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

Eoin D. O’sullivan, Katie J. Mylonas, Rachel Bell, Cyril Carvalho, David P. Baird, Carolynn Cairns, Kevin M. Gallagher, Ross Campbell, Marie Docherty, Alexander Laird, Neil C. Henderson, Tamir Chandra, Kristina Kirschner, Bryan Conway, Gry H. Dihazi, Michael Zeisberg, Jeremy Hughes, Laura Denby, Hassan Dihazi, David A. Ferenbach

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Progressive fibrosis and maladaptive organ repair result in significant morbidity and millions of premature deaths annually. Senescent cells accumulate with ageing and after injury and are implicated in organ fibrosis, but the mechanisms by which senescence influences repair are poorly understood. Using two murine models of injury and repair we show that obstructive injury generates senescent epithelia which persist after resolution of the original injury, promote ongoing fibrosis and impede adaptive repair. Depletion of senescent cells with ABT-263 reduces fibrosis in reversed ureteric obstruction and after renal ischaemia-reperfusion injury. We validate these findings in humans, showing that senescence and fibrosis persist after relieved renal obstruction. We next characterise senescent epithelia in murine renal injury using single cell RNA-Seq. We extend our classification to human kidney and liver disease and identify conserved pro-fibrotic proteins which we validate in vitro and in human disease. We demonstrate that increased levels of Protein Disulfide Isomerase Family A Member 3 (PDIA3), augments TGFβ mediated fibroblast activation. Inhibition of PDIA3 in vivo significantly reduces kidney fibrosis during ongoing renal injury and as such represents a new potential therapeutic pathway. Analysis of the signalling pathways of senescent epithelia connects senescence to organ fibrosis, permitting rational design of anti-fibrotic therapies.

Original languageEnglish
Journal JCI Insight
Issue number22
Publication statusPublished - 22 Nov 2022


Dive into the research topics of 'Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis'. Together they form a unique fingerprint.

Cite this