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 with COL4A1/A2 SVD-related mutations. This model revealed that these mutations induce apoptosis, migration defects, ECM remodeling, and transcriptome changes in mural cells. Importantly, these mural cell defects exert a detrimental effect on endothelial cell tight junctions through paracrine actions. COL4A1/A2 models also express high levels of matrix metalloproteinases (MMPs), 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.

脑小血管疾病 (SVD) 影响大脑中的小血管，是中风和痴呆的主要原因。新出现的证据支持血液和大脑界面处的细胞外基质 (ECM) 在 SVD 病理进展中的作用，但这一点仍然缺乏表征。为了解决 ECM 在 SVD 中的作用，我们使用来自具有COL4A1 / A2 SVD 相关突变的患者的人类诱导多能干细胞，开发了壁细胞和内皮细胞的共培养模型。该模型揭示这些突变会诱导壁细胞凋亡、迁移缺陷、ECM 重塑和转录组变化。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模型还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 异常和壁细胞表型变化。这些数据为靶向 MMP 作为 SVD 的治疗机会提供了基础。