The Human Lung Cell Atlas: A High-Resolution Reference Map of the Human Lung in Health and Disease

Abstract

Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas.

Keywords: Human Cell Atlas; single-cell RNA sequencing; spatial transcriptomics; systems biology.

Figure 1.

The discovery of the pulmonary ionocyte. The first systematic analysis of the diversity of epithelial cells lining the airways by single-cell technology was recently reported in the mouse (3). In addition to finding an unexpected diversity of club, tuft, and goblet cells in the murine airway, a new airway epithelial cell type was discovered. This novel cell type specifically expresses the transcription factor Foxi1, and its composite gene expression profile resembles those of specialized ion-transporting cells in fish gills, frog skin, and mammalian kidney. As these diverse cell types are collectively referred to as ionocytes, the new pulmonary epithelial cell has been coined a “pulmonary ionocyte.” Surprisingly, these cells also expressed the majority of Cftr (cystic fibrosis transmembrane conductance regulator gene), whose mutation causes cystic fibrosis (CF). The investigators found that deletion of Foxi1 in mice resulted in the loss of mature ionocytes and significantly altered mucus viscosity. FOXI1⁺ pulmonary ionocytes were also found to line the airways of human lung and express high levels of CFTR. Their role in ion transport, regulation of mucus, and high CFTR expression suggests that pulmonary ionocytes play a critical role in CF biology and disease.

Figure 2.

Cell types and cell states in the human lung cell atlas. (A) SFTPC-positive alveolar type-2 (AT2) cell clusters observed in lung parenchyma are shown in a dimension-reduced UMAP plot (left upper and lower panel). The heat map in the right panel shows constitutive genes defining AT2 cell type identity across eight healthy donors and clusters of genes that have been found to significantly differ between AT2 cells of different individuals. Hence, the constant features define the cell type, which can adopt multiple molecular phenotypes, or cell states, on the basis of the variable features. Adapted from Reference 53. (B) Data collected in the Human Lung Cell Atlas project will be used to define cell type identity in a hierarchical approach, which defines cell type by similarity metrics of their marker genes across many individuals. On the basis of these cell type identities and observed variation in facultative gene modules within the different cell types, we will generate predictive models of gene regulation that can be experimentally tested. These models will put (disease) genes in the context of their cell type–specific “gene regulatory environments” and predict the appearance of both constitutive and facultative gene modules as a function of time and space as occurring during lung development or regenerative and immune responses. HP = hypersensitivity pneumonitis; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; MERFISH = multiplexed error-robust fluorescence in situ hybridization; scATAC-seq = single-cell Assay for Transposase-Accessible Chromatin sequencing; scRNA-seq = single-cell RNA sequencing; SSc = systemic sclerosis; UMAP = uniform manifold approximation and projection.