Scientists at the University of Illinois at Chicago analyzed gene expression data from more than 35,000 blood vessel cells from mouse lungs and identified two subtypes.
One subtype, which they call immune endothelial cells, or immunoECs, preferentially expressed more genes involved in inflammation and immune response regulation. The devEC subtype, for developing endothelial cells, expressed more genes involved in cell development, such as cell regeneration and proliferation.
The findings are published in the journal JCI Insight. They could lead to better treatments for lung infections, which can be dangerously exacerbated by uncontrolled inflammation.
The UIC team, led by Dr. Jalees Rehman, classified the subtypes by extracting lung tissue from mice engineered to express a fluorescent protein only on the endothelial cells of blood vessels. Using a fluorescent cell sorter, the scientists isolated endothelial cells from the lungs. They then sequenced the RNA of thousands of individual endothelial cells and classified them based on their prominent genetic signatures.
They found multiple groups of endothelial cells, with two dominant cell types, immunoEC and devEC, that changed over time during inflammation.
“Throughout our experiments, we consistently observed that lung blood vessel cells appear to have these different functions and groupings, with the two predominant groups becoming even more distinct when responding to infection or stress,” said Rehman, professor of the department of the UIC. of pharmacology and regenerative medicine and the department of medicine of the Faculty of Medicine. “Importantly, we also analyzed publicly available data sets from human lungs and found similar distinct groups of endothelial cells that we had observed in mouse lungs.”
In their experiments, Rehman and his colleagues studied cells from mice with healthy lungs and mice with damaged lungs or those fighting infections due to a bacterial toxin or influenza virus. While both subtypes were present in healthy and diseased lungs, the gene expression profiles of each subtype diverged further in response to infection or injury.
As disease or injury progressed, immunoECs expressed more immune response genes, such as major histocompatibility complex genes that act as a beacon for infection-fighting T cells. As the lungs improved, the devECs expressed more repair genes, such as the vascular development gene Sox17, which promotes the growth and regeneration of blood vessels. By analyzing the RNA profiles of lung endothelial cells obtained from non-human primates infected with SARS-CoV-2, the researchers also found distinct groups of lung endothelial cells.
“Part of the endothelial cells of the blood vessels become highly inflammatory and part of them retain that ability to regenerate,” Rehman said. “Our data also suggested that over time, the developmental subtype, which is essentially primed to regenerate, gives rise to cells that begin to proliferate and regenerate blood vessels that were damaged during infection.”
UIC scientists say understanding the wobbly balance between the subtypes and exploiting this division of labor could lead to specific treatments for conditions involving the blood vessels of the lungs, such as acute respiratory distress syndrome, which occurs during severe lung infections. . In these infections, immunoECs may play a key role in activating the initial immune response needed to fight pathogens. However, during severe infections, the immune system can overreact and start damaging its own lung tissue even after the virus or bacteria are gone.
“This study tells us that if we want to treat the blood vessels in the lungs, we need to specifically target the subtype that is out of balance. If the immune response is excessive, as is often the case in severe cases of COVID-19, it could be important to dampen immune regulatory endothelial cell activity while enhancing regenerative endothelial cell growth,” Rehman said. “By understanding that blood vessel cells have these different functions, we can work on therapies that are more targeted to one type of blood vessel cell than another type of blood vessel cell.”
Rehman said the findings are also a good reminder that our lungs are always in contact with the outside world, and this may be why the blood vessels in the lungs need such a fine balance between endothelial cell subtypes, that can activate or amplify the immune system. response, while other endothelial cells can help repair blood vessels after the infection begins to subside.
“We are always breathing in pathogens, unlike other organs like the heart or brain, which are much more protected from pathogens from the outside world. That’s why that balance, this intricate system that has both an inflammatory and a regenerative response, is so important in the lungs,” Rehman said.
The JCI Insight paper, “Single-cell transcriptomic profiling of lung endothelial cells identifies dynamic inflammatory and regenerative subpopulations,” is co-authored by the UIC research team, which included Lianghui Zhang, Shang Gao, Zachary White, Yang Dai, and Asrar Malik. .
The research was supported by grants from the National Institutes of Health (R01HL157489, P01HL060678, P01HL151327, R01HL90152, and R01HL152515) and the American Heart Association (18CDA34110068).