During lung development, the alveolar region, which is essential for gas exchange, is subdivided into smaller units by the formation of new walls (septa) to maximise the respiratory surface area of the lung. This process, called alveologenesis, is initiated by the formation of septal ridges that contain multiple mesenchymal cell types, including alveolar myofibroblasts (MyoFBs), lipid-rich matrix fibroblasts and adventitial fibroblasts, all of which remain poorly understood. In this work, David Ornitz and colleagues define the repertoire of lung fibroblasts, their lineage-specific differentiation programmes and associated gene expressions, with a focus on transient MyoFBs that are crucial during initial alveologenesis but absent in adult lungs. First, the authors find that MyoFB maturation progresses linearly in the mouse neonatal lung, deriving from a lineage distinct from that of matrix and adventitial fibroblasts. Further, the signalling molecules FGF9 and FGF18 showed increasing expression as MyoFBs mature, indicating a potential role for these ligands in regulating MyoFB lineage-specific functions. Overall, this work characterises the transcriptome and differentiation pathways of lung fibroblasts during alveologenesis that will likely serve as a comprehensive resource to the research community for future work.
