A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormalities
A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormalities
复制标题
COL4A1/A2 小血管疾病的新型人类 iPSC 模型揭示了基质金属蛋白酶在细胞外基质异常中的关键致病作用
DOI：
10.1101/2023.02.23.529680
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Al-Thani M
中科院分区：
文献类型：
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作者：
Al-Thani M
脑血管病（SVD）影响大脑中的小血管，是中风和痴呆的主要原因。新出现的证据支持位于血液和脑交界面的细胞外基质（ECM）在SVD病理进展中的作用，但这方面的特征尚不明确。为了研究ECM在SVD中的作用，我们利用col4a1 / a2svd相关突变患者的人诱导多能干细胞建立了壁细胞和内皮细胞的共培养模型。该模型显示，这些突变诱导壁细胞凋亡、迁移缺陷、ECM重塑和转录组改变。重要的是，这些壁细胞缺陷通过旁分泌作用对内皮细胞紧密连接产生有害影响。COL4A1/ a2模型也表达高水平的基质金属蛋白酶（MMP），抑制MMP活性可部分挽救ECM异常和壁细胞表型改变。这些数据为靶向MMP治疗SVD提供了基础。本文描述了一种新的人类ipsc衍生的由胶原IV （COL4A1/A2）突变引起的遗传性SVD模型。在患者和小鼠模型中，表达COL4A1/A2突变的壁细胞具有突出的ECM异常，并导致内皮细胞缺陷。在COL4A1/A2模型中，MMP抑制可以挽救ECM和内皮细胞异常
Cerebral small vessel disease (SVD) affects the small vessels in the brain and is a leading cause of stroke and dementia. Emerging evidence supports a role of the extracellular matrix (ECM), at the interface between blood and brain, in the progression of SVD pathology but this remains poorly characterized.To address ECM role in SVD, we developed a co-culture model of mural and endothelial cells using human induced pluripotent stem cells from patients withCOL4A1/A2SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodelling and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cells tight junctions through paracrine actions.COL4A1/A2models also express high levels of matrix metalloproteinases (MMP) and inhibiting MMP activity partially rescues the ECM abnormalities and mural cell phenotypic changes. These data provide a basis for targeting MMP as a therapeutic opportunity in SVD.HighlightsA novel human iPSC-derived model of genetic SVD due to collagen IV (COL4A1/A2) mutations is describedMural cells expressingCOL4A1/A2mutations have prominent ECM abnormalities as seen in patients and mouse models and contribute to endothelial cells defectsECM and endothelial cells abnormalities can be rescued by MMP inhibition in theCOL4A1/A2model