A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

Abstract

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

“…Integrated UMAP overlay of our dataset (in red, Fig. 1F) with the published two datasets by He et al 9 , and Sountoulidis et al 10 , (combined, in grey) showed that 51 of the 58 cell clusters (~88%) were common amongst all three datasets (Fig. 1G and Extended Data Fig.…”

“…Moreover, due to the technical difficulties of accurately discerning "proximal" versus "distal" airways, our data could not resolve regional differences between proximal vs distal specific cell types, as has previously been shown 9 . Despite these technical differences, our data unbiasedly captured many of the cell types/states and developmental trajectories previously observed in recent datasets 9,10,33 . Finally, while our data aimed to prevent over-clustering by using Clustree to identify the optimal resolution for sub-clustering, it is possible that this method may not have resolved finer differences in cell states resulting in lower cell types/states identified.…”

“…Single-cell atlases of the adult human pulmonary system have illuminated the roles of key cell types in homeostasis and some diseases [3][4][5][6] . However, our understanding of the cells that form the developing fetal lung has largely been extrapolated from mouse studies 7,8 , and not until recently have there been studies leveraging scRNA-seq to characterize the developing human fetal lung tissue 9,10 . While some conserved pathways regulating lung development are common between mouse and human, studies have identified species-specific differences in lung cell types and cellular distributions, which can impact function and disease pathogenesis.…”

Single-cell RNA sequencing reveals the developmental program underlying proximal–distal patterning of the human lung at the embryonic stage

“…The rich diversity of cell origins in early lung development suggests the orchestration of different cell types from three germ layers upon organogenesis and proximal–distal patterning. Recently, human lung cell atlases from pseudoglandular to saccular stages were characterized at single-cell resolution 8 , 9 , 15 , 16 (Supplementary information, Fig. S1a ).…”

MyeloidZfhx3Deficiency Protects Against Hypercapnia-induced Suppression of Host Defense Against Influenza A Virus

“…While our findings emphasize the importance of Zfhx3 as a mediator of CO 2 effects on AMØs, we also demonstrate expression of Zfhx3 mRNA and protein in alveolar epithelial cells (Supplemental Figure 1B and 1D). Moreover, single-cell RNA sequencing documents Zfhx3 expression in a broad array of cell types during human lung development 37 , and specifically in AMØs, alveolar epithelial cells, ciliated and mucus-secreting airway epithelial cells, fibroblasts, smooth muscle cells, adventitial cells and others in adult mouse and human lungs 38,39 . Widespread expression among many, but not all, cell types during development and in the adult lung suggests that Zfhx3 has multiple functions, as would be expected for such a large and complex protein.…”