"Nature" New Cell Atlas - Brain Vascular Diagram

These cells make up only 0.
3 percent of brain cells, but also constitute the blood-brain barrier, a key interface that prevents pathogens and toxins from entering the brain, while allowing key nutrients and signals to pass through
.

Researchers from MIT have now performed extensive analysis of these hard-to-find human brain tissue cells, creating a comprehensive map of brain blood vessel cell types and their functions

Their research also revealed differences between brain blood vessel cells from healthy and Huntington's disease patients, which could provide new targets for potential treatments for Huntington's disease
.

Disruption of the blood-brain barrier is associated with Huntington's disease and many other neurodegenerative diseases, often years before other symptoms appear

"We think this could be a very promising route, because the cerebrovasculature is much closer to therapy than cells farther in the brain's blood-brain barrier," says Picower, MIT's Department of Brain and Cognitive Sciences Institute member Myriam Heiman said
.

Heiman and Manolis Kellis, professors of computer science at the MIT Computer Science and Artificial Intelligence Laboratory (CSAIL) and members of the Broad Institute of MIT and Harvard, are Senior author of the study, which was published today in the journal Nature
.

Francisco Garcia, a graduate student in MIT's Department of Brain and Cognitive Sciences, and Na Sun, in the Department of Electrical Engineering and Computer Science, are lead authors of the paper

A comprehensive cellular atlas

Cerebrovascular cells form a network of blood vessels that deliver oxygen and nutrients to the brain, and they also help remove debris and metabolites
.

The dysfunction of this irrigation system is thought to be responsible for the accumulation of deleterious effects seen in Huntington's disease, Alzheimer's disease and other neurodegenerative diseases

Many types of cells are found in the cerebrovascular system, but because they represent only a small fraction of brain cells, it is difficult to obtain enough cells for large-scale analysis by single-cell RNA sequencing
.

Such studies can decipher the gene expression patterns of individual cells, providing a wealth of information about the function of specific cell types, based on which genes are activated in those cells

For the study, the MIT team obtained more than 100 samples of human postmortem brain tissue, as well as 17 samples of healthy brain tissue removed during surgery to treat seizures
.

Tissue from brain surgery was obtained from younger patients compared to postmortem samples, which allowed the researchers to also identify age-related differences in the vasculature

The researchers performed single-cell RNA sequencing on more than 16,000 brain vascular cells and used the gene expression patterns of these cells to classify them into 11 distinct subtypes
.

These cells include endothelial cells that line blood vessels, parietal cells (including pericytes in the walls of capillaries) and smooth muscle cells (which help regulate blood pressure and flow), as well as fibroblasts

"This study allows us to zoom in on this incredible central cell type that drives all the functions of the brain," Kellis said.
"What
we're doing here is understanding the diversity of these building blocks and cell types at an unprecedented resolution.

Sex, they make up the vasculature of hundreds of individuals

The researchers also found evidence of a phenomenon known as zoning
.
This means that endothelial cells that line blood vessels express different genes depending on where they are located - in arterioles, capillaries or venules
.
In addition, of the hundreds of genes they found, only about 10 percent of the genes that were expressed differently in these three regions were the same as the ribbon genes previously found in the mouse cerebral vasculature
.

"We saw a lot of features that are unique to humans," Heiman said.
"Our
study provides a range of markers and a deep dive into gene function in these three distinct regions
.
We believe that from the perspective of the human cerebrovascular system, These things are important because conservation between species is not perfect
.
"

barrier rupture

The researchers also used their Neovasculature Atlas to analyze a set of postmortem brain tissue samples from patients with the disease, demonstrating its broad utility
.
They focused on Huntington's disease, a condition in which abnormalities of the cerebrovascular system include leakage of the blood-brain barrier and increased blood vessel density
.
These symptoms often appear before other symptoms of Huntington's disease and can be seen with functional magnetic resonance imaging (fMRI)
.

In this study, the researchers found that, compared with healthy cells, cells from Huntington's patients showed changes in the expression of a number of genes, including reduced expression of the gene MFSD2A, a key transporter that restricts the passage of lipids across the blood-brain barrier
.
They believe that the loss of this transporter, along with other changes they observed, could lead to increased leakage of the barrier
.

They also found that genes involved in the Wnt signaling pathway were up-regulated, promoting new blood vessel growth, and vascular endothelial cells showed unexpectedly strong immune activation, which may further lead to dysregulation of the blood-brain barrier
.

Because cerebrovascular cells can enter the body through the bloodstream, they could be an attractive target for treating Huntington's disease and other neurodegenerative diseases, Heiman said
.
The researchers now plan to test whether they can deliver potential drugs or gene therapies to these cells, and to study what therapeutic effects they might have on a mouse model of Huntington's disease
.

"Considering that cerebrovascular dysfunction occurs years before more specific disease symptoms appear, perhaps this is a contributing factor to disease progression," Heiman said.
"
If this is true, we can prevent it, which could be an important factor.
" Treatment opportunities
.
"

The researchers also plan to analyze more RNA-sequencing data from their tissue samples than just the cerebrovascular cells they examined in this paper
.

"Our goal is to build a systematic single-cell map to navigate brain function in health, disease, and aging across thousands of human brain samples," Kellis said
.
"This study is the first very small part of this atlas, looking at 0.
3 percent of cells
.
We are actively analyzing the other 99 percent of exciting collaborations, and many insights continue
.
"

Francisco J.
Garcia, Na Sun, Hyeseung Lee, Brianna Godlewski, Kyriaki Galani, Blake Zhou, Julio Mantero, David A.
Bennett, Mustafa Sahin, Manolis Kellis, Myriam Heiman.
Single-cell dissection of the human brain vasculature .
Nature , 2022