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人诱导多能干细胞衍生的壁细胞作为遗传性脑小血管病的体外模型。

Human iPS cell-derived mural cells as an in vitro model of hereditary cerebral small vessel disease.

机构信息

Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.

Department of Molecular Innovation in Lipidemiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibeshinmachi, Suita-shi, Osaka, 564-0018, Japan.

出版信息

Mol Brain. 2020 Mar 19;13(1):38. doi: 10.1186/s13041-020-00573-w.

DOI:10.1186/s13041-020-00573-w
PMID:32188464
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7081541/
Abstract

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.

摘要

伴有皮质下梗死和白质脑病的脑常染色体显性动脉病（CADASIL）是最常见的遗传性脑小血管病形式之一，由 NOTCH3 突变引起。我们的研究小组之前曾报道过 NOTCH3 细胞外结构域（N3ECD）在 CADASIL 特异性颗粒性亲脂性物质中的存在，并在 CADASIL 尸检大脑中增加 PDGFRβ 免疫反应性。在这里，我们旨在使用诱导多能干细胞（iPSC）建立一种能够重现这些 CADASIL 表型的 CADASIL 体外模型。我们已经改进了内皮细胞的分化方案，以获得具有特征性特性的成熟壁细胞（MCs）。来自三个 CADASIL 患者（p.Arg182Cys、p.Arg141Cys 和 p.Cys106Arg 突变）的 iPSC 被分化为 MCs，并比较了它们的功能和分子特征。分化的 CADASIL MCs 重现了先前报道的致病性变化：增加 PDGFRβ 和丝状肌动蛋白网络的异常结构/分布，以及 N3ECD/LTBP-1/HtrA1 免疫阳性沉积物。CADASIL MCs 的迁移率增强，但通过 NOTCH3 或 PDGFRB 的敲低而受到抑制。CADASIL MCs 对 PDGF-BB 的反应性发生改变。源自患者的 MCs 可以重现 CADASIL 病理学，因此有助于理解发病机制和开发潜在的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/70662bcf31f5/13041_2020_573_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/de19950ebae3/13041_2020_573_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/7b3d7f6ab0ff/13041_2020_573_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/d35e83dbc7e0/13041_2020_573_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/5d90d4c48382/13041_2020_573_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/b5697fe7e5f8/13041_2020_573_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/70662bcf31f5/13041_2020_573_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/de19950ebae3/13041_2020_573_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/7b3d7f6ab0ff/13041_2020_573_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/d35e83dbc7e0/13041_2020_573_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/5d90d4c48382/13041_2020_573_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/b5697fe7e5f8/13041_2020_573_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d4d4/7081541/70662bcf31f5/13041_2020_573_Fig6_HTML.jpg

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