'Cell atlas' of brain vasculature connects stroke with novel immune
cells

Date:
January 27, 2022
Source:
University of California - San Francisco
Summary:
In work that will enhance the study of such disparate diseases
as stroke and dementia, researchers have catalogued all the cells
that form the blood vessels of the human brain, along with their
locations and the genes transcribed in each.



FULL STORY ==========================================================================
In work that will enhance the study of such disparate diseases as stroke
and dementia, researchers at UC San Francisco have catalogued all the
cells that form the blood vessels of the human brain, along with their locations and the genes transcribed in each.


==========================================================================
The atlas characterizes more than 40 previously unknown cell types,
including a population of immune cells whose communication with the
brain's vascular cells contributes to the bleeding of a hemorrhagic
stroke. This devastating form of stroke accounts for 10-15 percent of
all strokes in the U.S., mostly among younger people. About half of
hemorrhagic strokes are fatal.

The findings will serve as a foundation for new research on brain
vasculature globally, the scientists said.

"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," said Ethan Winkler, MD, PhD, a neurosurgeon
and research associate at the UCSF Weill Institute for Neurosciences
and one of the lead authors of the study, which appears in the Jan. 27
issue of Science.

Tangles in the brain's vasculature The team, headed by Adib Abla,
MD, associate professor of neurological surgery and Daniel Lim, MD,
PhD, professor of neurological surgery, both members of the UCSF Weill Institute for Neuroscience, along with Tomasz Nowakowski, PhD, analyzed
cells in arteriovenous malformations, or AVMs, tangles of poorly formed arteries in the brain that are often the source of a hemorrhagic stroke.

They compared the AVMs with samples of normal brain vasculature from
five volunteers who were already undergoing brain surgery for epilepsy.



========================================================================== UCSF, ranked #1 in neurosurgery by U.S. News, is a leading national
center for brain AVM surgery and care.

Some of the 44 samples of AVM tissue, acquired during delicate surgeries performed by Abla, Chief of Neurological Surgery, had been removed from
the patient's brain while still intact, and other samples were only
removed after they had started to bleed. The three varieties of tissue -- normal, intact AVMs, and AVMs that had bled -- allowed the researchers
to get a fuller picture of differences between how the cells function
normally and in different states of disease.

In collaboration with the Cerebrovascular Research Center, the team used single-cell mRNA sequencing on more than 180,000 cells to determine
which genes were being expressed in the differing samples and matched
gene expression with a cell's location. Chang Kim, a graduate student in bioinformatics at UCSF and co-lead author of the study, then developed
computer analyses that compared gene expression in the normal and
diseased cells.

An Immune Cell Surprise The results revealed not only a variety of new
cell types, but a population of immune cells that appear to communicate
with smooth muscle cells in the diseased arteries and weaken them,
resulting in a stroke. Scientists have suspected that the immune system is activated by malformations like AVMs. But Nowakowski said, "without this
study, we wouldn't be able to pinpoint this very specific population of
cells in the blood that might be the key drivers of disease progression." Identifying these specific immune cells completely changes how researchers
can think about treating this sort of vascular disease, he added. If
the cells circulate in the blood, it may be possible to reduce stroke
risk by modulating the immune system.



========================================================================== "This opens up huge therapeutic potential," said Nowakowski.

That potential extends beyond stroke. The map can help investigate any neurovascular disease, including one of the most common: dementia.

"Many forms of dementia, including Alzheimer's, appear to have a vascular underpinning," said Lim. "We need an atlas like this to better understand
how changes in the vasculature can contribute to the loss of cognition
and memory." "This work was a really a beautiful collaboration between surgeon-scientists and molecular biologists, occurring in a place with incredible access to clinical specimens," said Lim. "It's what makes
the Weill Institute of Neuroscience at UCSF so special." While many institutions don't have access to all of these critical resources, they
will have access to the dataset from this study, Lim added. Nowakowski
believes that this information will allow researchers across the world to perform much less expensive analyses on large numbers of patients, which
is the only way to get a fuller picture of how vascular diseases operate.

"Understanding cerebrovascular disease at the cellular and molecular level
will take the work of many researchers into new directions," Lim said.

A "Periodic Table" for Cells The team's study contributes to the Human
Cell Atlas, an international effort to create cell reference maps for
the entire body.

Nowakowski calls these atlases a "periodic table of cell types." Just
as the chemical periodic table organizes elements into a structure that
allows chemists to draw relationships between them based on where they
appear in the table, human cell atlases reveal the locations of cells
in the body and the resulting interactions between them.

While there is a lot of work taking place around the world to generate
these atlases for different organs and tissues, many of them only map
the geographic locations of cells. The comparison of normal and abnormal
cells in this research takes it to a higher level, providing extremely
refined guidance for drug development.

"Our study really demonstrates how a cell atlas can be utilized,"
Nowakowski said. "With our 'periodic table' as a reference, we can start
asking which cells might go wrong in disease and very precisely target
those cells for therapy." Additional authors include Jayden Ross, Joseph Garcia, Eugene Gil, David Wu, Kunal Raygor, Kazim Narsinh, Helen Kim,
Shantel Weinsheimer, Daniel Cooke, Nalin Gupta, and Edward Chang of UCSF.

This work was supported by NIH grants U54NS065705, R01NS034949,
R01NS099268, R01EB012031, R01NS034467, 5P01AG052350, R01NS112357,
F32CA228372 and U01MH115747, a Brain Aneurysm Foundation grant, Schmidt
Futures AI Accelerator grant, and other philanthropy.

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
University_of_California_-_San_Francisco. Original written by Robin
Marks. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ethan A. Winkler, Chang N. Kim, Jayden M. Ross, Joseph H. Garcia,
Eugene
Gil, Irene Oh, Lindsay Q. Chen, David Wu, Joshua S. Catapano,
Kunal Raygor, Kazim Narsinh, Helen Kim, Shantel Weinsheimer, Daniel
L. Cooke, Brian P. Walcott, Michael T. Lawton, Nalin Gupta, Berislav
V. Zlokovic, Edward F. Chang, Adib A. Abla, Daniel A. Lim, Tomasz
J. Nowakowski. A single-cell atlas of the normal and malformed
human brain vasculature.

Science, 2022; DOI: 10.1126/science.abi7377 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220127141558.htm

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