UCSF researchers Jaymin Kathiriya, PhD, Chaoqun Wang, PhD, Drs. Kathiriya and Wang, under supervision Hal Chapman, MD and Tien PengMD, respectively, used stem cell organoid models to reveal a new stem cell pathway observed in severely damaged lungs of COVID-19 patients and idiopathic pulmonary fibrosis patients.
This study provided a roadmap to understand how severely damaged lungs can regenerate and scar, and provided a possible route to reverse the remodeling by targeting abnormal stem cell differentiation.
It has been previously accepted that the regenerative capacity of alveolar stem cells (AEC2s) worked similarly in mice and humans. The researchers unexpectedly found that human AEC2s (hAEC2s), unlike murine AEC2s, are highly converted to functional basal cells by hints of pathological fibroblasts.
In vitro single-cell analysis of the hAEC2-to-basal cell pathway revealed the existence of transitional cell types and basal cell subgroups previously identified in lungs with idiopathic pulmonary fibrosis (IPF).
Utilizing a new fibroblast / hAEC2 organoid medium, the authors were able to model stem cell metaplasia or abnormal stem cell differentiation observed in severe alveolar damage.
In addition, the finding that hAEC2s can produce pathological transitional cell types and stem cells provided experimental confirmation of the stem cell pathway seen in diseased human lungs.
“The first time we saw hAEC2 differentiate into stem cells, it was so striking that we thought it was a mistake,” Peng said.
“But rigorous validation of this new trajectory has provided tremendous information on how the lungs regenerate in response to serious injury, and a possible route to repair the damage,” Peng added.
The finding that hAEC2s undergo progressive transdifferentiation into metaplastic stem cells is not unique to IPF. Alveolar metaplastic basal cells are also common in parts of the scleroderma and COVID lungs, and these are mixed with transitional cells in areas of active remodeling.
The general discovery of transitional cells in hAEC2-derived organoids as well as in hAEC2 xenografts and fibrotic lung histological analyzes suggested that hAEC2s are the major source of metaplastic basal cells in diseases with severe alveolar damage.
The study provided a basis for future research to identify therapeutic targets that can prevent or reverse metaplastic differentiation in severe lung injury and whether other components of the fibrotic niche, such as endothelial cells and immune cells, can control the metaplastic phenotype.
Source: The Nordic Page