Stem cell-derived hepatocytes for the treatment of liver disease

Liver disease is one of the leading causes of premature death, accounting for 3.7% of total mortality and over 10,000 lives in the UK each year.

A small but significant proportion of these deaths are due to inherited genetic defects in metabolic genes whose expression is restricted to the liver's main cell type, the hepatocyte. This group of diseases is known as the "inherited metabolic disorders" of the liver or IMDs.

Despite progress in advanced therapeutics such as gene therapy, the only curative option for these patients remains a liver transplant.

Unfortunately, the demand for liver transplantation is still far greater than the number of available donor livers and many patients, often children, do not find a donor in time. An alternative approach currently under development involves transplantation of cells instead of whole organs.

Hepatocytes isolated from healthy donor tissue (primary human hepatocytes; PHH) successfully repopulate the livers of IMD patients as well as non-human disease models.

Unfortunately, as with whole organ transplantation, donor scarcity prevents wider use of PHH in routine clinical practice.

Pluripotent stem cell-derived hepatocytes (PSC-Heps) represent an exciting new approach to address this problem since they can be potentially produced in unlimited quantities and used in all patients without the need for harmful immunosuppression.

We previously developed a robust methodology for generating hepatocytes from clinical grade induced (iPSC) and embryonic (ESC) pluripotent stem cells but unlike PHH, PSC-Heps did not work in our non-human models and are therefore unlikely to work in patients. Why is this the case?

PHH transplants used in patients turn out to be a mixture of mature, highly functional hepatocytes and specific extracellular molecules.

Our overarching hypothesis is that iPSC-Hep therapy is therefore failing right now due to (1) a lack of essential extracellular components and (2) the sub-optimal maturity of the hepatocytes being produced.

Together, these factors prevent donor iPSC-Heps repopulating the host liver as non-cancerous entities and their downstream use in humans.

Our objective in this project is to apply advances we have made in both the domains of biomechanical engineering and hepatocyte maturation to study extracellular and intracellular mechanisms regulating donor cell repopulation in vivo.

It is hoped that the outcomes from these experiments will generate the critical preclinical data needed to move iPSC-Heps towards the clinic. The primary beneficiaries of this project will accordingly be patients with IMDs and researchers in cell therapy.