M Olsson Lindvall

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive and irreversible scarring of the lung tissue. Development of new efficacious and safe treatments is hampered by limited understanding of disease pathogenesis, lack of predictive preclinical models, and narrow therapeutic index of candidate drugs targeting complex biologies. Here, we tackle these aspects by generating spatially resolved transcriptomic maps of fibrotic lungs from clinical samples and a preclinical mouse model. We utilized the Visium platform to study parenchyma biopsies from four healthy lungs and regions of varying fibrotic severity from four IPF patient lungs. By mapping single cell RNA-seq data spatially, we were able to detect distinct fibroblast populations in different regions of the lesioned IPF lung, as well as the presence of various immune cell populations. To study lung fibrosis preclinically in vivo, the bleomycin mouse model is the most widely used alternative, although its translatability to human disease is disputed. Visium data from mouse lungs collected at two time points following bleomycin administration were generated, which allowed us to characterize the fibrotic lesions and inflammatory areas in their spatiotemporal context. In addition, mass spectrometry imaging was performed on adjacent tissue sections to provide paired spatial metabolomics. Herein, we have generated spatial maps of the lung fibrosis transcriptome from IPF lung biopsies and bleomycin-injured mouse lungs, providing an extensive resource to probe disease pathogenesis and animal model translatability.

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.