Stem cell-derived liver models allow scientists to develop new techniques for the potential treatment of liver disease
1 Nov 2017
Scientists at the MRC Centre for Regenerative Medicine at the University of Edinburgh have developed a new technique using stem cells to generate a liver ‘model’. Using this model, the team have focused on developing new techniques that could reduce the need for liver transplants. In 2016, microRNAs to treat drug-induced toxicity were developed, followed by stem cell implants to treat liver disease in 2018.
Liver physiology and disease is often studied in the lab using cells derived from donor organs or liver cancer cell lines. However, both these sources of cells have inherent disadvantages; the former eventually runs out while the later can have chromosomal abnormalities.
In an effort to address this problem, Dr David Hay at the MRC Centre for Regenerative Medicine at the University of Edinburgh has developed a technique for producing liver cells from stem cells. Dr Hay’s innovative research was funded through a UK Regenerative Medicine Platform Award, and demonstrates how this scheme is accelerating the progress of translational medicine. Liver cells produced through stem cells could be invaluable to industry in drug development as they can provide a consistent and easily reproducible supply of human cells.
In 2016, Dr Hay and his team used these stem cell-derived liver cells to model the effects of paracetamol overdose. Although paracetamol is usually safe and effective when taken at recommended levels, it can sometimes damage the liver and the risk of liver damage increases with doses over the recommended levels. The liver normally processes paracetamol by breaking it down into simpler compounds through a metabolic pathway called the sulfation pathway. When too much paracetamol is ingested, the liver cannot process enough of it through this pathway, leading to the production and accumulation of toxins that kill liver cells, resulting in irreparable liver damage. By modelling this process in the ‘liver in a dish’ system, Dr Hay and his team identified a type of tiny molecule known as a microRNA that increased the number of proteins used in the sulfation pathway. By treating the damaged liver cells with this novel microRNA, the team were able to boost the activity of this pathway, thereby reducing the number of dying liver cells. The team are now testing this molecule further, and if their preclinical assessments are successful, they intend to take these studies toward clinical trials.
Given the importance of these results, in 2015 Dr Hay and his team protected their method for cell production in partnership with Biolamina, the commercial provider of the extracellular matrix that the cells grow on. The team partnered with AstraZeneca in 2016 to screen compound libraries to examine their effect on liver cell biology. This partnership is expected to help understand the potential of lab-grown cells and how the method can be improved to treat liver disease in patients.
In 2018, Dr Hay and team published a study which shows the potential of stem cell-derived liver cells in helping to reduce the need for liver transplants. The stem cell-derived liver cells were used to treat Tyrosinaemia in mice. Tyrosinaemia is a genetic disease that results in the liver being unable to break down toxic products with potentially fatal effects. Mice with this disease experience symptoms such as weight loss and a build-up of toxins in the blood. Researchers created liver implants by inserting the stem cell-derived liver cells into a 3D mesh scaffold. The implants were shown to be successfully incorporated into the body of the mice. Treatment with these implants decreased the number of toxins present in the blood and the amount of weight loss in comparison to untreated mice. This research is significant as, if proven to be a safe technique, it could lead to the development of liver implants for use in humans and therefore reduce the need for liver transplants.
Award details: MR/L022974/1