Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells
Modeling CADASIL vascular pathologies with patient-derived induced pluripotent stem cells
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使用患者来源的诱导多能干细胞模拟 CADASIL 血管病理
DOI：
10.1007/s13238-019-0608-1
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发表时间：
2019-04-01
期刊：
影响因子：
21.1
通讯作者：
Liu, Guang-Hui
中科院分区：
文献类型：
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作者：
Ling, Chen;Liu, Zunpeng;Liu, Guang-Hui
伴有皮质下梗死和白质脑病的常染色体显性遗传性脑动脉病（CADASIL）是一种罕见的由aNOTCH 3突变引起的遗传性脑血管病。然而，潜在的细胞和分子机制仍然没有确定。在这里，我们从CADASIL患者的成纤维细胞中产生了非整合性诱导多能干细胞（iPSC），该患者具有异源NOTCH 3突变（c.3226C> T，p.R1076C）。从CADASIL特异性iPSC分化的血管平滑肌细胞（VSMC）显示出与疾病表型相关的基因表达变化，包括NOTCH和NF-κ B信号通路的激活、细胞骨架解体和过度细胞增殖。相比之下，在源自患者iPSC的血管内皮细胞（VEC）中未观察到这些异常。重要的是，NOTCH通路抑制剂可减少CADASIL VSMC中NF-κ B靶基因的异常上调，为CADASIL提供了潜在的治疗策略。总的来说，使用这种基于iPSC的疾病模型，我们的研究为研究CADASIL的致病机制和开发这种疾病的治疗策略提供了线索。
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary cerebrovascular disease caused by aNOTCH3mutation. However, the underlying cellular and molecular mechanisms remain unidentified. Here, we generated non-integrative induced pluripotent stem cells (iPSCs) from fibroblasts of a CADASIL patient harboring a heterozygousNOTCH3mutation (c.3226C>T, p.R1076C). Vascular smooth muscle cells (VSMCs) differentiated from CADASIL-specific iPSCs showed gene expression changes associated with disease phenotypes, including activation of the NOTCH and NF-κB signaling pathway, cytoskeleton disorganization, and excessive cell proliferation. In comparison, these abnormalities were not observed in vascular endothelial cells (VECs) derived from the patient's iPSCs. Importantly, the abnormal upregulation of NF-κB target genes in CADASIL VSMCs was diminished by a NOTCH pathway inhibitor, providing a potential therapeutic strategy for CADASIL. Overall, using this iPSC-based disease model, our study identified clues for studying the pathogenic mechanisms of CADASIL and developing treatment strategies for this disease.