Method Developed to Produce Functional Hepatocytes for Drug Testing

For the first time, scientists have generated liver cells from adult skin cells using induced pluripotent stem cell (iPSC) technology. The research paves the way for the creation of a stem cell library that can be used for in vitro hepatic disease models.

Presently primary human hepatocytes (PHHs) have become the "gold standard” cell type used in predictive drug toxicology. These cells are derived from dead or donor tissue. The cells can only survive for three to five days and do not have the ability to multiply. PHH cells are therefore a scarce and costly resource.

The study, led by researchers from the University of Edinburgh's MRC Center for Regenerative Medicine (Scotland, UK), revealed an alternative way of sourcing hepatocytes, by creating hepatic endoderm utilizing iPSC technology and then differentiating it into hepatocytes. The in vitro-derived hepatocytes showed similar attributes to PHH cells used for predictive drug toxicology assays, including CYP3A4 and CYP1A2 metabolism.

The method was successfully performed with a variety of polymorphic variants, with cells derived from males and females of different ethnic origins. Drug development is a long and cost-intensive business. Each new drug takes many years to develop and pre-approval costs are in the region of US$1.3 billion per approved drug. Frequently, drugs have to be withdrawn at this stage because of deleterious side effects.

The new method has the potential to supply an unlimited and effective source of hepatocytes. These hepatocytes are highly characterized and reproducible and therefore, should enable earlier use in the screening cascade used by industry for drug discovery.

Gareth Sullivan, from the University's MRC Center for Regenerative Medicine, said, "What we have been able to do will help drug discovery because it means we are able to test drugs for adverse reactions at a much earlier stage.”

Prof. Sir Ian Wilmut, director of the University's MRC Center for Regenerative Medicine, said, "We are now looking for ways to bring this technology into routine use for drug testing. This is an exciting opportunity and it gives me great pleasure to be able to turn the first recommendation of the UK Stem Cell Initiative into a reality.”

The research, which was conducted in collaboration with Harvard Medical School (Cambridge, MA, USA), was published in the October 2009 issue of the journal Hepatology. As well as using liver cells created from stem cell lines to test drugs, it is hoped the cells could ultimately be used in therapy for patients suffering from liver disease. They could also play a role to aid research into liver disease.

Related Links:
University of Edinburgh's MRC Center for Regenerative Medicine
Harvard Medical School