Using single-cell RNA sequencing, researchers have identified five unique cell types that are believed to drive idiopathic pulmonary fibrosis (IPF), a discovery that they said could potentially lead to earlier diagnosis and therapeutic drug targets. [Fotolia]

Using single-cell RNA sequencing, researchers have identified five unique cell types that are believed to drive idiopathic pulmonary fibrosis (IPF), a discovery that they said could potentially lead to earlier diagnosis and therapeutic drug targets.

The team—led by researchers at the Translational Genomics Research Institute (TGen), an affiliate of City of Hope, and Vanderbilt University Medical Center (VUMC)—pinpointed the five from 31 distinct cell subsets or states identified through an analysis of 114.396 cells sequenced.

“Together, our results provide substantial insight into the complexity, heterogeneity, and plasticity of the peripheral lung in human disease, building upon molecular atlasing efforts in the diseased and healthy lung,” the research team reported in in a study published yesterday in Science Advances, Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis.”

In their study, the researchers credited 10x Genomics and the Chan Zuckerberg Initiative for developing technology optimizations of the single-cell RNA sequencing; as well as the patients and organ donors whose lungs were studied.

Researchers analyzed tissue samples from 20 lungs with IPF provided by the Norton Thoracic Institute and VUMC, and tissue samples from 10 healthy lungs provided by the Donor Network of Arizona and the Tennessee Donor Services—of which eight came from current or former smokers who had undergone a period of mechanical ventilation.

Among the five IPF-linked cell types identified was KRT5/KRT17+, which appeared in the epithelium of the lungs, but only in individuals with pulmonary fibrosis.

“These cells are incredibly unique as they are clearly epithelial, but are also producing collagen and components of extra-cellular matrix, which make scar tissue,” Nicholas Banovich, Ph.D., an Assistant Professor in TGen’s Integrated Cancer Genomics Division and co-senior author of the study, said in a statement. “They are directly contributing to fibrosis.”

In addition to the KRT5/KRT17+ cells, the study identified a cell type marked by the gene SCGB3A2 that are found almost exclusively in in IPF. Unlike other airway epithelial cells, these cells appear to attempt to repair damage to the lung through their ability to  transform into type 1 alveolar cells (AT1), through which oxygen is taken into the body, and carbon dioxide expelled .

“In addition to becoming AT1 cells, our results suggest the SCGB3A2+ cells can also become the  KRT5/KRT17+ cells. It actually appears that, during the transformation into AT1 cells, the process is being hijacked and instead of helping repair the lungs these cells are pushed toward this weird pro-fibrotic epithelial cell that continues to drive fibrosis,” Banovich added.

Two other cells limited to IPF and unveiled by the study are distinct subsets of fibroblasts, marked by high levels of the genes PLIN2 or HAS1.

Another significant finding, according to Banovich, was the high degree of plasticity shown by cells in the lung epithelium.

“Classically, the field used a small number of genes to determine cell types. With the single cell RNA sequencing approach, we find that it is often hard to draw a firm line between different types of cells,” Banovich said. “Instead of thinking of them as discrete cell types, we should think of them more along a continuum, and given the right stimulus, these cells can change their state.”

The study’s findings are the first to be published under a combined $6.1 million in federal grants toward revealing the origins of IPF and other lung diseases. The U.S. Department of Veterans Affairs co-funded the study through grants, as did the Doris Duke Charitable Foundation, and Boehringer Ingelheim Pharmaceuticals.

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