TABLE 1.
Progenitor/stem cells involved in the alveolar regeneration after injury.
| Progenitor/stem cells | Selective markers | Localization | Daughter cells | Reported in | Contributions to alveolar repair | References |
| AEC2 | SPC+/HTII-280+ | Alveoli | AEC2; AEC1 | Human; bleomycin-injured mice | AEC2 can self-renew and give rise to AEC1 during normal condition or under injury. | Aso et al., 1976; Barkauskas et al., 2013 |
| AEC1 | Hopx+Igfbp2– | Alveoli | AEC2; AEC1 | Mice post PNX | Only Hopx+Igfbp2– AEC1 generate AEC2 and AEC1 in vitro or in mice under PNX. | Jain et al., 2015; Wang et al., 2018 |
| α6β4+ cells | α6+β4+SPC– | Alveoli; Airway | CC10+ cells; AEC2; Krt5+ cells | Human; bleomycin-injured mice | In bleomycin-injured mice, α6β4+ cells quickly expand and express mature epithelial cell markers like CC10 and SPC. Human α6β4+ cells can differentiate into Krt5+ cells and CC10+ cells in vitro. | McQualter et al., 2010; Chapman et al., 2011; Li et al., 2013 |
| DASCs | Krt5+p63+ | Distal airway | Club cells; AEC1; AEC2 | Human; influenza-, bleomycin-injured mice | DASCs can regenerate airway or alveolar epithelium after severe injury by quick expansion and generation of conducting airway or alveolar epithelial cells. | Kumar et al., 2011; Zuo et al., 2015; Shi et al., 2019 |
| LNEPs | CC10–β4+ CD200+CD14+ | Distal airway | ΔNp63+Krt5+ cells; Club cells; AEC1; AEC2 | Influenza-, bleomycin-injured mice | LNEPs activate a ΔNp63 and Krt5 remodeling program after influenza infection or bleomycin injury in mice. Transplanted LNEPs can expand and differentiate into mature epithelial cells in the injured lung. | Vaughan et al., 2015 |
| Sox2+ progenitors | Sox2+H2-K1highp63– | Distal airway | AEC1; AEC2 | Bleomycin-injured mice | After mice were injured by bleomycin instillation, quiescent H2-K1 high cells can expand, migrate, and differentiate into AEC1 and AEC2 to rebuild the denuded alveolar epithelium. | Kathiriya et al., 2020 |
| Sox9+ progenitors | Sox9+Krt5+ p63+ | Conducting airway | Conducting airway epithelial cells; AEC1; AEC2 | Human; bleomycin- or naphthalene-injured mice | Transplanted Sox9+ progenitors can differentiate into various conducting or alveolar epithelial cells in injured mice. Engrafted human Sox9+ basal cells can improve lung function of bleomycin mice or patients with bronchiectasis. | Nichane et al., 2017; Ma et al., 2018 |
| BASCs | CC10+SPC+ | BADJ | AEC1; AEC2; Club cells; Ciliated cells | Influenza-, bleomycin- or naphthalene-injured mice | BASCs can differentiate into AEC2 and club cells upon influenza virus infection, AEC1 and AEC2 upon bleomycin injury, and club cells and ciliated cells upon naphthalene injury. | Tropea et al., 2012; Liu et al., 2019; Salwig et al., 2019; Liu et al., 2020 |
| v-CCs | CC10+Upk3a+ | BADJ; distal airway | AEC1; AEC2; Club cells; Ciliated cells | Bleomycin- or naphthalene-injured mice | v-CCs have greater potency to differentiate into ciliated cells and club cells during homeostasis or naphthalene injury, and differentiate into AEC1 and AEC2 after bleomycin-induced lung injury. | Giangreco et al., 2002, 2009; Guha et al., 2017 |
α6, integrin α6; AEC1 and AEC2, type 1 and type 2 alveolar epithelial cells; β4, integrin β4; BADJ, bronchioalveolar-duct junction; BASCs, bronchioalveolar stem cells; CC10, club cell 10-kDa protein; DASCs, distal airway stem/progenitor cells; ΔNp63, a p63 splice variant; Hopx, HOP homeobox; HTII-280, a 280- to 300-kDa protein specific to human type II cells; Igfbp2, insulin-like growth factor- binding protein 2; Krt5, keratin 5; LNEP, lineage-negative epithelial progenitors; PNX, pneumonectomy; SPC, surfactant protein C; Sox, sex determining region Y (SRY)-box; v-CCs, variant club cells; Upk3a, uroplakin 3a.