FINDINGS

A UCLA-led research team has discovered a molecular switch that determines whether tiny blood vessels in premature infants' lungs can regenerate after injury. A failure of this repair process is a hallmark of bronchopulmonary dysplasia, or BPD, a serious lung disease that affects babies born very early. It arises from a combination of premature birth, inflammation or infection, and exposure to the high levels of oxygen and breathing support that are necessary to keep these infants alive during a critical period of lung development.

The researchers found that in BPD, the blood vessel cells in the lungs begin producing a shortened, nonfunctional isoform - a version of a protein - called NTRK2, which has been extensively studied in the nervous system but not in the pulmonary vasculature. When this shortened isoform dominates, the lung cannot rebuild the delicate network of tiny blood vessels needed for healthy breathing.

The team used messenger RNA, or mRNA - temporary instructions that tell cells how to make specific proteins - to restore production of the healthy, full-length protein isoform. This mRNA was packaged in lipid nanoparticles engineered to selectively deliver the therapy to lung endothelial cells, which line the inner surface of blood vessels, minimizing off-target effects in other lung cell types. In mouse models of BPD, this targeted approach restored blood vessel growth and supported the formation of healthy lung air sacs.

BACKGROUND

Bronchopulmonary dysplasia is one of the most common and challenging complications of extreme prematurity. Infants born very early often rely on supplemental oxygen and mechanical ventilation, interventions that are lifesaving but can injure the fragile, still-developing lungs.

BPD disrupts the formation of the tiny air sacs and blood vessels that allow oxygen exchange, which can leave children with long-term breathing difficulties, frequent hospitalizations and an increased risk of chronic lung disease. Currently, there are no treatments that repair the underlying vascular damage. Medical care focuses on managing symptoms rather than restoring normal lung growth.

The UCLA study provides a molecular explanation for why the lung's natural repair program falters, and points to a strategy that may be able to restart it.

METHOD

The research team used single-nucleus multiomic sequencing, which shows how genes work and are controlled inside individual cells, to analyze donated lung tissue from human infants with and without BPD. They discovered that the lung tissue with BPD contained a dysfunctional population of endothelial cells that overproduce the truncated NTRK2 isoform. The team then identified the regulatory pathways that drive these cells to shift from the full-length, repair-promoting form of NTRK2 to the shortened isoform that blocks vascular regeneration.

To test whether restoring the correct isoform could revive lung repair, the researchers delivered healthy, full-length NTRK2 messenger RNA directly to lung endothelial cells in newborn mice exposed to high oxygen - a standard model of BPD. They found the treatment increased blood vessel growth, improved the formation of healthy air sacs and reversed the structural damage caused by oxygen injury.

The team also tested the therapy in human blood vessel organoids, small 3D tissues grown from human induced pluripotent stem cells - cells that have been reprogrammed to a stem-like state from which they can produce nearly any cell type - that replicate key features of human vascular biology. Under high-oxygen conditions, these organoids typically show poor vessel growth. When treated with the full-length NTRK2 mRNA, the organoids produced more new blood vessels and formed a healthier, more organized vascular system.

IMPACT

The findings offer a new explanation for why premature lungs sometimes fail to recover after oxygen injury. By pinpointing an imbalance between healthy and truncated gene isoforms as a root cause of vascular failure, the study opens the door to targeted, disease-modifying treatments for BPD.

The successful use of this isoform-specific mRNA therapy in both mouse models and human stem cell-derived organoids suggests that the approach could one day advance toward clinical testing. The treatment strategy could also have broader implications for treating other diseases 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 down," said senior author Mingxia Gu, 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 lung rebuild the blood vessel network that infants need for healthy breathing."

The team plans to conduct additional preclinical studies to assess long-term safety and refine dosing, with the goal of eventually adapting the therapy for human infants. They also aim to explore whether similar gene-isoform strategies could promote vascular repair in other organs or injury settings.

JOURNAL

The study was published in the journal Cell Stem Cell.

AUTHORS

Other UCLA authors are Yunpei Zhang, Xiangdi Mao, Anmin Wang, Wusiman Maihemuti, Omar Milbes, Kavya Pandrangi, Colin Patrick Johnson and Varun Sekar. A full list of authors can be found in the paper.

FUNDING

This work was supported by the Cincinnati Children's Research Foundation, the National Institutes of Health and the American Heart Association.