Liver tissue under the skin may buy time for a failing liver

Liver disease claims the lives of more than 2 million people every year. Nevertheless, no approved medicine can help a severely damaged liver return to function in the long term.

For the most seriously ill people, the only real lifeline is often a new liver from a donor, but organs are in short supply, and many people become too ill while they wait.

Researchers are therefore searching for a renewable source of liver tissue that can support patients before the damage becomes irreversible. Now, an international research team has shown that small pieces of human liver tissue can be produced from a clinical-grade stem cell line, shipped to an external laboratory and still produce human albumin after being transplanted into mice.

In the experiment, the researchers grew the liver tissue from stem cells, sent it to an external laboratory and let a third party transplant the material into mice. Afterwards, they could measure human albumin in the blood – a protein normally produced by the liver.

There is still a long way to go before this could benefit patients, but the experiment addresses a key problem: the liver tissue had to work not only in the developers’ own hands but also after leaving the laboratory.

“Our aim is to find a treatment that is as simple and minimally invasive as possible for the large group of patients with liver disease who have no other options. The idea is to create a renewable source of human liver tissue from stem cells and help to shift a failing liver from an exhausted state to a functioning one,” explains David Hay, Professor of Tissue Engineering at the Centre for Regenerative Medicine at the University of Edinburgh, United Kingdom and CEO of Stimuliver ApS, at the BioInnovation Institute, Denmark.

The research has been published in Cells.

Tiny spheres of liver tissue must find the bloodstream

The work begins with stem cells, which are directed in two different directions in the laboratory: towards liver cells, which carry out biochemical work, and towards endothelial cells, which can help the tissue fragment find the bloodstream.

The liver cells produce proteins and metabolise substances foreign to the body. The blood-vessel cells are necessary because tissue without a blood supply quickly runs short of oxygen and nutrients.

In the laboratory, the researchers encourage the cells to cluster into small spheres measuring around 0.4 millimetres in diameter. Here, the first beginnings of blood vessels form, so the result is not just a clump of cells but organised tissue.

Over six weeks, the spheres matured in the laboratory. They produced more albumin and maintained stable production of alpha-1-antitrypsin, and the level of a fetal-like liver protein fell. At the same time, the liver cells’ own enzymes continued to metabolise substances. They did not merely resemble liver tissue; they behaved like it.

These types of biochemical tasks make the liver so difficult to replace. It does not merely filter waste from the blood; it constantly builds, transforms and breaks down substances. This is why previous forms of liver dialysis have had only limited effect for people with advanced disease.

“It is crucial that the liver tissue has its own tiny blood vessels, because without them it cannot connect to the body’s circulatory system. As the blood flows past, the liver cells can, in principle, convert toxins into a form that the body can eliminate, and it is precisely this ability that fails among patients with severe liver disease,” explains David Hay.

The liver tissue had to work in someone else’s hands

The innovation lay not only in the liver tissue itself but in what happened afterwards.

After quality control, the material was packaged and sent to an external contract laboratory, which transplanted it into mice in two locations. Some of the tissue was placed beneath the kidney capsule, where tissue often receives a good blood supply. In other animals, liver tissue was placed under the skin on a small scaffold made from the material polycaprolactone – the location the team would prefer to develop further towards a single implant.

Human albumin was detectable at both sites after transplantation. Under the kidney capsule, the signal was present for at least two weeks. Under the skin, it was strongest in the first few days and had returned to baseline after two weeks. That decline matters.

It highlights both the potential and the greatest technical challenge: the liver tissue works, but it has to work for longer if it is to help people. In the study, the researchers also point to durability as a key focus of future work.

Several links in the chain held up: the stem cells were grown, guided towards liver and vascular cells, assembled into small pieces of tissue, quality controlled, dispatched and still produced a measurable signal in the hands of people other than those who had developed the method. For patients, this is not yet a treatment. But if the technology is to be used in hospitals, it must work outside the protected environment of the university laboratory.

“We wanted to show that the process can be scaled and moved from the university into industry. That is why Stimuliver ApS sent the liver tissue to an independent laboratory, which transplanted it and looked for basic human liver function. It is an important milestone when a third party can repeat our results,” says David Hay.

Not a new liver – but help from the sidelines

The result does not stand alone. Other cell-based treatments for liver disease are already being tested among humans, including using macrophages for patients with cirrhosis. The field is moving towards patients along several different paths.

What is new is not the idea of cell therapy itself but that a specific type of stem cell–based liver tissue with its own early vascular network can be moved from an academic prototype to a more industry-oriented process and still function in the hands of a third party. The study brings together several pieces of the puzzle: a renewable cell source, small vascular networks, laboratory function, external transplantation and a measurable signal in the blood.

The aim is for a finished implant to be inserted under the skin in a small procedure under local anaesthetic.

Once in place, the implant is intended to attract blood vessels, connect to the circulation and contribute some of the functions the liver loses when the patient has least time to spare. This is not about building a new liver under the skin but about giving the diseased liver help from the sidelines.

For patients with severe liver disease, scar tissue can disturb blood flow and weaken the organ’s biochemical work. Waste products build up in the blood, and the body loses its balance. David Hay hopes that even limited external support may be enough to push the liver back from the dangerous edge, where the kidneys and brain also begin to fail.

A living implant may do what machines cannot

That is the hope behind the implant. Once the liver begins to fail seriously, the kidneys and brain often follow, and when several organs fail, around 40% of patients die within four weeks. In that window, even temporary help can be crucial. Other forms of liver support are built on the same idea. Here, the team is trying to use living tissue rather than a machine.

If the liver is supported in time, its own ability to heal may be given a chance before the patient slides into irreversible organ failure.

“The liver is amazing at regenerating. You can remove 70% of it in mice, and within a month it has grown back to its original size and function. So, if our implant can take some of the burden off the patient’s own liver, the organ might be given the chance to heal itself and get out of the danger zone,” says David Hay.

The team has set up the company Stimuliver ApS to take the technology forward.

The next step is to test high-grade tissue manufacture, cell safety and stability in vivo, and how the graft interacts with the immune system. Only then can the researchers begin to ask whether the small implant can support a diseased liver in humans.

“If it proves to be safe and effective, the hope is to keep patients’ liver function afloat and perhaps even trigger regeneration. I do not want to promise too much, but cautiously speaking, I believe that in three years’ time we could be ready for a small clinical trial,” says David Hay.