Therapeutic Extracellular Vesicles from Mesenchymal Stromal Cells: Can they help us restore lung development and evade BPD?

Abstract

There is currently no single effective therapy for either the prevention or treatment of bronchopulmonary dysplasia (BPD), whose incidence is on the rise. Therefore, the need for new tools to treat and reduce risks of further complications associated with extreme preterm birth is urgent. Therapies based on transplantation of mesenchymal stromal cells (MSCs) have shown effectiveness in preclinical models, and promise in recent Phase 1 clinical trials of preterm infants at high risk for BPD. Our studies over the past decade have established that the main therapeutic vector of MSCs is present in their secretome, and is comprised by Extracellular Vesicles (EV), including exosomes. These vectors are small (less than 150nm), lipid bilayer‐enclosed structures secreted by almost all cells. Their varied origin, biogenesis and molecular composition implicate them in diverse and pivotal physiological roles, the most intriguing of which is an effective method of cell‐to‐cell communication dubbed the ‘New Endocrinology’. Consequently, MSC exosomes/small EVs (termed MEx) represent promising novel reagents for therapeutic applications. Work from our group has shown that MEx can restore lung function in rodent experimental models of BPD. MEx treatment suppresses lung inflammation and lung emphysema and restores normal lung development when administered either prenatally to a high risk pregnancy (i.e., preeclampsia or chorioamnionitis), or postnatally, to neonatal mice exposed to hyperoxia‐induced lung injury. Importantly, MEx modulate both innate and adaptive immunity through their effect on lung monocyte/macrophage phenotypes and thymic T cell development as well as promoting bone marrow ‐ derived myeloid cells to adopt a non‐classical signature. Our observations support the hypothesis that reprogrammed monocytes, of bone marrow origin, mediate the protective effects of MEx therapy on the lung and other organs. MEx thus provide a novel platform for therapeutic intervention in the perinatal period to treat tissue injury associated with inflammatory insults and to restore lung development to a physiologic path.Support or Funding InformationSupported in part by NIH grants R01HL146128; United Therapeutics Research Grant; and Charles H. Hood Foundation Major Grants Initiative