Illustration of the lungs to represent lung disease, which can be diagnosed using specialist ultrasound

New research uncovers details of how severe injuries trigger lung stem cells to scar. The study, from UCSF researchers, also points to a potential target for reversing this process. The team used organoid models to study stem cell differentiation in lungs severely injured from COVID-19 and idiopathic pulmonary fibrosis.

The work was featured December 30 in Nature Cell Biology. The lead authors are Jaymin Kathiriya, Ph.D., and Chaoqun Wang, Ph.D.

Severe injuries to the lung from diseases such as COVID-19 trigger abnormal stem cell repair that alters the architecture of the lung. The aberrant stem cell differentiation in response to injury can prevent the restoration of normal lung function.

The regenerative capacity of alveolus (AEC2s) stem cells is believed to operate similarly in mice and humans. But these researchers found that human AEC2s (hAEC2s), unlike mouse AEC2s, robustly transdifferentiate into functional basal cells with cues from pathological fibroblasts.

According to their work, hAEC2s, but not mAEC2s, can differentiate into KRT5+ basal cells in organoid culture and xenotransplant. Moreover, they found pro-fibrotic mesenchymal niche-derived factors that promote hAEC2-to-basal cell transdifferentiation. They also found that basal cells and advanced alveolar-basal intermediates are surrounded by aberrant, CTHRC1hi pro-fibrotic mesenchyme.

Their results point to hAEC2s as a source of metaplastic KRT5+ basal cells in severe alveolar injuries and provide a potential explanation for the reported appearance of aberrant hAEC2s with basaloid features in the transcriptomes of IPF and other severe lung injures such as COVID pneumonia.

Single-cell analysis of the hAEC2-to-basal cell trajectory in vitro revealed the presence of transitional cell types and basal cell subsets previously identified in lungs with Idiopathic Pulmonary Fibrosis (IPF).

Using a novel fibroblast/hAEC2 organoid platform, the authors modeled the stem cell metaplasia, or abnormal stem cell differentiation, seen in severe alveolar injury. Furthermore, the discovery that hAEC2s can generate pathologic transitional cell types and basal cells provides experimental confirmation of a stem cell trajectory that is seen in diseased human lungs.

“The first time we saw hAEC2s differentiating into basal cells, it was so striking that we thought it was an error,” said Peng. “But rigorous validation of this novel trajectory has provided enormous insight on how the lung remodels in response to severe injury, and a potential path to reverse the damage.”

The finding that hAEC2s undergo progressive transdifferentiation to metaplastic basal cells is not unique to IPF. Alveolar metaplastic basal cells are also common in sections of scleroderma and COVID lungs, and these are intermingled with transitional cells in areas of active remodeling.

The common finding of transitional cells in hAEC2-derived organoids as well as hAEC2 xenografts and in histologic analyses of fibrotic lungs, suggest hAEC2s are a major source of metaplastic basal cells in diseases with severe alveolar injury.

The study provides the groundwork for future research to identify therapeutic targets that might prevent or reverse metaplastic differentiation in severe lung injury, and whether other components of the fibrotic niche such as endothelial cells and immune cells are able to drive the metaplastic phenotype.

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