Contribution of <i>Trp63^CreERT2</i>-labeled cells to alveolar regeneration is independent of tuft cells.

Abstract

Viral infection often causes severe damage to the lungs, leading to the appearance of ectopic basal cells (EBCs) and tuft cells in the lung parenchyma. Thus far, the roles of these ectopic epithelial cells in alveolar regeneration remain controversial. Here, we confirm that the ectopic tuft cells are originated from EBCs in mouse models and COVID-19 lungs. The differentiation of tuft cells from EBCs is promoted by Wnt inhibition while suppressed by Notch inhibition. Although progenitor functions have been suggested in other organs, pulmonary tuft cells don't proliferate or give rise to other cell lineages. Consistent with previous reports, <i>Trp63^CreERT2</i> and <i>KRT5-CreERT2</i>-labeled ectopic EBCs do not exhibit alveolar regeneration potential. Intriguingly, when tamoxifen was administrated post-viral infection, <i>Trp63^CreERT2</i> but not <i>KRT5-CreERT2</i> labels islands of alveolar epithelial cells that are negative for EBC biomarkers. Furthermore, germline deletion of <i>Trpm5</i> significantly increases the contribution of <i>Trp63^CreERT2</i>-labeled cells to the alveolar epithelium. Although Trpm5 is known to regulate tuft cell development, complete ablation of tuft cell production fails to improve alveolar regeneration in <i>Pou2f3^-/-</i> mice, implying that Trpm5 promotes alveolar epithelial regeneration through a mechanism independent of tuft cells.