Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary cerebral small vessel diseases and is caused by mutations in NOTCH3. Our group has previously reported incorporation of NOTCH3 extracellular domain (N3ECD) in the CADASIL-specific granular osmiophilic materials and increase of PDGFRβ immunoreactivity in CADASIL postmortem brains. Here, we aimed to establish an in vitro model of CADASIL, which can recapitulate those CADASIL phenotypes, using induced pluripotent stem cells (iPSCs). We have refined a differentiation protocol of endothelial cells to obtain mature mural cells (MCs) with their characteristic properties. iPSCs from three CADASIL patients with p.Arg182Cys, p.Arg141Cys and p.Cys106Arg mutations were differentiated into MCs and their functional and molecular profiles were compared. The differentiated CADASIL MCs recapitulated pathogenic changes reported previously: increased PDGFRβ and abnormal structure/distribution of filamentous actin network, as well as N3ECD/LTBP-1/HtrA1-immunopositive deposits. Migration rate of CADASIL MCs was enhanced but suppressed by knockdown of NOTCH3 or PDGFRB. CADASIL MCs showed altered reactivity to PDGF-BB. Patient-derived MCs can recapitulate CADASIL pathology and are therefore useful in understanding the pathogenesis and developing potential treatment strategies.

中文翻译：

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人类iPS细胞来源的壁细胞是遗传性脑小血管疾病的体外模型。

具有皮质下梗塞和白脑病的脑常染色体显性遗传性动脉病（CADASIL）是遗传性脑小血管疾病的最常见形式之一，由NOTCH3的突变引起。我们的研究小组先前曾报道将NOTCH3细胞外域（N3ECD）掺入CADASIL特定的粒状同嗜性材料中，并增加了CADASIL死后大脑中PDGFRβ的免疫反应性。在这里，我们旨在建立一个CADASIL体外模型，该模型可以使用诱导性多能干细胞（iPSC）概括这些CADASIL表型。我们已经完善了内皮细胞的分化协议，以获得具有其特征的成熟壁细胞（MCs）。来自三名患有p.Arg182Cys，p.Arg141Cys和p。的CADASIL患者的iPSC。将Cys106Arg突变分化为MC，并比较其功能和分子谱。差异化的CADASIL MC概括了先前的致病性变化：PDGFRβ的增加和丝状肌动蛋白网络以及N3ECD / LTBP-1 / HtrA1免疫阳性沉积物的异常结构/分布。CADASIL MCs的迁移速率得到增强，但被NOTCH3或PDGFRB的敲低抑制。CADASIL MCs显示对PDGF-BB的反应性改变。患者来源的MC可以概括CADASIL病理，因此有助于理解发病机理和制定潜在的治疗策略。以及N3ECD / LTBP-1 / HtrA1免疫阳性沉积物。CADASIL MCs的迁移速率得到增强，但被NOTCH3或PDGFRB的敲低抑制。CADASIL MCs显示对PDGF-BB的反应性改变。患者来源的MC可以概括CADASIL病理，因此有助于理解发病机理和制定潜在的治疗策略。以及N3ECD / LTBP-1 / HtrA1免疫阳性沉积物。CADASIL MCs的迁移速率得到增强，但被NOTCH3或PDGFRB的敲低抑制。CADASIL MCs显示与PDGF-BB的反应性改变。患者来源的MC可以概括CADASIL病理学，因此有助于理解发病机理和制定潜在的治疗策略。