A correctable immune niche for basal-epithelial stem-cell reprogramming and post-viral lung diseases

Epithelial barriers are programmed for defense and repair but are also frequently the site of long-term remodeling disease. In general, this paradigm features activation of epithelial stem cells that coordinate organ development but persist into adult life to regenerate damaged tissues. Here we identify a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functions as an early sentinel niche for basal-epithelial stem cells (basal-ESC) growth and feed-forward inflammation in mouse models of epithelial injury due to respiratory viral infections. This niche function depends on Gpnmb-CD44 signaling so that transient but properly timed antibody blockade of ligand or receptor provides long-lasting disease correction in these injuries. These same control points are found for mouse and human basal-ESC-derived organoids, and the corresponding biomarkers track with comparable lung diseases in humans. Together, the findings identify a mechanism to explain and modify basal-ESC reprogramming in what is otherwise a stereotyped, primordial response to epithelial injury. Overall design: Total lung RNA were extracted from SeV-infected WT and Wfdc21KO mice at 12, 21, and 49 days post infection or control PBS challenge and was purified and subjected to scRNAseq using the 10x Genomics platform