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Single-Cell Atlas of Human Lung Highlights Differences Between Healthy, Diseased States

NEW YORK – Several teams of international researchers have built the Human Lung Cell Atlas (HLCA), which they said is the most comprehensive cell map of the human lung.

In a paper published in Nature Medicine on Thursday, the researchers presented their findings and said that the HLCA will serve as universal reference for future single-cell lung studies on pulmonary health and disease.

"It is an important step to develop new therapies, as well as novel diagnostic and prognostic markers for lung diseases," senior author Martijn Nawijn, professor at the University Medical Center Groningen in the Netherlands, told GenomeWeb.

For their study, Nawijn and colleagues combined into a single atlas 49 datasets from nearly 40 previously published single-cell RNA sequencing studies of the human respiratory system. These studies contained information from 2.4 million cells from 486 people, a number far greater than previously published studies. While the core of the Human Lung Cell Atlas is data from healthy lungs, the team also took datasets from more than 10 different lung diseases and projected these onto the healthy data to understand disease states. One of the biggest challenges of developing the integrated Human Lung Cell Atlas was that researchers use different names for the same cell type, or the same name for different cells, lead author, Lisa Sikkema, a Ph.D. student at the Institute of Computational Biology at Helmholtz Munich, said in a statement. "So, as a team we worked to standardize them using the data in the atlas," she noted.

Analysis of the data also led to the discovery of rare cell types in human lungs, such as ionocytes, tuft cells, neuroendocrine cells, and specific immune cell subsets, which are difficult to identify in individual datasets, according to the researchers.

The researchers also used the HLCA to understand how cells change with a person's, age, sex, body mass index, and smoking status. For instance, they found that sex is most associated with transcriptomic variation in lymphatic endothelial cells, whereas BMI is most associated with variation in B and T cells. "These associations provide a systematic overview of the effects of biological and technical factors on the transcriptional state of lung cell types," the authors wrote.

However, the most important finding, according to Nawijn, was that some cell types were common in multiple lung diseases but were not seen in healthy people. One of these was profibrotic monocyte-derived macrophages, which were present across lung diseases including COVID-19, pulmonary fibrosis, and lung carcinoma.

"It seems like some biological processes are common among many diseases, which indicates that you could use the same therapy for these multiple diseases," said Nawijn.

While the HLCA could prompt new therapeutic innovations, it still has major limitations. For example, 65 percent of the HLCA core data came from individuals of European ethnicity and most of them were men. It did not include data from children and people of old age, said Nawijn.

Researchers have already started working on the second iteration of the atlas, which aims to have diverse donor sample sets. Nawijn said he hopes this next version gets published in three years, "otherwise, our findings will be relevant for only a small proportion of people, and we don't want that."

The project involved nearly 100 partners from more than 60 departments worldwide, with key contributions from Helmholtz Munich, University Medical Center Groningen, and Northwestern University. The team is part of the Human Cell Atlas Lung Biological Network, which is rooted in the Chan Zuckerberg Initiative Seed Networks for the Human Cell Atlas, and the EU-funded lung network DiscovAIR, according to a statement. The overarching Human Cell Atlas initiative, begun in 2016, aims to map every cell type in the human body.