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A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormal…
A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases in extracellular matrix abnormal…
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Length:
20 minutes
Released:
Feb 23, 2023
Format:
Podcast episode
Description
Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.02.23.529680v1?rss=1
Authors: Al-Thani, M., Goodwin-Trotman, M., Bell, S., Patel, K., Fleming, L. K., Vilain, C., Abramowicz, M., Allan, S. M., Wang, T., Cader, Z., Horsburgh, K., Van Agtmael, T., Sinha, S., Markus, H. S., Granata, A.
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 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.
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http://biorxiv.org/cgi/content/short/2023.02.23.529680v1?rss=1
Authors: Al-Thani, M., Goodwin-Trotman, M., Bell, S., Patel, K., Fleming, L. K., Vilain, C., Abramowicz, M., Allan, S. M., Wang, T., Cader, Z., Horsburgh, K., Van Agtmael, T., Sinha, S., Markus, H. S., Granata, A.
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 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.
Copy rights belong to original authors. Visit the link for more info
Podcast created by Paper Player, LLC
Released:
Feb 23, 2023
Format:
Podcast episode
Titles in the series (100)
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