A new atlas of cells that carry blood to the brain
Single-cell gene expression analyses of human cerebrovascular cells can
help reveal new drug targets for Huntington's disease.
Date:
February 15, 2022
Source:
Massachusetts Institute of Technology
Summary:
Researchers created a comprehensive atlas of the types of cells
found in the brain cerebrovasculature, which provides oxygen and
nutrients to the brain and helps form the blood-brain barrier. They
also found significant differences between healthy cells and those
from Huntington's disease patients.
FULL STORY ========================================================================== While neurons and glial cells are by far the most numerous cells in the
brain, many other types of cells play important roles. Among those are cerebrovascular cells, which form the blood vessels that deliver oxygen
and other nutrients to the brain.
========================================================================== Those cells, which comprise only 0.3 percent of the brain's cells, also
make up the blood-brain barrier, a critical interface that prevents
pathogens and toxins from entering the brain, while allowing critical
nutrients and signals through. Researchers from MIT have now performed
an extensive analysis of these difficult-to-find cells in human brain
tissue, creating a comprehensive atlas of cerebrovascular cell types
and their functions.
Their study also revealed differences between cerebrovascular cells
from healthy people and people suffering from Huntington's disease,
which could offer new targets for potential ways to treat Huntington's
disease. Breakdown of the blood-brain barrier is associated with
Huntington's and many other neurodegenerative diseases, and often occurs
years before any other symptoms appear.
"We think this might be a very promising route because the
cerebrovasculature is much more accessible for therapeutics than the
cells that lie inside the blood-brain barrier of the brain," says Myriam Heiman, an associate professor in MIT's Department of Brain and Cognitive Sciences and a member of the Picower Institute for Learning and Memory.
Heiman and Manolis Kellis, a professor of computer science in MIT's
Computer Science and Artificial Intelligence Laboratory (CSAIL) and a
member of the Broad Institute of MIT and Harvard, are the senior authors
of the study, which appears today in Nature. MIT graduate students
Francisco Garcia in the Department of Brain and Cognitive Sciences, and
Na Sun in the Department of Electrical Engineering and Computer Science,
are the lead authors of the paper.
A comprehensive atlas Cerebrovascular cells make up the network of blood vessels that deliver oxygen and nutrients to the brain, and they also
help to clear out debris and metabolites. Dysfunction of this irrigation
system is believed to contribute to the buildup of harmful effects seen in Huntington's disease, Alzheimer's, and other neurodegenerative diseases.
==========================================================================
Many types of cells are found in the cerebrovasculature, but because
they make up such a small fraction of the cells in the brain, it has
been difficult to obtain enough cells to perform large-scale analyses
with single-cell RNA sequencing. This kind of study, which allows the
gene expression patterns of individual cells to be deciphered, offers
a great deal of information on the functions of specific cell types,
based on which genes are turned on in those cells.
For this study, the MIT team was able to obtain over 100 human
postmortem brain tissue samples, and 17 healthy brain tissue samples
removed during surgery performed to treat epileptic seizures. That brain surgery tissue came from younger patients than the postmortem samples,
enabling the researchers to also recognize age-associated differences
in the vasculature. The researchers enriched the brain surgery samples
for cerebrovascular cells using centrifugation, and ran postmortem
sample cells through a computational "sorting" pipeline that identified cerebrovascular cells based on certain markers that they express.
The researchers performed single-cell RNA-sequencing on more than 16,000 cerebrovascular cells, and used the cells' gene-expression patterns
to classify them into 11 different subtypes. These types included
endothelial cells, which line the blood vessels; mural cells, which
include pericytes, found in the walls of capillaries, and smooth muscle
cells, which help regulate blood pressure and flow; and fibroblasts,
a type of structural cell.
"This study allowed us to zoom in to this incredibly central cell type
that facilitates all of the functioning of the brain," Kellis says. "What
we've done here is understand these building blocks and this diversity
of cell types that make up the vasculature in unprecedented resolution,
across hundreds of individuals." The researchers also found evidence for
a phenomenon known as zonation. This means that the endothelial cells that
line the blood vessels express different genes depending on where they are located -- in an arteriole, capillary, or venule. Furthermore, among the hundreds of genes they identified that are expressed differently in the
three zones, only about 10 percent of them are the same as the zonated
genes that have been previously seen in the mouse cerebrovasculature.
==========================================================================
"We saw a lot of human specificity," Heiman says. "What our study
provides is a list of markers and insights into gene function in
these three different regions. These are things that we believe are
important to see from a human cerebrovasculature perspective, because
the conservation between species is not perfect." Barrier breakdown The researchers also used their new vasculature atlas to analyze a set of postmortem brain tissue samples from disease patients, demonstrating
its broad usefulness. They focused on Huntington's disease, where cerebrovasculature abnormalities include leakiness of the blood-brain
barrier and a higher density of blood vessels. These symptoms usually
appear before any of the other symptoms associated with Huntington's,
and can be seen using functional magnetic resonance imaging (fMRI).
In this study, the researchers found that cells from Huntington's
patients showed many changes in gene expression compared to healthy
cells, including a decrease in the expression of the gene for MFSD2A,
a key transporter that restricts the passage of lipids across the
blood-brain barrier. They believe that the loss of that transporter,
along with other changes they observed, could contribute to increased
leakiness of the barrier.
They also found upregulation of genes involved in the Wnt signaling
pathway, which promotes new blood vessel growth and that endothelial
cells of the blood vessels showed unexpectedly strong immune activation,
which may further contribute to blood-brain barrier dysregulation.
Because cerebrovascular cells can be accessed through the bloodstream,
they could make an enticing target for possible treatments for
Huntington's and other neurodegenerative diseases, Heiman says. The
researchers now plan to test whether they might be able to deliver
potential drugs or gene therapy to these cells, and study what therapeutic effect they might have, in mouse models of Huntington's disease.
"Given that cerebrovascular dysfunction arises years before more
disease- specific symptoms, perhaps it's an enabling factor for disease progression," Heiman says. "If that's true, and we can prevent that,
that could be an important therapeutic opportunity." The researchers also
plan to analyze more of the RNA-sequencing data from their tissue samples, beyond the cerebrovascular cells that 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 says. "This study is one of the first bite-sized
pieces of this atlas, looking at 0.3 percent of cells. We are actively analyzing the other 99 percent in multiple exciting collaborations,
and many insights continue to lie ahead." The research was funded
by the Intellectual and Developmental Disability Research Center
and Rosamund Stone Zander Translational Neuroscience Center at Boston Children's Hospital, a Picower Institute Innovation Fund Award, a Walter
B. Brewer MIT Fund Award, the National Institutes of Health, and the
Cure Alzheimer's Fund.
special promotion Explore the latest scientific research on sleep and
dreams in this free online course from New Scientist -- Sign_up_now_>>> ========================================================================== Story Source: Materials provided by
Massachusetts_Institute_of_Technology. Original written by Anne
Trafton. Note: Content may be edited for style and length.
========================================================================== Journal Reference:
1. 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; DOI: 10.1038/s41586-022-04521-7 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220215125507.htm
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