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, 26 (3), 346-358.e4

Distinct Airway Epithelial Stem Cells Hide Among Club Cells but Mobilize to Promote Alveolar Regeneration

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Distinct Airway Epithelial Stem Cells Hide Among Club Cells but Mobilize to Promote Alveolar Regeneration

Jaymin J Kathiriya et al. Cell Stem Cell.

Abstract

Lung injury activates specialized adult epithelial progenitors to regenerate the epithelium. Depending on the extent of injury, both remaining alveolar type II cells (AEC2s) and distal airway stem/progenitors mobilize to cover denuded alveoli and restore normal barriers. The major source of airway stem/progenitors other than basal-like cells remains uncertain. Here, we define a distinct subpopulation (∼5%) of club-like lineage-negative epithelial progenitors (LNEPs) marked by high H2-K1 expression critical for alveolar repair. Quiescent H2-K1high cells account for virtually all in vitro regenerative activity of airway lineages. After bleomycin injury, H2-K1 cells expand and differentiate in vivo to alveolar lineages. However, injured H2-K1 cells eventually develop impaired self-renewal with features of senescence, limiting complete repair. Normal H2-K1high cells transplanted into injured lungs differentiate into alveolar cells and rescue lung function. These findings indicate that small subpopulations of specialized stem/progenitors are required for effective lung regeneration and are a potential therapeutic adjunct after major lung injury.

Keywords: MHC(high) airway progenitors; alveolar injury and regeneration; bleomycin injury; dedifferentiation; lung epithelial stem cells; oxygenation; single cell transcriptomics; transplantation.

Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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