Dual Recombinases-Mediated Genetic Tracing Reveals the Cellular Origin of Alveolar Stem Cells after Lung Injury
LIU Kuo, MENG Xinfeng, ZHOU Bin*
Lung repair and regeneration have emerged as a pivotal area of research in pulmonology. In some lung diseases, the alveolar epithelial structure is damaged and requires the involvement of alveolar stem cells to regenerate the damaged areas. Consequently, elucidating the origins of alveolar stem cells holds immense clinical importance for the prevention and treatment of lung diseases. Previous studies have consistently identified AT2 cells (alveolar epithelial type II cells) as alveolar stem cells, capable of self-renewal and differentiation into AT1 cells. Nevertheless, recent investigations have proposed an alternative hypothesis, suggesting that AT2 cells can also originate from bronchiolar club cells and alveolar AT1 cells. However, the conventional lineage tracing techniques employed in these studies have been plagued with non-specific labeling issues, resulting in inconclusive findings. To address this controversy, this team has developed a suite of more precise dual recombinases-mediated genetic tools for the specific labeling of lung epithelial cell types. By integrating these tools with multiple lung injury models, this article has uncovered that new AT2 cells can originate from club cells and BASCs (bronchoalveolar stem cells), in addition to the self-renewal of AT2 cells, but not from AT1 cells. Furthermore, the study has revealed that the Notch signaling pathway plays a crucial role in regulating the transition of club cells and BASCs into AT2 cells. Elucidating the origins of AT2 cells during lung repair provides novel insights for the treatment of lung diseases. The dual recombination lineage tracing technique established in this article holds vast potential for broader applications in the fields of developmental biology, genetics, and regenerative medicine.
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