A mesothelial differentiation gateway drives fibrosis

Safwen Kadri, Adrian Fischer, Martin Mück-Häusl, Wei Han (), Amal Kadri, Yue Lin, Lin Yang, Shaoping Hu, Haifeng Ye, Pushkar Ramesh, Meshal Ansari, Herbert B. Schiller, Hans-Günther Machens and Yuval Rinkevich ()
Additional contact information
Safwen Kadri: Helmholtz Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
Adrian Fischer: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Martin Mück-Häusl: Helmholtz Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
Wei Han: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Amal Kadri: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Yue Lin: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Lin Yang: Helmholtz Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
Shaoping Hu: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Haifeng Ye: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Pushkar Ramesh: Helmholtz Zentrum München, Member of the German Center of Lung Research (DZL)
Meshal Ansari: Helmholtz Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
Herbert B. Schiller: Helmholtz Munich, Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL)
Hans-Günther Machens: Technical University of Munich, Klinikum Rechts der Isar
Yuval Rinkevich: Chinese Institutes for Medical Research

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Internal organs are encased by a supportive epithelial monolayer of mesodermal origin, termed mesothelium. The nature, evolution and function of mesothelial cells, and their genetic regulation impacting disease development are insufficiently understood. Here, we generate a comprehensive organ-wide single-cell transcriptomic compendium of mesothelium across healthy and diseased mouse and human organs, delineating the evolution of conserved activated states of mesothelial cells in response to disease. We uncover genetic drives behind each cell state and reveal a conserved metabolic gate into multipotent proteolytic, inflammatory and fibrotic cell differentiation, in mouse and human. Using lung injury models in mice, in combination with mesothelial cell-specific viral approaches, we show that direct metabolic reprogramming using Ifi27l2a and Crip1 on organ surfaces, blocks multipotent differentiation and protects mouse lungs from fibrotic disease. These findings place mesothelial cells as cellular exemplars and gateway to fibrotic disease, opening translational approaches to subvert fibrosis across a range of clinical indications.

Date: 2025
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DOI: 10.1038/s41467-025-63990-2

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