B75-35 Cross-Species Comparison of Tissue-Level Regenerative Programs in Post-Pneumonectomy Lung Regeneration

Rationale

Post pneumonectomy lung regeneration (PPLR) has been recognized since the early twentieth century as a representative model of lung regeneration. In rat models, progressive reconstruction of alveolar architecture and broader network features of the regenerative process have been increasingly characterized. However, it remains unclear whether the major regenerative programs identified at the tissue scale in rats are conserved across species. We hypothesized that the regenerative programs observed in rat PPLR are also conserved in mice, and that lung regeneration proceeds not as uniform regrowth but as a structured spatiotemporal reorganization that begins at tissue boundaries. The objective of this study was to test whether regenerative niche formation, dynamics, and resolution described in rats are also observed in mice.

Methods

Using left pneumonectomy models in rats and mice, residual lungs at postoperative days 0, 3, 7, and 14 were analyzed by integrated histopathology, single cell RNA sequencing, and Xenium spatial transcriptomics. These datasets were combined to compare histological, cellular, and spatial features of lung regeneration between species.

Results

Both rats and mice exhibited conserved tissue reorganization programs during PPLR. Rather than regenerating uniformly, residual lungs were reorganized into temporally distinct regenerative niches. In the early phase, pleural activation and inflammatory circuits predominated and established intercellular interaction networks concentrated at the lung surface. In the mid phase, regenerative niches characterized by coordinated epithelial, endothelial, and mesenchymal reconstruction with vascular remodeling expanded throughout the residual lung. In the late phase, tissue connectivity was reorganized toward patterns consistent with alveolar maturation. Direct cross-species comparison demonstrated that these niche dynamics, including emergence, expansion, and resolution, were highly conserved between rats and mice.

Conclusion

PPLR in both rats and mice is governed by evolutionarily conserved spatiotemporal tissue programs. These findings demonstrate that regenerative principles previously identified in rats are preserved in mice and that lung regeneration proceeds through reversible transitions between organized tissue states rather than simple cellular expansion. This work establishes a comparative framework for lung regeneration and provides a foundation for directly linking rodent regenerative programs to emerging spatial datasets from human lung biology, including those from diseases such as idiopathic pulmonary fibrosis, in order to examine conserved and dysregulated tissue programs.

This abstract is funded by: None