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

Epithelial barriers are programmed for defense and repair but are also the site of long-term structural remodeling and disease. In general, this paradigm features epithelial stem cell (ESCs) that are called on to regenerate damaged tissues but can also be reprogrammed for detrimental remodeling. Here we identify a Wfdc21-dependent monocyte-derived dendritic cell (moDC) population that functions as an early sentinel niche for basal-ESC reprogramming in mouse models of epithelial injury after respiratory viral infection. Niche function depends on moDC delivery of ligand Gpnmb to basal-ESC receptor CD44 so that properly timed antibody blockade of ligand or receptor provides long-lasting correction of reprogramming and broad disease phenotypes. These same control points work directly in mouse and human basal-ESC organoids, and corresponding biomarkers track with comparable lung diseases in humans. Together, the findings identify a mechanism to explain and modify what is otherwise a stereotyped but sometimes detrimental response to epithelial injury. Overall design: Lung tissue RNA was purified from four mice per sample condition (moDCs or monocytes for 12 d after SeV infection or PBS control challenge) and subjected to RNAseq.