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

/SummaryCerebral 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