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

Maha Al-Thani, Mary Goodwin-Trotman, Steven Bell, Krushangi Patel, Lauren K Fleming, Catheline Vilain, Marc Abramowicz, Stuart M Allan, Tao Wang, M Zameel Cader, Karen Horsburgh, Tom Van Agtmael, Sanjay Sinha, Hugh S Markus, Alessandra Granata

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2386-2399
Number of pages14
JournalStem Cell Reports
Volume18
Issue number12
DOIs
Publication statusPublished - 12 Dec 2023

Keywords

  • Humans
  • Induced Pluripotent Stem Cells
  • Endothelial Cells
  • Brain/pathology
  • Stroke/pathology
  • Extracellular Matrix
  • Matrix Metalloproteinases/genetics
  • Collagen Type IV/genetics

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