Lab-Grown ‘Small Blood Vessels’ Point to Potential Treatment for Major Cause of Stroke and Vascular Dementia

Cerebral small vessel disease (SVD) is a leading cause of age-related cognitive decline and contributes to almost half (45%) of dementia cases worldwide. It is also responsible for one in five (20%) ischemic strokes, the most common type of stroke.

The majority of cases of SVD are associated with conditions such as hypertension and type 2 diabetes, and tend to affect people in their middle age. However, there are some rare, inherited forms of the disease that can strike people at a younger age, often in their mid-thirties. Both the inherited and ‘spontaneous’ forms of the disease share similar characteristics.

Scientists used cells taken from skin biopsies of patients with one of these rare forms of SVD, which is caused by a mutation in a gene called COL4.

By reprogramming the skin cells, they were able to create induced pluripotent stem cells. The team then used these stem cells to generate cells of the brain blood vessels and create a model of the disease that mimics the defects seen in patients’ brain vessels.

Dr Alessandra Granata who led the study, said: “Despite the number of people affected worldwide by small vessel disease, we have little in the way of treatments because we don’t fully understand what damages the blood vessels and causes the disease. Most of what we know about the underlying causes tends to come from animal studies, but they are limited in what they can tell us.

“That’s why we turned to stem cells to generate cells of the brain blood vessels and create a disease model ‘in a dish’ that mimics what we see in patients.”

Our blood vessels are built around a type of scaffolding known as an extracellular matrix, a net-like structure that lines and supports the small blood vessels in the brain. The COL4 gene is important for the health of this matrix.

In their disease model, the team found that the extracellular matrix is disrupted, particularly at its so-called ‘tight junctions’, which ‘zip’ cells together. This leads to the small blood vessels becoming leaky — a key characteristic seen in SVD, where blood leaks out of the vessels and into the brain.

The researchers identified a class of molecules called metalloproteinases (MMPs) that play a key role in this damage. Ordinarily, MMPs are important for maintaining the extracellular matrix, but if too many of them are produced, they can damage the structure.

When the team treated the blood vessels with drugs that inhibit MMPs — an antibiotic and anti-cancer drug — they found that these reversed the damage and stopped the leakage.

Dr Granata added: “These particular drugs come with potentially significant side effects so wouldn’t in themselves be viable to treat small vessel disease. But they show that in theory, targeting MMPs could stop the disease. Our model could be scaled up relatively easily to test the viability of future potential drugs.”

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Sources:

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. A novel human iPSC model of COL4A1/A2 small vessel disease unveils a key pathogenic role of matrix metalloproteinases. Stem Cell Reports, 2023; DOI: 10.1016/j.stemcr.2023.10.014

University of Cambridge. “Lab-grown ‘small blood vessels’ point to potential treatment for major cause of stroke and vascular dementia.” ScienceDaily. ScienceDaily, 16 November 2023. <www.sciencedaily.com/releases/2023/11/231116141041.htm>.

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