Arrested Development: spatial exploration of divergent paths of alveolar regeneration in the bleomycin mouse model versus human lung fibrosis

Abstract

Development of efficacious and safe treatments for idiopathic pulmonary fibrosis (IPF) is challenged by limited understanding of disease mechanisms and lack of reliable preclinical models. Bleomycin-induced pulmonary fibrosis is the most widely used mouse model for IPF. We generated a unique atlas of spatially resolved transcriptome-wide maps of human IPF and mouse bleomycin lung tissues, and investigated the translational relevance of the mouse model. We identified both analogous and divergent cell populations between human and mouse lung samples. The recently identified aberrant basaloid epithelial cell population in humans and the mouse alveolar differentiation intermediate (ADI) cells exhibited similarities in pathway enrichment profiles, reflecting convergent biological processes in fibrosis. However, their functional roles appeared to diverge significantly. In the bleomycin model, ADI cells were associated with functional regenerative processes that were not identified in the proximity of human aberrant basaloid cells. This finding suggests that, in contrast to the bleomycin-injured mouse lung, the regenerative/reparative capability of the human IPF lung is compromised, and that alveolar tissue development is arrested or defective. In addition, our results highlight the translational value of the bleomycin model in the study of alveolar cell regeneration and differentiation. Taken together, our study provides an extensive resource of spatially resolved mechanistic insights into fibrotic lung molecular signatures, paving the way for a better understanding of IPF pathogenesis and development of relevant animal models.