Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures
Patient-Specific iPSC Model of a Genetic Vascular Dementia Syndrome Reveals Failure of Mural Cells to Stabilize Capillary Structures
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DOI：
10.1016/j.stemcr.2019.10.004
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发表时间：
2019-11-12
影响因子：
5.9
通讯作者：
Wang, Tao
中科院分区：
文献类型：
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作者：
Kelleher, Joseph;Dickinson, Adam;Wang, Tao
CADASIL(伴有皮质下梗塞和白质脑病的常染色体显性遗传性动脉病)是最常见的遗传性中风和血管性痴呆综合征，由NOTCH3基因突变引起。为了阐明这种情况的分子机制并确定药物靶点，我们建立了患者特异性诱导多能干细胞(IPSC)模型，并首次证明了患者IPSC来源的血管壁细胞(IPSC-MC)在结合和稳定内皮毛细血管结构方面失败。患者的IPSC-MC减少了血小板衍生生长因子受体β，减少了血管生成因子血管内皮生长因子(VEGF)的分泌，对凋亡损伤高度敏感，并可诱导邻近内皮细胞的凋亡。血管内皮细胞生长因子的补充显著挽救了毛细血管的不稳定。在IPSC-MC中，NOTCH3的小干扰RNA被击倒，揭示了突变体NOTCH3的功能增益机制。这些疾病机制可能会延迟CADASIL患者中风后的脑修复，导致这种情况下的脑低灌注率和痴呆，并将有助于识别潜在的药物靶点。
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is the most common form of genetic stroke and vascular dementia syndrome resulting from mutations in NOTCH3. To elucidate molecular mechanisms of the condition and identify drug targets, we established a patient-specific induced pluripotent stem cell (iPSC) model and demonstrated for the first time a failure of the patient iPSC-derived vascular mural cells (iPSC-MCs) in engaging and stabilizing endothelial capillary structures. The patient iPSC-MCs had reduced platelet-derived growth factor receptor beta, decreased secretion of the angiogenic factor vascular endothelial growth factor (VEGF), were highly susceptible to apoptotic insults, and could induce apoptosis of adjacent endothelial cells. Supplementation of VEGF significantly rescued the capillary destabilization. Small interfering RNA knockdown of NOTCH3 in iPSC-MCs revealed a gain-of-function mechanism for the mutant NOTCH3. These disease mechanisms likely delay brain repair after stroke in CADASIL, contributing to the brain hypoperfusion and dementia in this condition, and will help to identify potential drug targets.