A study by Kuo Liu and colleagues investigates the origins of alveolar stem cells (AT2 cells) during lung repair and regeneration. Using dual recombinase-mediated intersectional genetic approaches, the researchers found that AT2 cells are derived from existing AT2 cells, club cells, and bronchiolar alveolar stem cells (BASCs), but not from terminally differentiated AT1 cells. This suggests that AT1 cells do not contribute to AT2 cells during lung homeostasis or injury. The study also reveals that club cells can regenerate the majority of alveoli after severe lung injuries, while Notch signaling plays a distinct role in regulating the cell fates of club cells and BASCs. The findings highlight the importance of precise genetic lineage tracing in understanding the roles of various epithelial cell types in alveolar regeneration. The study demonstrates that club cells have significant plasticity and can regenerate most of the damaged alveoli, while BASCs and AT2 cells also contribute to alveolar repair. The research provides new insights into the mechanisms of lung regeneration and could have implications for disease therapy. The study also highlights the limitations of previous genetic tools and the need for more specific methods to trace cell origins accurately. The results suggest that club cells and BASCs have distinct roles in alveolar repair, with club cells showing greater plasticity and potential for regeneration. The study underscores the importance of understanding the complex interplay between different cell types in lung repair and regeneration.A study by Kuo Liu and colleagues investigates the origins of alveolar stem cells (AT2 cells) during lung repair and regeneration. Using dual recombinase-mediated intersectional genetic approaches, the researchers found that AT2 cells are derived from existing AT2 cells, club cells, and bronchiolar alveolar stem cells (BASCs), but not from terminally differentiated AT1 cells. This suggests that AT1 cells do not contribute to AT2 cells during lung homeostasis or injury. The study also reveals that club cells can regenerate the majority of alveoli after severe lung injuries, while Notch signaling plays a distinct role in regulating the cell fates of club cells and BASCs. The findings highlight the importance of precise genetic lineage tracing in understanding the roles of various epithelial cell types in alveolar regeneration. The study demonstrates that club cells have significant plasticity and can regenerate most of the damaged alveoli, while BASCs and AT2 cells also contribute to alveolar repair. The research provides new insights into the mechanisms of lung regeneration and could have implications for disease therapy. The study also highlights the limitations of previous genetic tools and the need for more specific methods to trace cell origins accurately. The results suggest that club cells and BASCs have distinct roles in alveolar repair, with club cells showing greater plasticity and potential for regeneration. The study underscores the importance of understanding the complex interplay between different cell types in lung repair and regeneration.