
In a recent study published in Nature Communications, researchers addressed the critical role of vascular endothelial cells in lung repair. The work, led by Andrew Vaughan, PhD, an assistant professor in the Department of Biomedical Sciences at the University of Pennsylvania School of Veterinary Medicine, examined techniques that deliver vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs). The research team confirmed this method’s ability to enhance modes of repair for damaged blood vessels, much like how plumbers patch sections of broken pipes and add new ones.
“While our lab, and others, has previously shown that endothelial cells are among the unsung heroes in repairing the lungs after viral infections like the flu, this tells us more about the story and sheds light on the molecular mechanisms at play,” said Dr. Vaughan. “Here we’ve identified and isolated pathways involved in repairing this tissue, delivered mRNA to endothelial cells and consequently observed enhanced recovery of the damaged tissue. These findings hint at a more efficient way to promote lung recovery after diseases like COVID-19.”
Investigators uncovered VEGFA’s association to lung repair while studying the use of single cell RNA sequencing to identify transforming growth factor beta receptor 2 (TGF-BR2) as a major signaling pathway. (This paper was published in Science Translational Medicine.) They found that when TGF-BR2 was absent, VEGFA activation ceased. This deficiency impacts the blood vessel cells’ ability to multiply and renew, which is critical in the exchange of oxygen and carbon dioxide in the lungs’ air sacs.
“We’d known there was a link between these two pathways, but this motivated us to see if delivering VEGFA mRNA into endothelial cells could improve lung recovery after disease-related injury,” said first author Gan Zhao, PhD, a postdoctoral researcher in the Vaughan Lab at Penn Vet.
The Vaughan Lab collaborated with Michael J. Mitchell, PhD, whose lab specializes in LNPs, to determine if this mRNA delivery would be feasible. Mitchell is an associate professor in the Department of Bioengineering at the University of Pennsylvania School of Engineering and Applied Science, and the director of the Lipid Nanoparticle Synthesis Core at the Penn Institute for RNA Innovation.
“LNPs have been great for vaccine delivery and have proven incredibly effective delivery vehicles for genetic information,” said Dr. Mitchell, a coauthor of the paper. “But the challenge here was to get the LNPs into the bloodstream without them heading to the liver, which is where they tend to congregate as its porous structure lends favor to substances passing from the blood into hepatic cells for filtration. So, we had to devise a way to specifically target the endothelial cells in the lungs.”
Lulu Xue, PhD, a postdoctoral researcher in the Mitchell Lab at Penn Engineering and a co-first author of the paper, said they built the LNPs to have an affinity for lung endothelial cells (known as extrahepatic delivery) to bypass the liver.
“We’ve seen evidence in the literature suggesting it’s doable, but the systems we’d seen were made up of positively charged lipids which were too toxic,” Dr. Xue said. “This led me to developing an ionizable lipid that’s not positively charged when it enters the bloodstream but gets charged when it gets to the endothelial cells, thereby releasing the mRNA.”
The research team’s LNP proved effective in delivering VEGFA into endothelial cells of its animal models, which resulted in a pronounced improvement in vascular recovery. Researchers saw improved oxygen levels and a decrease in lung inflammation, damage and scarring, shown by lower levels of certain markers in lung fluid. The treatment also positively reduced tumor size in models that had lung tumors.
“Although we went in hoping for this outcome, it was a real thrill to see how effective, safe and efficiently this all panned out, so we’re looking forward to testing this delivery platform for other cell types in the lung,” Dr. Vaughan said. “It will be important to evaluate whether TGFB signaling is important in other injury contexts, including chronic conditions like emphysema and COPD. With this proof-of-concept being well validated, we’re sure that we’ll pave the way for new mRNA-based strategies for treating lung injury.”
“Being able to target the lungs is potentially life-changing for someone with lung cancer or cystic fibrosis," said Dr. Mitchell.