Biliary atresia (BA) is a rare medical condition, occurring in small infants, in which the bile ducts outside and inside the liver become scarred and blocked. This results in a build-up of bile in the liver causing damage. This damage leads to scarring, tissue loss and cirrhosis. The current treatment for patients with BA is a surgical procedure known as a hepatic portoenterostomy (HPE). Despite HPE being successful in 60-85% of patients, it is not a cure for the disease. Over 75% of patients will need a liver transplant before the age of 20.
The exact cause of BA is yet unknown although it is hypothesised that either a genetic variant, viral infection or toxin triggers the immune system, causing an abnormal inflammatory response which in turn causes damage to the cells lining the bile ducts.
This project aims to investigate the effect that Mesenchymal Stem/stromal Cells (MSCs) have on the fibro-inflammatory processes contributing to progressive liver injury in BA. By establishing two disease models using organoid technology and precision-cut liver slices this project aims to investigate the effect MSCs have on epithelial damage and fibrosis seen in BA and therefore the potential of using MSCs as a novel treatment.
Although BA was identified over 200 years ago, the aetiology is unknown. The presence of inflammation (bile duct injury, fibrosis, and biliary cirrhosis) and proinflammatory cytokines in the liver and bile ducts at the time of diagnosis suggests the host immune response mediates the progressive injury. Steroids, with their anti-inflammatory properties, have been explored as a possible treatment. Although some studies have shown initial improvement in bile flow, Liver transplant rate has remained unchanged. Furthermore, steroid side effects, including stunting growth in young children, have been demonstrated. Mesenchymal stem/stromal cells (MSCs) are multipotent cells with potent regenerative and immunomodulatory properties. They have received much attention in recent years for their clinical effects in numerous medical conditions. MSCs preferentially home to damaged tissue, where they serve as a reservoir of growth factors and regenerative molecules. They initiate immunomodulation by targeting a range of innate and adaptive immune cells by direct interaction and by secreting soluble factors. Furthermore, MSCs exhibit anti-fibrotic properties and can directly and indirectly inhibit hepatic stellate cell activation. Moreover, the low immunogenicity MSCs possess enables allogeneic cells to be used as “off-the-shelf” products. Their safety for use as Advanced Therapy Medicinal Products (ATMP) has been widely evaluated. Currently there are over 1000 clinical trials associated with MSC cell therapies registered with www.clinicaltrials.gov. Additionally, MSC cell therapy has been employed to treat Bronchopulmonary Dysplasia (BPD) in premature infants which showed MSC treatment was safe and feasible in a preterm cohort and demonstrated a significant reduction in cytokine levels and lower severity of BPD. This poises MSCs as a strong candidate for use in a clinical trial for treating BA, following a display of efficacy in this work.
This PhD project will build on the work currently ongoing within the Dhawan lab which is focussing on the immunomodulatory effects of MSCs on peripheral blood mononuclear cells (PBMCs) which have been collected from over 30 BA patients. Furthermore, plasma samples have been analysed and have revealed that the peripheral immune profile in BA patients can determine clinical outcomes. This preliminary data has highlighted potential early targets for MSC immunomodulation in BA, to potentially reduce liver transplantation rates. This has motivated our lab to establish in vitro model systems of the disease, in collaboration with the Sampaziotis lab (University of Cambridge), as part of this PhD project, to further investigate the effect of MSCs as a cell therapy. These investigations will hopefully provide the fundamental insights needed to progress to a clinical trial.
Award Scheme Name: INCTB22
For enquiries please contact Jessica Nulty [Email Address Removed]
Please see the studentship webpage for full details on how to submit an application
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