Fatal COVID-19 ARDS associated with incomplete AEC1 differentiation from the transitional state without senescence or fibrosis

Ting, Christopher; Aspal, Mohit; Vaishampayan, Neil; Huang, Steven K.; Riemondy, Kent; Wang, Fa; Farver, Carol; Zemans, Rachel L.

COVID-19 ARDS is associated with prolonged respiratory failure and high mortality, but the underlying mechanisms are unknown. ARDS results from injury to the alveolar epithelial cell (AEC) barrier; clinical recovery requires epithelial regeneration. During physiologic regeneration, AEC2s proliferate, exit the cell cycle, and transiently assume a transitional state before differentiating into AEC1s; transitional cells persist with ineffectual AEC1 differentiation in pulmonary fibrosis. It is unknown why transitional cells differentiate into AEC1s during physiologic regeneration but persist with ensuing scar in fibrosis and whether incomplete AEC1 differentiation from transitional cells without fibrosis may underlie prolonged respiratory failure in COVID-19 ARDS. Immunostaining of postmortem COVID-19 ARDS lungs revealed abundant transitional cells. They were typically cuboidal or partially spread, occasionally flat, but rarely expressed AEC1 markers. They formed organized monolayers on alveolar septa without fibrosis. Immunostaining and/or meta-analysis of scRNAseq datasets revealed that transitional cells in two mouse models of physiologic regeneration, COVID-19 ARDS, and fibrosis express markers of cell cycle exit but only in fibrosis express a specific senescence marker. These data suggest that in COVID-19 ARDS, physiologic AEC1 differentiation from transitional cells is incomplete, thus underlying prolonged barrier permeability and respiratory failure, but as in physiologic regeneration, is ongoing without fibrosis.