Defining cardinal functions of lung progenitors during regeneration

PROJECT SUMMARY The respiratory system is constantly exposed to environmental insults, requiring robust mechanisms for repair and regeneration. However, the impact of acute lung injury on cell lineage behavior, both in the short and long term, remains poorly understood, particularly in the context of chronic lung diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). This research aims to address how acute injury disrupts tissue homeostasis and contributes to long-term pathological changes that affect lung regeneration. We have utilized a multi-modal approach to investigate the short- and long-term consequences of viral injury on the respiratory system. Our methods include cell type-specific lineage tracing, pulsed single-cell analysis, histological spatial analysis, and cross-species comparison with a unique human lung disease biobank. These data have been integrated with temporal cell fate mapping to record stem and progenitor cell responses, including proliferation and differentiation after injury. Our findings reveal that progenitor cells within the alveolus respond in a uniquely phased manner: the immune system reacts first, followed by epithelial and mesenchymal progenitors, and finally endothelial progenitors. We identified persistent changes in specific progenitor lineages and overall our studies highlight the importance of progenitor proliferation in lung regeneration, revealing that loss of progenitor activity leads to varying outcomes, such as emphysema or improved regeneration, depending on the affected lineage. These findings support the hypothesis that acute lung injury induces persistent alterations in progenitor cell behavior, including altered proliferation. We propose that the loss of this proliferative capacity leads to unpredictable phenotypes in lung regeneration, resembling those seen in human lung diseases. This work lays the foundation for future studies aimed at developing targeted therapies to restore progenitor function and improve lung regeneration after injury.