An international research team reports that the developing human lung has been mapped in great detail while uncovering new links between developmental cells and lung cancer in the process. This latest study “A human fetal lung cell atlas uncovers proximal-distal gradients of differentiation and key regulators of epithelial fates”, appears in Cell and is part of the Human Cell Atlas initiative to map every cell type in the human body.

Scientists at the Wellcome Sanger Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI), the Gurdon Institute at the University of Cambridge, and collaborators, examined which genes are activated in different stages of lung development, one cell at a time. They combined this with spatial technologies, which pinpoint the exact location of cells, to create the Developmental Lung Cell Atlas, showing how the respiratory system comes into being.

“We present a multiomic cell atlas of human lung development that combines single-cell RNA and ATAC sequencing, high-throughput spatial transcriptomics, and single-cell imaging. Coupling single-cell methods with spatial analysis has allowed a comprehensive cellular survey of the epithelial, mesenchymal, endothelial, and erythrocyte/leukocyte compartments from 5–22 post-conception weeks,” the investigators wrote.

“We identify previously uncharacterized cell states in all compartments. These include developmental-specific secretory progenitors and a subtype of neuroendocrine cell related to human small cell lung cancer. Our datasets are available through our web interface. To illustrate its general utility, we use our cell atlas to generate predictions about cell-cell signaling and transcription factor hierarchies which we rigorously test using organoid models.”

A freely available resource

The atlas provides a unique and freely available resource that describes not only the individual cells that are created while the lungs are forming, but also how these processes are controlled by genes, according to the researchers, who added that it also acts as a guidebook to healthy lung development and can be used as a baseline to investigate how lung diseases originate. It could also be used to create new models to study lung conditions and test potential therapies.

To create this Developmental Lung Cell Atlas, researchers from the Wellcome Sanger Institute and collaborators combined single-cell sequencing of early-stage cells with spatial technologies to generate an in-depth dataset of lung development. The Atlas describes which cell types are present in the developing lung architecture and how these are regulated.

The team, which identified 144 cell types, such as intermediate and transitional cell types, including a subtype that could be linked to the development of human small cell lung cancer later in life, used the atlas to make predictions about how lung cells develop, especially which genes are the key players driving this process. They then used organoid models to validate the emerging hypotheses, demonstrating that the atlas can be used to accurately predict the stages and cells involved in tissue development.

A separate study is using this dataset to investigate neonatal lung disease, with the aim of uncovering insights about the causal mechanisms and developing new organoid models to aid further research.

“Our high-resolution computational analysis has identified previously undescribed and rare populations in the developing human lung,” said Peng He, PhD, co-first author from the Wellcome Sanger Institute and EMBL-EBI.

“In these new populations, we found one that is associated with a poorly understood type of small lung cell cancer in adults. While further research is required to understand the link, this shows the important insights into mechanisms shared by development and disease that can be found using our unique cell atlas. In addition to this, by including chromatin accessibility data and in vitro perturbation experiments, our work shows how key transcription factors can individually dictate lineage choices, allowing us to start to understand the regulatory logic that controls differentiation pathways.”