Spatiotemporal transcriptome atlas of developing mouse lung.

Abstract

The functional development of the mammalian lung is a complex process that relies on the spatial and temporal organization of multiple cell types and their states. However, a comprehensive spatiotemporal transcriptome atlas of the developing lung has not yet been reported. Here we apply high-throughput spatial transcriptomics to allow for a comprehensive assessment of mouse lung development comprised of two critical developmental events: branching morphogenesis and alveologenesis. We firstly generate a spatial molecular atlas of mouse lung development spanning from E12.5 to P0 based on the integration of published single cell RNA-sequencing data and identify 10 spatial domains critical for functional lung organization. Furthermore, we create a lineage trajectory connecting spatial clusters from adjacent time points in E12.5-P0 lungs and explore TF (transcription factor) regulatory networks for each lineage specification. We observe the establishment of pulmonary airways within the developing lung, accompanied by the proximal-distal patterning with distinct characteristics of gene expression, signaling landscape and transcription factors enrichment. We characterize the alveolar niche heterogeneity with maturation state differences during the later developmental stage around birth and demonstrate differentially expressed genes, such as Angpt2 and Epha3, which may perform a critical role during alveologenesis. In addition, multiple signaling pathways, including ANGPT, VEGF and EPHA, exhibit increased levels in more maturing alveolar niche. Collectively, by integrating the spatial transcriptome with corresponding single-cell transcriptome data, we provide a comprehensive molecular atlas of mouse lung development with detailed molecular domain annotation and communication, which would pave the way for understanding human lung development and respiratory regeneration medicine.