Genetic tools for targeting neuroendocrine cells: Unveiling their plasticity in lung regeneration.

Pulmonary neuroendocrine cells (PNECs) and calcitonin gene-related peptide (CGRP) play important roles in maintaining lung homeostasis and repairing injury. PNECs are widely recognized as progenitor cells in the bronchial epithelium, capable of participating in bronchial injury repair; however, whether they can also contribute to alveolar epithelial regeneration remains to be conclusively determined. Moreover, genetic tools for studying the dynamic plasticity of PNECs following lung injury are limited. Therefore, in this study, we first developed a genetic tool for mapping PNEC expression-the CGRP-membraneGFP (CGRP-mGFP) knock-in mouse line-and used this model to capture the proliferative dynamics of PNECs after bronchial injury. Additionally, we generated an Ascl1-CreER knock-in line for lineage tracing of PNECs and demonstrated that following severe lung injury, PNECs possess dual-lineage differentiation potential: they not only differentiate into bronchiolar Club cells but also migrate in small numbers to the alveolar region and differentiate into alveolar epithelial cells, thereby contributing to alveolar repair. Our findings provide new insights into the plasticity of PNECs and the mechanisms of lung regeneration.