A research team from UCLA has identified a molecular switch that controls blood vessel growth in preterm infants’ lungs. When the switch occurs and fails to promote regeneration, a baby can develop bronchopulmonary dysplasia (BPD) — a serious lung disease that impacts infancy through years beyond.
The discovery was described in the paper, “Rebalancing NTRK2 Isoforms Promotes Vascular Regeneration in Bronchopulmonary Dysplasia,” published in the journal, Cell Stem Cell.
In babies with BPD, pulmonary blood vessel cells produce a shortened, nonfunctioning isoform called NTRK2. According to a UCLA news release, this type of protein has been examined extensively in the nervous system but not in the lungs. Researchers found that when NTRK2 takes over, the lungs cannot rebuild the network of tiny blood vessels a baby needs to breathe and have healthy lung function.
Currently, there is no cure for the vascular damage that occurs as a result of BPD. Treatment is focused on lessening symptoms. The new study, which demonstrates the molecular cause of the body’s inability to naturally repair the lungs, could create a therapeutic strategy to regenerate the healing process.
To obtain these molecular findings, the research team applied single nucleus, multiomic sequencing to analyze donated human infant lung tissue with and without BPD. The lung tissue from infants with BPD showed an abnormally high amount of endothelial cells responsible for the dysfunctional NTRK2 isoforms. This provided understanding on the regulatory pathways that drive these cells to switch from producing functional, full-length isoforms to the truncated ones that prevent vascular regeneration.
Researchers used newborn mouse models with BPD to test their findings. They administered mRNA packaged in lipid nanoparticles to deliver a therapy that restored production of the normal, full-length NTRK2 protein isoforms. The targeted approach resulted in increased blood vessel growth, improved formation of healthy air sacs and reversed structural damage caused by oxygen injury in the mice.
The UCLA team also tested the therapy in human blood vessel organoids and received similar results — new pulmonary blood vessel production and a healthier, more fully formed vascular system.
Authors of the study said their findings could lead to an innovative, disease-modifying therapy for BPD, as well as treatments for other conditions involving blood vessel injury.
“Our work shows that BPD is more than a complication of premature birth. The disease progresses when the lung’s natural repair system is shut own,” said senior author Mingxia Gu, MD, PhD, an associate professor of anesthesiology and perioperative medicine at the David Geffen School of Medicine at UCLA and a member of the UCLA Broad Stem Cell Research Center. “If we can restore the healthy version of this gene, we can turn the repair process back on and help the lungs rebuild the blood vessel network that infants need for healthy breathing.”
The researchers said they plan to assess long-term safety and refine dosing by conducting additional preclinical studies, with the ultimate goal of adapting the therapy for use in human premature infants.
