Histological signatures map anti-fibrotic factors in mouse and human lungs by Jason L. Guo1,2,7, Michelle Griffin1,2,7, Jung-Ki Yoon2,3,7, David M. Lopez1,2 ISBN 101038/S41586025087273 instant download

Histological signatures map anti-fibrotic factors in mouse and human lungs by Jason L. Guo1,2,7, Michelle Griffin1,2,7, Jung-Ki Yoon2,3,7, David M. Lopez1,2 ISBN 101038/S41586025087273 instant download

Fibrosis, the replacement of healthy tissue with collagen-rich matrix, can occur following injury in almost every organ1,2. Mouse lungs follow a stereotyped sequence of fbrogenesis-to-resolution after bleomycin injury3, and we reasoned that profling post-injury histological stages could uncover pro-fbrotic versus anti-fbrotic features with functional value for human fbrosis. Here we quantifed spatiotemporally resolved matrix transformations for integration with multi-omic data. First, we charted stepwise trajectories of matrix aberration versus resolution, derived from a high-dimensional set of histological fbre features, that denoted a reversible transition in uniform-todisordered histological architecture. Single-cell sequencing along these trajectories identifed temporally enriched ‘ECM-secreting’ (Csmd1-expressing) and ‘pro-resolving’ (Cd248-expressing) fbroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial–transcriptional neighbourhoods by fbroblast subtype, identifying distinct fbrotic versus non-fbrotic biomolecular milieu. Critically, pro-resolving fbroblast instillation helped to ameliorate fbrosis in vivo. Furthermore, the fbroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fbrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fbrosis at protein level additionally uncovered analogous fbroblast subtypes and neighbourhoods in human disease. Collectively, these fndings establish an atlas of pro- and anti-fbrotic factors that underlie lung matrix architecture and implicate fbroblast-associated biological features in modulating fbrotic progression versus resolution.