Abstract/Summary 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 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/A2 models 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. Highlights A novel human iPSC-derived model of genetic SVD due to collagen IV ( COL4A1/A2 ) mutations is described Mural cells expressing COL4A1/A2 mutations have prominent ECM abnormalities as seen in patients and mouse models and contribute to endothelial cells defects ECM and endothelial cells abnormalities can be rescued by MMP inhibition in the COL4A1/A2 model

A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormalities