GSE172251
Heterogeneous mesenchymal cell types modulate neonatal lung development and its response to hyperoxia
During the first days of life, the lung surface area increases explosively to enable efficient oxygen exchange. Alveolarization and angiogenesis involve profound changes within the lung mesenchyme to modulate extracellular matrix composition, tissue elasticity, and coordination with the lung epithelium and endothelium. To define the cell types and states populating the perinatal lung mesenchyme, we performed single cell transcriptomics and in-situ imaging in mice and discovered an extremely heterogeneous and dynamic landscape of fibroblasts, airway smooth muscle-like, and mural cells spanning fourteen distinct populations. In the fibroblast and airway smooth muscle-like compartments, bipotent progenitors differentiate rapidly within one day of birth and then again towards the end of alveolarization, while mural cell types are characterized by slow, gradual changes. Glucocorticoid release, retinoic acid inactivation, and oxygen sensing are controlled by specific stromal progenitors. A population of myofibroblasts arises postnatally, peaks at the onset of alveolarization and disappears before three weeks of age. Paracrine signaling with dozens of lung cell types decreases after birth and especially during alveolarization. Nonetheless, alveolarization is the most proliferative developmental stage, followed by a shift towards cell quiescence. Exposure to hyperoxia during the first week of life delayed the transcriptomic changes of normal development, mirroring the arrested development observed in human neonatal bronchopulmonary dysplasia (BDP). Hyperoxia also caused a severe loss of pericytes and myofibroblasts and reduced their proliferation, decreased mesenchymal-endothelial communications, gave rise to a small novel population of contractile alveolar fibroblasts and increased matrix adhesion and contractility across the mesenchyme. Overall design: scRNA-Seq on FACS sorted cells