu, Xu Yubin, Zhou Miqi, Dong Runze, Jin Peifeng, Chen Xiufang, Fan Xiaofang, Li Ming, Gong Yongsheng, Wang Yongyu
Department of Cell Biology, Institute of Hypoxia Medicine, School of Basic Medical Sciences Wenzhou Medical University Zhejiang China.
Department of Gerontology Xinhua Hospital, Shanghai Jiao Tong University School of Medicine Shanghai China.
J Am Heart Assoc. 2025 May 6;14(9):e037826. doi: 10.1161/JAHA.124.037826. Epub 2025 Apr 16.
Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the Fibrillin-1 gene, which encodes the extracellular matrix protein fibrillin-1. Patients with MFS are predisposed to aortic aneurysms and dissections, significantly contributing to mortality. Emerging evidence suggests that endothelial cell (EC) senescence plays a critical role in the pathogenesis of aortic aneurysms in MFS. This study aims to elucidate the role of EC senescence in the development of aortic aneurysms in MFS using a vascular model derived from human induced pluripotent stem cells.
We generated human induced pluripotent stem cells lines from 2 patients with MFS carrying specific Fibrillin-1 mutations and differentiated these into ECs. These MFS-hiPSC-derived ECs were characterized using immunofluorescence, reverse transcription-quantitative polymerase chain reaction, and Western blotting. Functional assays including cell proliferation, scratch wound, tube formation, NO content detection, and senescence-associated β-galactosidase staining were conducted. RNA sequencing was performed to elucidate underlying signaling pathways, and pharmacological inhibition of the transforming growth factor-beta pathway was assessed for its therapeutic potential. MFS-hiPSC-derived ECs recapitulated the pathological features observed in Marfan aortas, particularly pronounced cellular senescence, decreased cell proliferation, and abnormal transforming growth factor-beta and NF-κB signaling. These senescent ECs exhibited diminished proliferative and migratory capacities, reduced NO signaling, increased production of inflammatory cytokines, and attenuated responses to inflammatory stimuli. Importantly, senescence and dysfunction in MFS-hiPSCderived ECs were ameliorated by transforming growth factor-beta signaling pathway inhibitor, SB-431542, suggesting a potential therapeutic strategy.
This study highlights the pivotal role of endothelial cell senescence in the pathogenesis of aortic aneurysms in MFS. Our human induced pluripotent stem cells-based disease model provides new insights into the disease mechanisms and underscores the potential of targeting the transforming growth factor-beta pathway to mitigate endothelial dysfunction and senescence, offering a promising therapeutic avenue for MFS.
马凡综合征（MFS）是一种由原纤维蛋白-1基因（Fibrillin-1）突变引起的遗传性结缔组织疾病，该基因编码细胞外基质蛋白原纤维蛋白-1。MFS患者易患主动脉瘤和主动脉夹层，这是导致死亡的重要原因。新出现的证据表明，内皮细胞（EC）衰老在MFS主动脉瘤的发病机制中起关键作用。本研究旨在使用源自人诱导多能干细胞的血管模型，阐明EC衰老在MFS主动脉瘤发展中的作用。
我们从2名携带特定原纤维蛋白-1突变的MFS患者中生成了人诱导多能干细胞系，并将其分化为内皮细胞。使用免疫荧光、逆转录定量聚合酶链反应和蛋白质免疫印迹对这些源自MFS患者诱导多能干细胞的内皮细胞进行了表征。进行了包括细胞增殖、划痕伤口、管形成、一氧化氮含量检测和衰老相关β-半乳糖苷酶染色在内的功能测定。进行RNA测序以阐明潜在的信号通路，并评估转化生长因子-β通路的药理学抑制作用的治疗潜力。源自MFS患者诱导多能干细胞的内皮细胞重现了马凡主动脉中观察到的病理特征，特别是明显的细胞衰老、细胞增殖减少以及转化生长因子-β和核因子-κB信号异常。这些衰老的内皮细胞表现出增殖和迁移能力减弱、一氧化氮信号传导减少、炎性细胞因子产生增加以及对炎症刺激的反应减弱。重要的是，转化生长因子-β信号通路抑制剂SB-431542改善了源自MFS患者诱导多能干细胞的内皮细胞的衰老和功能障碍，提示了一种潜在的治疗策略。
本研究强调了内皮细胞衰老在MFS主动脉瘤发病机制中的关键作用。我们基于人诱导多能干细胞的疾病模型为疾病机制提供了新的见解，并强调了靶向转化生长因子-β通路以减轻内皮功能障碍和衰老的潜力，为MFS提供了一条有前景的治疗途径。
