Ferenbach, David

Mylonas, Katherine

Forbes, Stuart

Hughes, Jeremy

Docherty, Marie-Helena

2024-06-03T10:34:59Z

2024-06-03T10:34:59Z

2024-06-03

Senescence is a cellular process resulting in irreversible growth arrest, an altered transcriptome and a pro-inflammatory, pro-fibrotic secretome. Senescent cells are a highly heterogenous cell group with distinct context dependent roles. The induction of cellular senescence is a physiological response to acute stimuli in several contexts in vivo including cancer defence, wound healing, and organogenesis during embryonic development. However, the persistence and accumulation of senescent cells in response to cell stress, ageing and tissue injury associates with tissue dysfunction and impaired regeneration. In experimental models of ageing and/or injury, depletion of long-lived senescent cells both before and after injury improves organ function and regenerative capacity. Much of this heterogeneity of senescent cell behaviour remains unexplained. A key reason for this pertains to the fact that senescence itself, by virtue of its induction by genotoxic damage and cell stress, is induced by injury and age. Therefore, senescent cells associate very strongly with both. Without separating senescence from injury and from age, it is not possible to determine the exact contribution of senescent cells themselves to tissue injury or fibrosis. To understand if senescent epithelial cells can directly cause tissue dysfunction vs being bystanders to dysfunction requires a separation of senescence and injury. This PhD examined the hypothesis that epithelial senescence in the absence of age and injury was sufficient to initiate renal fibrosis. By using Pax8, a gene highly expressed in the renal epithelium but very lowly outside of the kidney to drive an inducible cre-recombinase system, it was possible to generate renal cortical epithelial senescence without injuring mice and to show that isolated renal epithelial senescence in young immunocompetent female mice was sufficient to initiate fibrosis in the absence of injury. This model allowed us to define the onset of senescence, and to study the evolution of senescent cells in vivo over time. This has not been possible in other models of induction such as injury or age as it is impossible to understand exactly when a cell became senescent in response to a senescence-inducing stimulus, and it is furthermore not possible to delineate what component of any observed inflammatory cell infiltrate is due to injury vs that due to senescence. We showed that in young female uninjured mice, there was a suggestion that senescent epithelial cells were cleared over time and this is in contrast to the persistence of senescent cells after injury which we have observed in other models of senescence induction. These results demonstrate that epithelial senescence induction is profibrotic in the absence of injury to other cell lineages. Of importance, these results also suggest mechanisms in the healthy adult kidney which allow detection and physiologic clearance of acutely senescent cells and prevent ongoing fibrosis. Understanding how these pathways are lost with ageing and chronic injury may lead to new routes to promote clearance of profibrotic senescent epithelia.

https://hdl.handle.net/1842/41830

http://dx.doi.org/10.7488/era/4553

en

The University of Edinburgh

Cellular Senescence in the Kidney. Marie-Helena Docherty, Eoin D. O’Sullivan, Joseph V. Bonventre and David A. Ferenbach. Journal of the American Society of Nephrology (2019).

Cellular Senescence and Senotherapies in the Kidney: Current Evidence and Future Directions. Marie-Helena Docherty, David P. Baird, Jeremy Hughes and David A. Ferenbach. Frontiers in Pharmacology (2020).

Cellular senescence inhibits renal regeneration after injury in mice, with senolytic treatment promoting repair. Sci. Trans Med. Katie Mylonas, Eoin D. O’Sullivan, Duncan Humphries, David P. Baird, Marie-Helena Docherty, Sarah A. Neely, Paul J. Krimpenfort, Annette Melk, Roland Schmitt, Sofia Ferreira-Gonzalez, Stuart Forbes, Jeremy Hughes, David A. Ferenbach (2021)

The Role of Ageing and Parenchymal Senescence on Macrophage Function and Fibrosis. Front Immunol. Ross A Campbell, Marie-Helena Docherty, David A Ferenbach, Katie J Mylonas

Single-cell analysis of senescent epithelia reveals targetable mechanisms promoting fibrosis. JCI Insight. Eoin D. O’Sullivan, Katie J. Mylonas, Rachel Bell, Cyril Carvalho, David P. Baird, Carolynn Cairns, Kevin M. Gallagher, Ross Campbell, Marie-Helena Docherty, Alexander Laird, Neil C. Henderson, Tamir Chandra, Kristina Kirschner, Bryan Conway, Gry H. Dihazi, Michael Zeisberg. Jeremy Hughes, Laura Denby, Hassan Dihazi, and David A. Ferenbach (2022).

Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis. Sci. Trans. Med. Eoin D. O’Sullivan, Katie J. Mylonas, Cuiyan Xin, David P. Baird, Cyril Carvalho, Marie-Helena Docherty, Ross Campbell, Kylie P. Matchett, Scott H Waddell, Alexander D Walker, Kevin M Gallagher, Siyang Jia, Steve Leung, Alexander Laird, Julia Wilflingseder, Michaela Willi, Maximillian Reck, Sarah Finnie, Angela Pisco, Sabrina Gordon-Keylock, Alexander Medvinsky, Luke Boulter, Neil C. Henderson, Kristina Kirschner, Tamir Chandra, Bryan Conway, Jeremy Hughes, Laura Denby, Joseph V Bonventre, and David A. Ferenbach

Chronic Kidney Disease

CKD

fibrosis

senescent cells

mouse model

Impact of primary renal epithelial senescence induction in the murine kidney

The Impact of Primary Renal Epithelial Senescence Induction in the Murine Kidney

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy