A study on the systemic transmission of cellular senescence and its role in acute liver failure

Kiourtis, Christos (2021) A study on the systemic transmission of cellular senescence and its role in acute liver failure. PhD thesis, University of Glasgow.

Full text available as:
[img] PDF
Download (150MB)


Cellular senescence is a stress response observed in a wide range of pathologies. Its cytostatic properties make senescence an inhibitor of normal repair and regeneration after tissue injury. Senescence has been reported to have a negative effect on several diseases of the liver including acute liver failure, a rare but deadly disease. In this disease, senescence has been shown to block proper regeneration following acute liver injury and this has been associated with a worse prognosis. Acute liver failure is a syndrome that also affects numerous extra hepatic organs, including the kidneys, the brain and the lung. This multi-organ failure presents a clinical challenge as it occurs in more than 50% of acute liver failure patients, its etiology remains largely unknown and supportive care, using organ support e.g. ventilation and haemofiltration, is the main way of managing it.

Senescent cells produce and secrete a diverse set of factors that can have various effects on the microenvironment of these cells. One effect of these factors is the transmission of senescence to nearby healthy cells, resulting in the propagation of the senescent phenotype. This phenomenon has been described both in cell culture as well as in mouse models. More specifically, work by us has revealed that senescent hepatocytes are able to induce a senescent phenotype to neighbouring non-senescent hepatocytes in a paracrine, TGFβ-dependent manner. Given the development of hepatic senescence and multi-organ failure during acute liver failure, in my project I sought to investigate a potential systemic transmission of senescence from the liver to other organs, particularly in the extra-hepatic organs affected during acute liver failure.

To do this I first characterised a mouse model of hepatocyte-specific induction of senescence. After establishing widespread liver senescence in this model, I then examined whether systemic transmission of senescence occurs in this model. I observed the development of renal, brain and lung senescence, accompanied by elements of renal dysfunction, repair and reprogramming following the induction of liver senescence. Further investigation using other mouse models as well as in vitro approaches revealed that systemic transmission of senescence is dependent on an active TGFβ signalling pathway. Inhibition of this pathway resulted in the prevention of senescence transmission both in vitro and in vivo, reduced the degree of renal repair and reprogramming in vivo and improved organ function.

In conclusion, these data provide evidence for the in vivo spread of senescence between organs. To our knowledge, this is the first time this phenotype is reported using a highly specific model of senescence induction. In the long term, this work may benefit the treatment of acute liver failure patients by providing potential new therapies for this disease.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Supervisor's Name: Bird, Dr. Thomas G.
Date of Award: 2021
Depositing User: Theses Team
Unique ID: glathesis:2021-82719
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 03 Mar 2022 09:15
Last Modified: 08 Apr 2022 16:47
Thesis DOI: 10.5525/gla.thesis.82719
URI: http://theses.gla.ac.uk/id/eprint/82719
Related URLs:

Actions (login required)

View Item View Item


Downloads per month over past year