Modelling COL4A1/2 SVD Associated Mutations—Towards New Treatment †
by
Maha Al-Thani
1,‡, 
Mary Goodwin-Trotman
1,‡,
Tom Van Agtmael
2,
Hugh S. Markus
3 and
Alessandra Granata
1,* 1
Department of Clinical Neurosciences, University of Cambridge and Royal Papworth Hospital, Cambridge CB2 0QQ, UK
2
School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow G12 8TA, UK
3
Department of Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK
*
Author to whom correspondence should be addressed.
†
Presented at the 2nd COL4A1-A2 International Conference, Rome, Italy, 10 February 2025.
‡
These authors contributed equally.
Proceedings 2025, 120(1), 11; https://doi.org/10.3390/proceedings2025120011
Published: 8 July 2025
Cerebral small vessel disease (SVD) is a leading cause of stroke and vascular dementia, yet its underlying mechanisms remain incompletely understood [1,2,3].
In particular, how mutations in collagen IV genes (COL4A1/A2) disrupt vascular structure and function is still being elucidated [4,5,6,7].
To address this, we developed a human in vitro model using induced pluripotent stem cells (iPSCs) derived from patients with COL4A1/A2 mutations [8]. These were differentiated into mural cells and endothelial cells, and co-cultured in a transwell setting to recreate a neurovascular environment.
We found that patient-derived mural cells exhibit significant abnormalities in extracellular matrix (ECM) organisation, increased apoptosis, and migration defects, along with transcriptomic changes [8,9]. When co-cultured with endothelial cells, these defective mural cells exacerbate endothelial dysfunction, leading to increased blood–brain barrier (BBB) permeability, a hallmark of SVD observed in patients [8]. This paracrine effect illustrates how mural cell pathology can directly compromise vascular integrity.
Importantly, we observed elevated matrix metalloproteinase (MMP) activity in the diseased state [8,10]. Treatment with MMP inhibitors led to partial restoration of the ECM structure, mural cell health, and significantly improved BBB integrity [11].
These findings not only recapitulate key features of the human disease but also provide a compelling case for MMPs as a therapeutic target in SVD, paving the way for future treatment strategies.
Author Contributions
A.G. contributed to the conception, design, supervision, and formal analysis of the COL4A1/A2 iPSC model data, to the writing and original draft preparation of the article and funding acquisition. M.A.-T. and M.G.-T. equally contributed to the acquisition and analysis of the data. T.V.A. provided the COL4A2 mutation iPSC and the review and editing of the manuscript. H.S.M. is the clinician for the patient with the COL4A1 mutation and contributed to the review and editing of the article, supervision of the study, and funding acquisition. All authors contributed to the article and approved the submitted version. All authors have read and agreed to the published version of the manuscript.
Funding
The present work was supported by a Stroke Association priority programme award in Advancing Care and Treatment of Vascular Dementia (grant 16VAD_04) in partnership with the British Heart Foundation and Alzheimer’s Society to T.V.A., A.G., and H.S.M.; A.G. was supported by the Medical Research Foundation mid-career fellowship (RG98759). This research was funded by the British Heart Foundation via the Cambridge British Heart Foundation Centre of Research Excellence (RE/18/1/34212) and a British Heart Foundation programme grant (RG/F/22/110052). Infrastructural support was provided by the Cambridge University Hospitals NIHR BRC (BRC-1215-20014). H.S.M. is supported by an NIHR Senior Investigator Award.
Institutional Review Board Statement
Cell culture experiments were approved by the local Ethics Committees at the University of Glasgow (200200029) and Cambridge University (Ethics REC NO 16/EE/0118).
Informed Consent Statement
Informed consent was obtained from all subjects involved in the study.
Data Availability Statement
The RNA-seq analysis data generated during this study have been deposited on Apollo-University of Cambridge Repository: https://doi.org/10.17863/CAM.100127 and is publicly available. Additional information can be downloaded from [8], https://doi.org/10.1016/j.stemcr.2023.10.014.
Acknowledgments
We thank the National Institute for Health and Care Research (NIHR), Cambridge Biomedical Research Centre (BRC), Cell Phenotyping Hub, and the Flow Cytometry Core facilities at the Cambridge Institute for Medical Research (CIMR). We also thank L. Vallier and the hiPSC core facility for generating the COL4A1 hiPSC line.
Conflicts of Interest
The authors declare no conflicts of interest.
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MDPI and ACS Style
Al-Thani, M.; Goodwin-Trotman, M.; Van Agtmael, T.; Markus, H.S.; Granata, A. Modelling COL4A1/2 SVD Associated Mutations—Towards New Treatment. Proceedings 2025, 120, 11. https://doi.org/10.3390/proceedings2025120011
AMA Style
Al-Thani M, Goodwin-Trotman M, Van Agtmael T, Markus HS, Granata A. Modelling COL4A1/2 SVD Associated Mutations—Towards New Treatment. Proceedings. 2025; 120(1):11. https://doi.org/10.3390/proceedings2025120011
Chicago/Turabian StyleAl-Thani, Maha, Mary Goodwin-Trotman, Tom Van Agtmael, Hugh S. Markus, and Alessandra Granata. 2025. "Modelling COL4A1/2 SVD Associated Mutations—Towards New Treatment" Proceedings 120, no. 1: 11. https://doi.org/10.3390/proceedings2025120011
APA StyleAl-Thani, M., Goodwin-Trotman, M., Van Agtmael, T., Markus, H. S., & Granata, A. (2025). Modelling COL4A1/2 SVD Associated Mutations—Towards New Treatment. Proceedings, 120(1), 11. https://doi.org/10.3390/proceedings2025120011
