Preterm Birth: Lung Complications and Stem Cells

Bronchopulmonary dysplasia (BPD) is the most common complication of prematurity characterized by a ‘reprogramming’ of lung growth with reduced alveoli, fewer blood vessels, and abnormal lung function. BPD has significant long-term pulmonary morbidities, including pulmonary hypertension (PH), airway hyperreactivity, abnormal pulmonary function test results, and, in some cases, emphysematous changes that persist into adulthood. Mesenchymal stem cells (MSCs) are recognized as potential cell-based therapy for diseases of the lung. These multipotent cells exhibit beneficial effects through anti-inflammatory, immunomodulatory, prosurvival and anti-fibrotic mechanisms that are not clearly defined. We showed that bone marrow-derived MSCs or their cell-free conditioned media (CM) prevent and reverse experimental lung injury in the neonatal mouse model of BPD. We isolated exosomes from human MSC-CM, termed MEX, and showed that they can prevent lung inflammation and PH in experimental models. A single dose of MEX given after 2 weeks of hyperoxic injury in neonatal mice abrogates inflammation and fibrosis and significantly improves alveolization. Exosomes are small vesicular structures produced by all cells that contain a distinct cargo which not only represents the cell of origin but is differentially-enriched in specific nucleic acid or lipid species. They serve as an important cell-to-cell communication mechanism. Our working hypothesis is that MEX restore lung homeostasis through immunomodulatory pathways, and enable lungspecific progenitor cells to repair lung injury. We will combine a multifaceted experimental design that includes studies on immune cell responses, human lung-on-a-chip microfluidic system, and human lung MSCs from infants with BPD to test the central hypothesis. Our specific aims are to (1) define the immunomodulatory properties of MEX and their effect on lung pathophysiology; and (2) elucidate the therapeutic efficacy of MEX in vivo on the neonatal hyperoxia model of BPD. Our goal is to develop the most optimal, well-characterized, and functional MSC exosome preparation for human application.