In a study published in Cell, the researchers led by Prof. ZHOU Bin from the School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences /the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences reported the cellular origin of alveolar epithelial stem cells during lung repair and regeneration by using dual recombinases-mediated genetic strategies.
The lungs are important respiratory organs of human beings, and the alveoli are important structures for the function of the lungs. The alveolar epithelium is composed of alveolar type I cells and type II cells, referred to as AT1 and AT2 cells. AT2 cells are the alveolar epithelial stem cells that are not only able to self-renew but also differentiate into daughter cells, AT1 cells.
In multiple lung diseases, AT2 cells could be damaged, so it is important to reveal the origin of AT2 cells after injuries. Previous studies discovered multiple origins of AT2 cells based on conventional single recombinase-mediated lineage tracing strategies. It is reported that AT1 cells and bronchiolar club cells can differentiate into AT2 cells after lung injury. In this study, researchers found that the traditional lineage tracing tools have the limitation of non-specific labeling. For example, the Hopx-based AT1 cell genetic tool and Scgb1a1-based club cell genetic tool could also label other known sources of AT2 cells, such as multipotent stem cells called bronchioalveolar stem cells (BASCs) located at bronchioalveolar-duct junction. The non-specific labeling of conventional genetic tools greatly interferes with the results of lineage tracing.
To resolve this scientific controversy, researchers developed a series of new genetic lineage tracers using dual recombinases recombination systems, Cre-loxP and Dre-rox, which greatly improved the accuracy and specificity of cell labeling. The AT1 cell, AT2 cell, BASCs, and club cells were specifically labeled by new genetic tools. Combined with lung injury mouse models, they found that AT2 cells, in addition to self-renewal, also derive from BASCs and club cells, but not from AT1 cells, which resolved years of scientific controversies in the lung field.
By using scRNA-seq and conditional gene knock-out, they further showed that club cells and BASCs had different cell differentiation pathways during the transition to AT2 cells, and were oppositely regulated by the Notch signaling pathway after lung injury. The inhibition of Notch signaling promotes the transition of BASCs to AT2 cells but inhibits the transition of club cells to AT2 cells.
This study provides new insights into lung repair and regeneration, and the newly developed lineage tracing strategies provide new technical methods for the fields of developmental biology, regenerative medicine, and genetics.
Contact: zhoubin@sibs.ac.cn
Reference: https://www.sciencedirect.com/science/article/pii/S0092867424003027
