New liver cells to treat disease

26 November 2019

Interview with 

David Hay, Edinburgh University

LIVER

PICTURE OF A LIVER

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Another organ high up the list in terms of transplant need is the liver. Here's Phil Sansom with a quick fire science...

Why might you need a liver transplant? It's a last ditch measure for either chronic liver diseases like cirrhosis, caused by long term alcohol abuse, or acute liver damage caused by overdoses of drugs like paracetamol and infections with some hepatitis viruses. Either way, it's a more common form of transplant. Last year there were 25,000 of them globally and they're generally very successful. Most people are eventually able to return to their normal activities afterwards, but it can take a year or more to fully recover and like other transplants, you'll need to take immunosuppressant medicines to stop your body attacking the new liver for the rest of your life.

David Hay from Edinburgh University has implanted lab-grown liver cells into mice with a serious liver problem due to the body not being able to process the amino acid tyrosine, and has since got them off medication, with in-tact immune systems. David told Adam Murphy about his work, explaining firstly why these mice needed new livers...

David - So these mice need new livers because as you said, they can't fully process the amino acid tyrosine and it leads to a build up of toxic products, which damage a number of different organs in the mice. So what we've done is use this as a test model to assess how good our liver tissue, that we produc in the laboratory, is in an InVivo setting in the mouse. And what we've done is, we've implanted this tissue underneath the skin of mice. So this is a piece of liver tissue which is operating a distinct site from the host's own liver and it's been able to support the mice when their medicine has been removed for at least 14 days in our experimental procedures, providing proof of concept that this is a viable approach to supporting failing liver function in mammals.

Adam - How do you get this liver tissue to implant in the first place?

David - What we do is we've been working with engineers at Edinburgh and we've been using a non woven fabric and putting our liver spheres and top of this fabric and then putting these underneath the skin of mice, so a very simple procedure to deliver tissue underneath the skin and then this tissue becomes vascularized. So it connects with the recipient circulation. And what we saw in those experiments was that the amino acid tyrosine could now be processed in the absence of medication - truly processed, so it wasn't toxic to the individual.

Adam - And what could this potentially mean for humans who have liver problems?

David - That's what we're trying to develop now, moving towards the clinic with this work, because we're trying to generate the liver implant that we could give to patients to support them when their liver is failing. Now this could be in the case someone who has an underlying liver disease and has a short period of decompensation where the liver doesn't function at a level which is consistent with good health. So what we're looking to do is use that as our test bed, really, for assessing how good the technology is. Is it safe to use? Is it efficacious? And will it make a difference to patients who may not have other treatment options?

Adam - So how do you go about doing that, then? How do you take a tiny little thing that can go on a mouse and size it up to something that can go on a person?

David - That's a very good question and that's something we're focusing on at the moment. So what we've done with our basic prototype is now moved us onto the next stage where we've semi-automated it and scaled up the amount of liver tissue that we can produce from stem cells, using the robotic setup at our center in Edinburgh. And the idea really is to produce tissue on mass that we can then use in the context of a human being, but also use this tissue as well to model at different aspects of liver disease in the dish. Maybe repurpose drugs, or test the safety of drugs too. So there's a number of different applications for this type of technology, and working at scale is paramount.

Chris- Can I just ask you a question, Dave, which was, I'm intrigued to know, when you make these little miniature livers, do they actually recapitulate the anatomy of a liver? Because if I took a piece of liver and I looked at it under a microscope and I looked at one of yours, would they look the same?

David - That's a good question. They wouldn't look the same. So what we are doing is producing three dimensional spheres and we have liver cells in there, so the main cell type of the liver called the hypothesize that performance most of the function and also endothelial cells, which forms the blood vessels. And what we're able to do is actually mix those at very early points in development in a dish. And then they self-assemble into these three-dimensional structures. So while we recapitulate certain aspects of the liver, we're not able to fully recapitulate the architecture of the liver at the moment. And that's something that we're looking at working with our engineering colleagues to provide, if you like, a template that guides this tissue formation in a dish.

Adam - So even though it doesn't look like a full liver, it still helps these mice out.

David - That's correct, yes. And importantly, it quickly connects to the host circulation, which is essential if we're going to provide liver support from an ectopic site.

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