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Brain Vascular Malformation Insights Gleaned From Single-Cell Atlas

NEW YORK – Using single-cell RNA sequencing and spatial transcriptomics, a University of California, San Francisco-led team put together a catalogue of transcriptional features in vasculature tissues from normal brain samples and samples affected by a brain malformation condition linked to increased stroke risk.

"Many forms of dementia, including Alzheimer's, appear to have a vascular underpinning," co-senior and co-corresponding author Daniel Lim, a neurological surgery and neurosciences researcher at UCSF, said in a statement. "We need an atlas like this to better understand how changes in the vasculature can contribute to the loss of cognition and memory."

As they reported in Science on Thursday, the researchers used 10X Genomics Chromium scRNA-seq and the Rebus Esper platform from Rebus Biosciences to look at transcriptional features and spatially-resolved RNA profiles, respectively, in more than 74,535 individual cells in normal artery, vein, arteriole, capillary, and venule tissues isolated from cerebral cortex samples for five individuals with epilepsy who were treated with targeted lobectomies.

They went on to compare  profiles in that brain vasculature cell set with RNA data generated for another 106,853 brain vasculature cells in surgical samples from five individuals with brain arteriovenous malformation and to available mouse cerebrovascular data, teasing apart human-specific features as well as expression and cell type features specific to the vascular malformation samples.

In cells isolated from the normal brain vasculature samples, for example, the team tracked down 15 gene expression-based clusters, including profiles consistent with endothelial, pericyte, smooth muscle, and perivascular fibroblast cell types and expression clusters pointing to previously unappreciated cell subtypes.

When they compared the normal cell atlas to the 11 expression clusters identified using the arteriovenous malformation scRNA-seq profiles, the researchers homed in on brain malformation-related shifts in endothelial cell clusters and vascular patterning, along with interactions contributing to vascular inflammation.

By bringing in bulk RNA sequence data from more than two-dozen ruptured arteriovenous malformation samples and 13 unruptured arteriovenous malformation samples, meanwhile, the team got a look at genes that are differentially expressed during the brain hemorrhage process, highlighting changes in vascular cells and the immune microenvironment that coincided with the brain malformation ruptures.

"This research gives us the map and the list of targets to start developing new therapies that could change the way we treat a lot of cerebrovascular diseases," co-first author Ethan Winkler, a neurosurgeon and neurosciences researcher at UCSF's Weill Institute for Neurosciences, said in a statement.

"We recognize that this atlas represents only a first step toward a comprehensive census of the human cerebrovasculature," Lim, Winkler, and their co-authors wrote, though they suggested that the findings so far "should inform future studies in other brain regions or cerebrovascular diseases to accelerate mechanistic understanding and therapeutic targeting of the human cerebrovasculature."