Balancing dysplastic repair versus regeneration in the lung

About This Grant

PROJECT SUMMARY Lung injury can lead to improper repair and regeneration, promoting chronic diseases like emphysema and fibrosis. Following severe injury, basal stem cells migrate into the alveolar niche, displacing local AT2 progenitors and creating a “stem cell collision,” where basal cells outcompete AT2 cells, disrupting normal tissue repair. This impairs the AT2 cells’ ability to restore homeostasis through euplastic regeneration. Our preliminary data suggests that this basal cell invasion generates an injury-induced tissue niche (iTCH) comprised of basal stem cells and Pdgfra+ alveolar fibroblasts (AF1s), which are activated during injury and establish a signaling feedback loop, including Notch and Wnt pathways. In mice, AF1 cells are the primary mesenchymal response to injury, differentiating into AF2 cells. This differentiation is unidirectional, with minimal AF2 proliferation or AF1 reversion. We also found that basal cell invasion is regulated by Trp63 expression and Sox2, which suppress basal cell expansion after injury. Notably, iTCH formation is controlled by Notch signaling in AF1s, not basal stem cells. Loss of Notch signaling in AF1s disrupts iTCH formation and prevents dysplastic repair, a feature observed in human fibrotic diseases, including post-COVID-19 fibrosis. In contrast, chronic diseases such as COPD show altered Wnt signaling. These findings suggest that aberrant signaling in iTCHs could serve as a biomarker for lung diseases. We hypothesize that an emergent niche after acute injury determines whether tissue repair is dysplastic or euplastic by rewiring signaling pathways between lung cell lineages. The study aims to further investigate these pathways to better understand the mechanisms of lung repair.