Spatial Transcriptomics Unveils the Blueprint of Mammalian Lung Development

Mammalian lung development is a complex, highly orchestrated process involving the precise coordination of diverse cell types. Despite significant advances, the spatial gene expression patterns and regulatory mechanisms within the developmental niches of different lung structures remain incompletely understood. In this study, we present a comprehensive spatial transcriptomic atlas of mouse lung development, spanning from the early pseudoglandular to the alveolar stage. We further uncovered transcription factor (TF) regulatory landscapes by integrating the spatial epigenome, including novel TF-enhancer-driven regulons (eRegulons) critical for epithelial progenitors during early lung development. Our analysis also identified hundreds of spatiotemporally dynamic cell-cell communications, such as Bmp8b-mediated ligand-receptor signaling enriched in airway branching. Notably, we delineated the distinct developmental trajectories of alveolar AT1 and AT2 cells and revealed that collagen pathways facilitated their spatial convergence, forming primary alveoli during the canalicular-saccular transition. Together, this spatial transcriptomic atlas provides a foundational resource for understanding the complex cellular and molecular orchestration underlying mammalian lung development.