Respiratory infections, such as those caused by SARS-CoV-2 or influenza, can damage the fragile capillary network of the lungs, affecting oxygen delivery and carbon dioxide removal. To overcome this damage, the lungs rely on the regenerative capacity of vascular endothelial cells. According to scientists at the University of Pennsylvania, as valuable as these cells are, they can benefit from a little help.
The scientists, led by Dr. Andrew Vaughan, focused on repair pathways involving vascular endothelial growth factor (VEGFA) and TGF-receptor 2 (TGF-R2). Using animal models and human tissue samples, scientists have shown that delivery of VEGFA via lipid nanoparticles (LNPs) can greatly enhance the repair mode of damaged blood vessels.
Details were recently published in an article in Science Translational Medicine titled "TGF-R2 Signaling Coordinates Pulmonary Vascular Repair in Mouse and Human Tissues After Viral Injury."
Mice lacking endothelial TGFBR2 showed long-term damage and a reduction in vascular repair," the authors of the article wrote. "Loss of endothelial TGFBR2 prevents the expression of autocrine VEGFA, reduces endothelial proliferation, and impairs the renewal of temperament cells, which are thought to be essential for alveolar gas exchange. ”
We have developed a lipid nanoparticle that targets the lung endothelium, Lung-LNP (LULNP)," the authors continued. "Lulnps delivers VEGFA mRNA, a key TGF-R2 downstream effector, that ameliorates the impaired regenerative phenotype of TGFBR2 deficiency in endothelial cells during influenza injury. ”
Vaughan's team and other researchers have previously shown that endothelial cells are one of the unsung heroes of repairing lungs after viral infection. But Vaughan's team noted that its work suggests that a "more nuanced understanding of the underlying mechanisms that drive lung endothelial reconstruction" could inform efforts to facilitate ** vascular repair.
Here, we have identified and isolated the pathways involved in the repair of this tissue, delivering mRNA to endothelial cells, whereby enhanced recovery of damaged tissue has been observed," Vaughan said. "These findings suggest a more effective way to promote lung recovery after illnesses such as COVID-19. ”
The team found that VEGFA was involved in this recovery, while they used single-cell RNA sequencing to identify TGF-R2 as the primary signaling pathway. The researchers found that when TGF-R2 was missing, it prevented the activation of VEGFA. The lack of this signal prevents vascular cells from reproducing and renewing themselves, which is essential for the exchange of oxygen and carbon dioxide in the tiny air sacs in the lungs.
We know there is a link between these two pathways, but this prompted us to see if delivery of VEGFA mRNA into endothelial cells can improve lung recovery after disease-related injury," said first author Dr. Gan Zhao, a postdoctoral researcher in Vaughan's lab.
Vaughn's lab then contacted Michael J. in the School of Engineering and Applied ScienceDr. Mitchell, whose lab specializes in LNP, is looking to see if it would be feasible to ship this mRNA cargo.
LNPs are very useful for vaccine delivery and have proven to be very effective delivery vehicles for genetic information," said Mitchell, associate professor of bioengineering at the University of Pennsylvania College of Engineering and co-author of the program. "But the challenge here is to get the LNPs into the bloodstream and not into the liver, which is where they tend to clump because its porous structure facilitates the passage of substances from the blood into the liver cells for filtration. Therefore, we must devise a method to specifically target the endothelial cells of the lungs.
The Mitchell lab's LNP has been shown to be effective in delivering VEGFA into endothelial cells, and as a result, the researchers have seen significant improvements in vascular recovery in their animal models. In animal models, researchers saw improvements in oxygen levels, and in some animal models, ** helped them regain weight better than the control group. These mice who received ** also had less inflammation in their lungs, which was manifested by lower levels of certain markers in their lung fluids, and they had less lung damage and scarring, and healthier blood vessels.
We look forward to testing this delivery platform in other cell types in the lungs, and it is important to assess whether TGF-R2 signaling is important in other injury settings, including chronic diseases such as emphysema and chronic obstructive pulmonary disease," Vaughan said. "With this proof-of-concept fully validated, we believe we will pave the way for a new mRNA-based strategy for lung injury.
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