In the intricate landscape of the human body, the lungs and their vasculature resemble a complex network akin to the plumbing system of a building. Within this anatomical framework, the lungs' blood vessels serve as vital conduits, facilitating the transportation of blood and essential nutrients for oxygenation and carbon dioxide removal. Just as pipes in a building can succumb to rust or blockages, respiratory viruses like SARS-CoV-2 or influenza can inflict damage, disrupting this intricate “plumbing system.”
In a recent scientific inquiry, researchers delved into the pivotal role of vascular endothelial cells in lung repair. Led by Andrew Vaughan of the University of Pennsylvania's School of Veterinary Medicine, their study, featured in Science Translational Medicine, showcased innovative approaches involving the delivery of vascular endothelial growth factor alpha (VEGFA) via lipid nanoparticles (LNPs). This novel technique aimed to bolster the repair mechanisms of damaged blood vessels, akin to the interventions of skilled plumbers tasked with patching and replacing sections of compromised piping.
Vaughan, Assistant Professor of Biomedical Sciences at Penn Vet, elaborated on their findings: “While our prior research, along with contributions from other laboratories, underscored the significance of endothelial cells in lung repair post-viral infections like influenza, our latest study delves deeper, unraveling the molecular intricacies underlying this phenomenon.”
He continued, “Through our investigation, we pinpointed and elucidated the pathways essential for tissue repair, leveraging mRNA delivery to endothelial cells to facilitate enhanced recovery post-injury. These insights offer promising avenues for promoting lung regeneration following diseases such as COVID-19.”
The study highlighted the involvement of VEGFA in the repair process, building upon previous research that identified transforming growth factor beta receptor 2 (TGFBR2) as a key signaling pathway.
Examining the interplay between these pathways, the researchers discovered that the absence of TGFBR2 impeded the activation of VEGFA. Consequently, blood vessel cells exhibited reduced proliferative capacity and self-renewal capabilities, critical for efficient gas exchange within the lung's alveolar sacs.
Gan Zhao, a postdoctoral researcher in the Vaughan Lab and the study's first author, remarked, “Our exploration into the synergy between these pathways motivated us to explore whether delivering VEGFA mRNA to endothelial cells could enhance lung recovery post-disease-related injury.”
Recognizing the potential of LNPs in facilitating mRNA delivery, the Vaughan Lab collaborated with Michael Mitchell of the School of Engineering and Applied Science, whose expertise centered on LNPs.
Mitchell, an Associate Professor of Bioengineering at Penn Engineering and a co-author of the study, highlighted the challenge of ensuring targeted delivery of LNPs to lung endothelial cells, bypassing the liver where they typically accumulate.
“We tailored the LNPs to exhibit an affinity for lung endothelial cells, enabling extrahepatic delivery beyond the liver,” explained Lulu Xue, a co-first author of the paper and a postdoctoral researcher in the Mitchell Lab.
Through innovative approaches and interdisciplinary collaboration, the study sheds light on novel strategies for enhancing lung repair mechanisms, offering hope for improved therapeutic interventions in the aftermath of respiratory diseases.
Source: University of Pennsylvania