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Abstract: PO0643

Single-Cell Analysis of Senescent Epithelia Reveals Targetable Mechanisms Promoting Fibrosis

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • O Sullivan, Eoin D., The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
  • Mylonas, Katie J., The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
  • Carvalho, Cyril, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
  • Docherty, Marie, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
  • Cairns, Carolynn, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, Edinburgh, United Kingdom
  • Gallagher, Kevin Michael, Western General Hospital, Edinburgh, Edinburgh, United Kingdom
  • Laird, Alexander, Western General Hospital, Edinburgh, Edinburgh, United Kingdom
  • Henderson, Neil, The University of Edinburgh MRC Human Genetics Unit, Edinburgh, Edinburgh, United Kingdom
  • Chandra, Tamir, The University of Edinburgh MRC Human Genetics Unit, Edinburgh, Edinburgh, United Kingdom
  • Kirschner, Kristina, University of Glasgow Institute of Cancer Sciences, Glasgow, Glasgow, United Kingdom
  • Conway, Bryan, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, Edinburgh, United Kingdom
  • Denby, Laura, The University of Edinburgh Centre for Cardiovascular Science, Edinburgh, Edinburgh, United Kingdom
  • Dihazi, Gry Helene, Georg-August-Universitat Gottingen Universitatsmedizin, Gottingen, Niedersachsen, Germany
  • Zeisberg, Michael, Georg-August-Universitat Gottingen Universitatsmedizin, Gottingen, Niedersachsen, Germany
  • Hughes, Jeremy, The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
  • Dihazi, Hassan, Georg-August-Universitat Gottingen Universitatsmedizin, Gottingen, Niedersachsen, Germany
  • Ferenbach, David A., The University of Edinburgh Centre for Inflammation Research, Edinburgh, Edinburgh, United Kingdom
Background

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. Here, we address the role of senescence in maladaptive repair and identify new anti-fibrotic targets.

Methods

We analyse human kidney tissue samples post deobstruction and corresponding murine models to test involvment of senescent cells in maladpative repair via pharmacological depletion. We use single cell RNA-Seq to examine these cells in more detail. We validate our findings using in-vitro models of senescence and fibroblast activation. Finally we use murine models of injury to test inhibition of in silico targets as anti-fibrotic.

Results

We demonstrate for the first time in man that senescence and fibrosis persist in kidneys in the aftermath of a resolved obstructive injury. Using a relevant murine model of injury and repair we show senescent epithelia persist after relief of ureteric obstruction and that depletion of senescent epithelia reduces fibrosis and promotes repair. We next characterise senescent epithelia in murine renal repair using single cell RNA-Seq for the first time. We extend our classification to human kidney and liver disease, identifying conserved pro-fibrotic molecules which we validate in vitro and in human disease. Inhibition of one of these molecules is essential for TGFb mediated fibroblast activation in vitro and in vivo. Importantly for translation, inhibition of this molecule in vivo significantly reduces kidney fibrosis after injury.

Conclusion

Our data shed light on the role of senescent epithelia in renal disease and identify a new anti-fibrotic molecule. Analysis of signaling pathways of senescent epithelia connects the important pathways such as the cell stress response to organ fibrosis, permitting rational design of anti-fibrotic therapies.

Graphical Abstract

Funding

  • Private Foundation Support