nothing is known about potential stem cells in the simple columnar epithelium lining the respiratory bronchioles. Importantly, recent single cell transcriptomic studies have revealed significant heterogeneity within the stem cell populations, both at steady state and during repair. For example, the basal cells of the pseudostratified epithelium include a subpopulation that appears biased towards differentiating into luminal or secretory cells [31, 36, 37]. Currently, it is not clear whether these subpopulations represent transitional components of a lineage hierarchy or distinct stem cells. Moreover, functionally, we do not know whether the different subpopulations differ in their ability to engraft into a damaged lung and behave as stem cells over the long term. This information is potentially important for cell replacement therapies, for which the reparative capacity of the donor cells should be optimal. To experimentally test different populations, we need to develop robust stem cell engraftment assays for different regions of the adult mouse lung, equivalent to bone marrow transplantation for HSCs. The gold standard definition of a stem cell is a cell that Human Approximately branching level 12 (varies between lobes) Trachea Alveolar ducts Main stem bronchi Lung lobe Mouse Submucosal gland Myoepithelial cell (p63+ Krt5+ smooth muscle actin+) Chapters 6 and 20 [17, 18] Cartilagenous airway with pseudostratified epithelium Basal cell (p63+ Krt5+ Ngfr+ heterogeneous) Chapters 5, 13, 20 and 22 [18–21] Bronchioles (non- cartilagenous airways, most distal are known as terminal bronchioles) Basal cell ? other cell types Neuroendocrine Rare cells in NEBs (Ascl1+Notch2+) Chapters 4 and 7 [22, 23] Respiratory bronchioles ? Chapter 9 [25] Alveoli Type 2 alveolar cell (Sftpc+ heterogenous for Axin2+ (mouse) HHIP+ (human)) Chapters 2, 10, 11 and 21 [24, 26–28] BASC Located at BADJ Scgb1a1 + Sftpc+ Chapters 7 and 10 [23, 24] Capillary endothelium PIvap+ or gCAP Chapters 3 and 12 [29–30] Bronchioles Club cells (Scgb1a1+) "Variant" club cells located near NEBs and at distal airway (Scgb1a1+ Up3ka+ Cyp2f2lo) H2-K1hi club cell LNEP/DASC basal cell (p63lo Krt5-heterogeneous) Figure 1 Schematic representation showing location of currently known stem cells in mouse and human adult lung. The intralobar human lung is shown from branch generation 12. A question mark indicates that it is currently not known whether such a stem cell type exists in the human lung. References can be found in the chapters cited. Additional references: for basal cells [31, 32, 33] for rare neuroendocrine cells [34] for AT2 cells [33] for capillary endothelium [35]. NEB: neuroendocrine body LNEP: lineage-negative epithelial progenitor DASC: distal airway stem cell. xi
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