The role of SOX9 in liver injury and regeneration A

Abstract

Chronic liver disease (CLD) affects approximately 1.5 billion people worldwide, posing a significant mortality and morbidity burden. CLD is characterised by progressive organ damage leading to fibrosis deposition and synthetic dysfunction. There are currently no anti-fibrotic therapies licensed for the treatment of liver fibrosis and identifying anti-fibrotic targets remains an urgent clinical priority. Fibrosis deposition in the liver is mediated by activation of hepatic stellate cells (HSCs). My supervisor's group has previously identified SOX9 as an important regulator of the profibrotic phenotype of activated HSCs and utilised murine fibrosis models to show that SOX9 depletion can alleviate liver fibrosis in toxic and cholestatic models of fibrosis which are predominantly Type 1/17 immune mediated models. In this thesis I have examined whether SOX9 is also important in Type 2 immune mediated fibrosis using the Schistosomiasis mansoni model of liver fibrosis. Data presented here supports the role of SOX9 as a master regulator of the profibrotic HSC, and identifies SOX9 as an aetiologically independent potential anti-fibrotic target. SOX9 has also been implicated as an oncogene, highly expressed in subsets of primary liver cancers, rendering it an attractive therapeutic target. However to date there is no data exploring whether targeting SOX9 will impact liver regeneration. Data presented in my thesis reveals SOX9 is upregulated in hepatocytes in the process of liver regeneration, although its depletion does not affect regenerative capacity. However, protein and transcriptomic data reveals SOX9 depletion does alter cell cycle and Hippo components in the regenerating liver, with potential implications for regeneration and cancer therapy. The oncogenic potential of SOX9 reveals its biological significance in cellular proliferation. Although previously published work has shown SOX9 lies downstream of mechanosignalling mediated HSC activation, it is unclear whether SOX9 proliferative pathways are relevant in HSC activation. SOX9 is known to regulate cellular proliferation by regulating the expression of the proto-oncogene B cell-specific Moloney murine leukaemia virus integration site 1 (Bmi1). This thesis provides novel data demonstrating Bmi1 is expressed in activated HSCs. BMI1 expression is attenuated upon SOX9 depletion, which is associated with reduced HSC activation. Moreover, pharmacological inhibition of BMI1 reduces markers of fibrosis and HSC activation, highlighting it as a potential anti-fibrotic target.

Date of Award	1 Aug 2024
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Neil Hanley (Supervisor) & Karen Piper Hanley (Supervisor)