Chronic liver disease: how could regenerative medicine help?

Chronic liver disease is the fifth biggest killer in the EU. Once serious damage has been done to the liver, it loses the ability to repair itself and this is a life-threatening problem. The only treatment currently available is a liver transplant. Could regenerative medicine help?

The liver is the only internal organ in the human body capable of regenerating itself after being damaged.

In chronic liver disease, damage to the liver over long periods of time leads to the accumulation of scar tissue that limits the ability of the liver to function and repair itself. This disease is the fifth largest killer in the EU and presently can only be treated with liver transplants.

Researchers have successfully used embryonic stem cells and induced pluripotent stem cells to make new liver cells in laboratories, which may potentially be used to treat liver disease in the future.

Researchers want to learn how stem cells in the liver are able to regenerate liver tissue. It may be possible to develop treatments that harness the natural ability of liver stem cells to regenerate the liver.

Treatments using pluripotent stem cells to create new liver cells for transplantation into the liver are being researched and developed. More work must be done to make sure that the liver cells created are safe and reliable.

Studies are also exploring if a person’s own bone marrow stem cells might be used to create cells that remove scar tissue from the damaged liver.

Liver transplants require patients to take immunosuppressants to prevent transplant rejection. Researchers are looking for new ways to make transplants of all kinds more resistant to immune rejection.

Many stem cell treatments could potentially avoid the issue of immune rejection, however a great amount of work must still be carried out to make sure that stem cell treatments, particularly pluripotent stem cell treatments, create reliable and predictable liver cells that are safe for transplantation in large enough quantities.

LiverThe liver is the largest organ of the human body. It does many jobs, including removing toxins from the blood, helping to digest food and fighting infections. It is the only organ in the body that can regenerate itself after damage.

A piece of mouse liver containing hepatocytes and oval cells
A piece of mouse liver containing hepatocytes and oval cells. Oval cells are thought to be the stem cells of the liver. They appear only to become active under certain circumstances, e.g. when hepatocytes cannot repair damage.

The cells that do the work in the liver are called hepatocytes. On average, each hepatocyte lives for around 200 to 300 days. In a healthy liver, hepatocytes can divide to make copies of themselves. This means they can replace the cells that die and can even repair some kinds of damage. If the liver is severely injured, another type of liver cell may come to the rescue: these cells are called oval cells. Oval cells are thought to be the liver’s resident stem cells and have the potential to make new hepatocytes. However, scientists are still investigating exactly what oval cells are, how they work and how we can make them produce hepatocytes more efficiently.

 

In chronic liver disease (also called cirrhosis), a lot of liver damage happens over a long period of time. The normal repair processes are impaired and scars are formed in the liver. The only currently available treatment for patients with chronic liver disease is an organ transplant. Transplants are expensive, the process requires lifelong immunosuppression and there are not enough organ donors to treat all the patients. Alternative therapies must therefore be found for patients with liver cirrhosis.

A piece of diseased mouse liver
A piece of diseased mouse liver; red staining indicates scarring

 

In the long term, stem cells might provide new ways to treat chronic liver disease:

  1. Researchers are working to identify liver stem cells more precisely, and to understand how they could be used to treat patients.
  2. Embryonic stem cells or induced pluripotent stem cells might be used to make new hepatocytes in the laboratory for patients whose liver can no longer regenerate. However, there are still a number of fundamental questions that must be answered before this kind of treatment can be deployed clinically. For example, it will be important to find out if stem cell-derived hepatocytes are safe to treat patients.

Hepatocyte-like cells grown from human embryonic stem cells
Hepatocyte-like cells grown from human embryonic stem cells

 

Another route to new treatments might be to use cells made from a patient’s own bone marrow to help repair damaged liver tissue. These cells are called macrophages. Under normal circumstances, macrophages cannot make new liver cells and scientists don’t yet understand exactly how they help the liver. However, macrophages have been tested in mice with damaged livers and early results look promising. In the laboratory:

  • Bone marrow cells are harvested from the thigh bone of a mouse.
  • The bone marrow contains a mixture of cells. The cells are grown under carefully controlled conditions to make many macrophages.
  • The macrophages are put into the diseased liver of the mouse.
  • The macrophages have a beneficial role in regenerating liver tissue and reversing scarring in the liver. When scarring is reduced, the liver is able to work better.

Mouse macrophage cells grown from bone marrow
Mouse macrophage cells grown from bone marrow

An important goal for research now is to understand what the macrophage cells do in the liver. This is an essential step before any treatment is developed for patients. Researchers are trying to answer this question and hope that the first clinical trials to test the safety of a macrophage-based treatment may begin in the next 5 years or so. There is a lot of work still to do, but if such a treatment can be developed, it will have an important advantage: The macrophage cells would be grown from the patient’s own bone marrow or blood so should not be rejected by the immune system, as sometimes happens with organ transplants.

Research is underway to gain a better understanding of the healthy liver and how new cell therapies could work. Scientists are also developing more effective ways to grow large numbers and tissue engineer liver cells (hepatocytes) from embryonic stem cells or induced pluripotent stem cells in the lab. Such research is not only useful for potential new therapies. In the shorter term, lab-grown hepatocytes are likely to play an important role in the development of new drugs and artificial liver support.

This factsheet was created by Caroline Pope and reviewed by David HayDavid Tosh and Clare Blackburn.
Cell images by Caroline Pope,  David Hay and Luke Bolter.


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