Overview: Fibrosis (or scarring) is a common step in the majority of chronic diseases that can affect any organ. Diagnosis is poor and there are currently no anti-fibrotic therapies. My lab is interested in uncovering the cellular and molecular basis of fibrosis to drive novel discoveries for diagnostic and therapeutic strategies. My lab has a major interested in how components of the pathological scar are produced and how this signals to surrounding cells to perpetuate the fibrotic response. The majority of our work to date has focussed on liver fibrosis (funded by MRC). However, we have active research projects in kidney (supported by KRUK & Kidneys for Life) and lung (funded by MRC) fibrosis.
Liver Fibrosis: Liver fibrosis is a major, increasing cause of death characterised by excessive extracellular matrix (ECM) production which causes scarring and disrupts tissue function. Several cell types contribute to fibrosis in the liver, but a major role is played by hepatic stellate cells as the primary source of myofibroblasts and ECM production. Under healthy conditions HSCs are ‘quiescent’ and non-proliferative. However, following injury and inflammation, HSCs become ‘activated’ into contractile, proliferative, migratory myofibroblasts, marked by the actin cytoskeleton protein, α-smooth muscle actin (αSMA). Activated HSCs deposit fibrotic ECM ultimately resulting in scarring, increased organ stiffness to perpetuate the process.
How are components of the scar regulated? The transcription factor Sex-determining Region Y (SRY) box 9 (SOX9) plays a key role in development of multiple organs. Mechanistic understanding of development has revealed roles for SOX9 regulating, amongst other aspects, cartilage extracellular matrix (ECM) production and cell proliferation (Mech. Dev, 2004; Trends in Mol. Med. 2011; Diabetes, 2013; Stem Cell Rep, 2017).
More recently, it transpires that SOX9 becomes expressed and induces destructive ECM components during liver fibrosis. We have shown SOX9 becomes ectopically expressed by liver myofibroblasts and regulates multiple aspects of ECM components in vitro and in vivo. Whereas in human liver fibrosis SOX9 prevalence in patient biopsy samples directly correlates with severity and predicts worsening fibrosis; representing a novel prognostic marker in liver disease (JBC, 2008; Hepatology, 2012, PlosOne, 2014; Nat. Comms, 2016; EMBO mol. Med, 2017).
How does increasing scar and stiffness signal to surrounding cells? Extracellular stiffness is a critical factor for HSC activation. The in vitro model for activating HSCs on tissue culture plastic exemplifies this. Using cell biology and transcriptomic approaches, my group has shown signalling via integrin beta-1 is important in the profibrotic response of HSCs. Inhibiting Integrin beta-1 in HSCs reduces the ability of HSCs to adhere to COL1-rich fibrotic ECM, with reduced actin organisation in the cytoskeleton. Downstream of Itgb1, we showed that Group 1 PAKs (PAK1, PAK2 and PAK3) were important in HSC activation and liver fibrosis. PAK1 emerged as the most important isoform. Blocking PAK function pharmacologically arrested liver fibrosis in vivo in mice in both CCl4 and BDL models and inhibited myofibroblast activation in vitro. Our data also identified the mechanosensitive transcription factor Yes Associated Protein-1 (YAP1) downstream of ITGB1 and PAK. Blocking YAP1 function with its inhibitor verteporfin lessened liver fibrosis. Interestingly, profibrotic factors SOX9, CTGF and GLI2 are all transcriptional targets of YAP1 (Nat. Comms, 2016; EMBO mol. Med, 2017).
Human Development, Stem Cells & Regenerative Medicine: In collaboration with Professor Neil Hanley, my lab maintains an interest in understanding pancreas and, more recently, liver development during human embryogenesis. This work includes stem cell platforms for regenerative medicine and toxicology screening (Hepatology, 2013; J.Hep, 2015; eLife, 2016; Stem Cell Rep, 2017). This is an active collaboration and which brings together our knowledge of development and fibrosis to uncover why regeneration is impaired during chronic diseases. In particular my group are investigating how aberrant expression of key development genes function in regeneration and disease in liver, kidney and lung.