Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity, characterized by arrest of normal lung development with reduced numbers of alveoli, fewer blood vessels, and associated inflammation leading to impaired lung function. It occurs in 30-40% of infants born at <28 weeks gestation, affecting ~15,000 infants per year. Historically, oxygen and ventilator-induced injury were prerequisites for BPD in premature infants with respiratory distress syndrome, but BPD is also found in very immature infants with few signs of initial lung injury.  BPD is associated with both adverse neurologic outcomes and significant long-term pulmonary morbidities: asthma, pulmonary hypertension and sometimes emphysema that persists into adulthood. Specific treatments are lacking: inhaled nitric oxide, antioxidants, vitamin A, caffeine, etc. have minimal effects; steroids decrease BPD, but may lead to neurologic impairments or increased mortality. Thus, the search for better treatment strategies to prevent and treat BPD continues.

We propose to test the effect of mesenchymal stem cell (MSC)-based treatments on neonatal models of BPD injury. MSCs are multipotent progenitor cells isolated from many sources, including the umbilical cord, and are being tested in human trials to treat BPD, but their mechanism of action is not fully elucidated and long term consequences of use in developing children are unknown. Our data show that MSCs provide lung protection by releasing extracellular vesicles (exosomes) that are delivered in place of cells and offer a safer, more effective treatment that avoids the tumorigenic potential of cell transplantation.  We will characterize MSC exosomes, determine their mechanism of action, and develop assays to determine their potency and efficacy, using cultured cells, human lung-on-a-chip assays, and preclinical models of BPD.