The role of resident lung mesenchymal stromal cells in normal and aberrant lung development

Abstract

Bronchopulmonary dysplasia (BPD) is the most common neonatal chronic lung disease occurring in premature infants due to ventilation and supplemental oxygenation. Lungs of BPD patients are characterized by growth arrest, alveolar hypoplasia and dysmorphic pulmonary circulation. No treatment for BPD is currently available. Preclinical studies uncovered the healing potential of cell-based therapies, in particular mesenchymal stromal cells (MSCs). Recent studies suggest an existence and potential repair capacity of resident lung (L)MSCs. In this study we have utilized two most commonly used rodent models of BPD characterized by alveolar hypoplasia and impaired lung vascularization: ventilation induced lung injury (VILI) and exposure to 85% normobaric hyperoxia. Using a single-cell RNA sequencing approach we identified the resident Sca1+ (Stem cell antigen-1+) cell population in the lungs of healthy and aberrantly developing mice on postnatal day (P) 3, P7 and P14. Population of Sca1+ cells increased with age in all lungs diseased lungs and was increased by hyperoxia at all time points investigated. Sca1+ LMSCs isolated from both, healthy and BPD mouse lungs, expressed characteristic stem cell markers (CD90, CD146, CD105), fibroblast-like phenotype in culture and showed an ability to form colonies in vitro. Moreover, LMSCs conditioned media increased migration of epithelial cells in vitro and both, LMSCs conditioned media, as well as LMSCs-derived exosomes induced network formation and spheroid sprouting in vitro. Our data suggest that LMSCs are able to modulate angiogenesis and may play a role in normal late lung development as well as in an aberrant development associated with BPD.