Progressive Increases in Mesenchymal Cell Diversity Modulate Lung Development and are Attenuated by Hyperoxia

Abstract

Early in life, the lung mesenchyme is extremely dynamic. We profiled the transcriptomes and locations of mesenchymal cells (MC) in the perinatal murine lung and observed cellular progressions of fibroblasts, myofibroblasts, airway smooth muscle (ASM), and mural cells, poised to modulate the extracellular matrix (ECM) with both subtype- and temporal-specific patterns. Within one day after birth, embryonic fibroblast precursors branched into two subtypes, alveolar and adventitial fibroblasts. ASM and myofibroblasts derived from a common precursor population that specifically expressed Crh, a hormone central to glucocorticoid release. Vascular smooth muscle cells and pericytes differentiated gradually. Fibroblast, myofibroblast, and pericyte proliferation peaked at 7 days after birth. Paracrine signaling among cell types decreased after birth and was hierarchical, with pericytes at the interface between endothelial cells and other MC. Postnatal hyperoxia delayed the developmental progression in cell type abundance and gene expression, mirroring the arrested development that characterizes the neonatal lung disease, bronchopulmonary dysplasia. Hyperoxia decreased pericyte and myofibroblast abundances and proliferation, dysregulated signaling, altered ECM modulation and, in males specifically, gave rise to a novel population of contractile fibroblasts. This study identifies the mesenchymal populations orchestrating lung development at the critical transition to air-breathing life and their distinct reactions to hyperoxia.