Lineage tracing reveals the origins and dynamics of macrophages in lung injury and repair

Macrophages play a vital role in tissue repair and regeneration following injury. However, the cell fate, dynamic change, and functional roles of macrophages from different origins during lung injury and repair are not fully understood. Here we used genetic lineage tracing and scRNA-seq approaches to explore the temporal and spatial roles of tissue-resident and recruited macrophages during pulmonary fibrosis. We observed a sharp reduction in tissue-resident macrophages during the early inflammatory phase, with their number stabilizing during recovery. Monocytes contributed substantially to the macrophage population during the fibrotic phase, initially differentiating into interstitial macrophages and later transitioning into alveolar macrophages through a transient state. Genetic ablation of monocytes led to a reduction in recruited macrophages and alleviated pulmonary fibrosis. Mechanistically, Notch signaling was found to negatively correlate with Wnt/β-catenin signaling in regulating monocyte recruitment and pulmonary fibrosis. Our study revealed the dynamic contributions and functions of macrophages from various sources in lung injury and regeneration.