Developmental dynamics of ovine lung in health and cystic fibrosis at single-cell resolution

The sheep lung has long been used to model aspects of the human lung, both its normal development and pathological changes that occur in ovine models of lung disease. The similarities between the two species provide an opportunity to investigate phases of lung development that are not accessible for investigation in humans, for example later in gestation. Here we use single cell (sc) RNA-seq to investigate the developmental dynamics of the sheep proximal and distal lung from mid gestation (80 days) through late gestation (120 days) and term (147 days). We identify changes in cell identity and abundance between the time points that illustrate many key features of mesenchymal, endothelial, and epithelial differentiation. Lastly we compare the single cell profiles through development of wildtype (WT) sheep with those of animals of the same breed engineered to have a loss-of-function mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Mutations in CFTR cause cystic fibrosis (CF) and the CFTR^-/- sheep exhibit many features of CF in humans. The results identify cellular signatures in the CFTR^-/- lung before birth that may facilitate the understanding of clinical features of CF in early postnatal life.