Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis.

Autor:	O'Sullivan ED; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia., Mylonas KJ; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Bell R; Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Carvalho C; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Baird DP; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Cairns C; Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Gallagher KM; Department of Urology, Western General Hospital, Edinburgh, United Kingdom., Campbell R; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Docherty M; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Laird A; Department of Urology, Western General Hospital, Edinburgh, United Kingdom.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Henderson NC; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Chandra T; MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Kirschner K; The Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.; Cancer Research UK Beatson Institute, Glasgow, United Kingdom., Conway B; Centre for Cardiovascular Science, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Dihazi GH; Institute for Clinical Chemistry/UMG-Laboratories., Zeisberg M; Clinic for Nephrology and Rheumatology, and., Hughes J; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom., Denby L; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia., Dihazi H; Clinic for Nephrology and Rheumatology, and.; Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Göttingen, Göttingen, Germany., Ferenbach DA; Centre for Inflammation Research, Queen's Medical Research Institute, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2022 Nov 22; Vol. 7 (22). Date of Electronic Publication: 2022 Nov 22.
DOI:	10.1172/jci.insight.154124
Abstrakt:	Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with aging and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using 2 murine models of injury and repair, we show that obstructive injury generated senescent epithelia, which persisted after resolution of the original injury, promoted ongoing fibrosis, and impeded adaptive repair. Depletion of senescent cells with ABT-263 reduced fibrosis in reversed ureteric obstruction and after renal ischemia/reperfusion injury. We validated these findings in humans, showing that senescence and fibrosis persisted after relieved renal obstruction. We next characterized senescent epithelia in murine renal injury using single-cell RNA-Seq. We extended our classification to human kidney and liver disease and identified conserved profibrotic proteins, which we validated in vitro and in human disease. We demonstrated that increased levels of protein disulfide isomerase family A member 3 (PDIA3) augmented TGF-β-mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduced kidney fibrosis during ongoing renal injury and as such represented a new potential therapeutic pathway. Analysis of the signaling pathways of senescent epithelia connected senescence to organ fibrosis, permitting rational design of antifibrotic therapies.
Databáze:	MEDLINE
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