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- 조회499
Nature, 19 March 2025 | https://doi.org/10.1038/s41586-025-08727-3
Histological signatures map anti-fibrotic factors in mouse and human lungs
Jason L. Guo 1,2,7, Michelle Griffin 1,2,7, Jung-Ki Yoon 2,3,7, David M. Lopez 1,2, Yili Zhu 4, John M. Lu 1,2, Georgios Mikos 1,2, Jennifer B. L. Parker 1,2, Shamik Mascharak 1,2, Camille Brenac 1, Nicholas J. Guardino 1,2, Darren B. Abbas 1, Dayan J. Li 1,2, Caleb Valencia 1,2, Norah E. Liang 1,2, Michael Januszyk 1,2, Howard Y. Chang 5,6, Derrick C. Wan 1, Tushar J. Desai 2,3 & Michael T. Longaker 1,2,*
1Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA.
2Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, Stanford, CA, USA.
4Cell Sciences Imaging Facility, Stanford University, Stanford, CA, USA.
5Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
6Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
7These authors contributed equally: Jason L. Guo, Michelle Griffin, Jung-Ki Yoon.
*Corresponding author: correspondence to Michael T. Longaker
2Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
3Department of Internal Medicine, Division of Pulmonary, Allergy and Critical Care, Stanford University School of Medicine, Stanford, CA, USA.
4Cell Sciences Imaging Facility, Stanford University, Stanford, CA, USA.
5Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
6Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
7These authors contributed equally: Jason L. Guo, Michelle Griffin, Jung-Ki Yoon.
*Corresponding author: correspondence to Michael T. Longaker
Abstract
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 fibrogenesis-to-resolution after bleomycin injury3, and we reasoned that profiling post-injury histological stages could uncover pro-fibrotic versus anti-fibrotic features with functional value for human fibrosis. Here we quantified 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 fibre features, that denoted a reversible transition in uniform-to-disordered histological architecture. Single-cell sequencing along these trajectories identified temporally enriched ‘ECM-secreting’ (Csmd1-expressing) and ‘pro-resolving’ (Cd248-expressing) fibroblasts at the respective post-injury stages. Visium-based spatial analysis further suggested divergent matrix architectures and spatial–transcriptional neighbourhoods by fibroblast subtype, identifying distinct fibrotic versus non-fibrotic biomolecular milieu. Critically, pro-resolving fibroblast instillation helped to ameliorate fibrosis in vivo. Furthermore, the fibroblast neighbourhood-associated factors SERPINE2 and PI16 functionally modulated human lung fibrosis ex vivo. Spatial phenotyping of idiopathic pulmonary fibrosis at protein level additionally uncovered analogous fibroblast subtypes and neighbourhoods in human disease. Collectively, these findings establish an atlas of pro- and anti-fibrotic factors that underlie lung matrix architecture and implicate fibroblast-associated biological features in modulating fibrotic progression versus resolution.
논문정보
- Research article
- 2025년 03월 (BRIC 등록일 2025-03-21)
- 국외 연구진
- 의약학 > 재생의학
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