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Chronic liver disease: how could gene and cell therapy help?

Chronic liver disease is a significant global health and economic problem, and is the eleventh leading cause of death worldwide. When the liver undergoes enough serious damage, it loses the ability both to function adequately and to repair itself. This is a life-threatening problem. The only treatment currently available is a liver transplant. Could regenerative medicine help?

Introduction to chronic liver disease

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

The cells carrying out this 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 is involved in the healing response. These cells are called hepatic progenitor cells (HPCs). HPCs are the liver’s resident stem cells and have been shown in mice to produce new hepatocytes during severe injury. Scientists have developed techniques to extract HPCs from the liver, grow them in large numbers in the lab, and then transplant these cells into injured mice, where they produce new hepatocytes. Scientists have shown that cells with similar properties to mouse HPCs are present in human livers and are investigating their potential to be a useful type of cell for therapy, including how to grow HPCs using clinically appropriate methods, and at a scale where they could be used in patients in the future.

In chronic liver disease, a lot of liver damage occurs over a long period of time – for example, due to a long-term infection. This damage reduces the amount of functional tissue in the liver. This severe damage also impairs the ability of hepatocytes to divide and repair the liver by inducing a process called ‘senescence' (causing cells to stop dividing, and so preventing damaged tissue from regenerating). Furthermore, long-term liver injury causes scar formation in the liver (cirrhosis).

Cirrhosis can lead to a wide range of health complications. These include swelling or bleeding of the veins in the oesophagus and stomach, reduced ability to form blood clots (carrying a risk of severe bleeding), and cognitive issue such as confusion. As cirrhosis progresses, it often causes a build-up of fluid in the lags or ankles (peripheral oedema) or in the spaces within the abdomen (ascites). This fluid build-up can be painful and restrict movement. In severe cases ascites fluid may becoming infected, and it may need to be drained with a tube.

Current treatments

The methods for managing the effects of cirrhosis vary depending on the cause of the damage. Patients may be advised to make lifestyle changes, such as changing their diet or avoiding alcohol. Medicines may also be used to reduce swelling or prevent infection.

The only currently available treatment for patients with advanced cirrhosis is liver transplantation. However, the number of patients in need of organ donation greatly exceeds the number of eligible donors. The process of matching donors with patients is made more complex by the need to make sure that they have matching ‘tissue types’, so that the tissue is not rejected by the body. When a successful transplant can occur, the process is costly, and, and the patient must undergo lifelong immunosuppression. Alternative therapies must therefore be found for patients with liver cirrhosis.

How might gene and cell therapy help?

Researchers are investigating whether gene and cell-based therapies might be used to treat and repair chronic cirrhosis. A major barrier to treating patients in need of a liver transplant is the availability of donor tissue. Being able to grow suitable numbers of donor hepatocytes in the lab could overcome this issue.

Another issue intrinsic to organ transplantation is the need for matching the donor tissue to the recipient, and the risk of rejection by the immune system. Technologies which produce hepatocytes from a patient’s own cells – such as iPS cells – could overcome this risk of rejection. Researchers are also investigating whether immune cells could be used to repair damaged tissue and reduce the patient’s immune response, reducing damage.

Tissue engineers are investigating whether it is possible to grow liver tissue suitable for transplant in lab setting. This would be a highly complex process, as the organ would need to be composed of multiple tissue types, correctly arranged and organised, to ensure its long-term survival and functioning in the body.

Next steps

Bio-artificial livers

Bio-artificial livers are a growing area of research that combine technology with biology. Similar to a dialysis machine, these are devices external to the body, through which patient’s blood would be passed and returned to the body. Unlike traditional devices, which use synthetic membranes to filter out toxins and waste, these devices would contain a chamber of healthy, living, hepatocytes. In theory, the cells in this device could remove toxins, produce essential proteins for the body (such as albumin for blood serum), and provide other vital roles of a healthy liver. As with hepatocyte transplant treatments, obtaining large enough numbers of human hepatocytes to live in these bio-artificial livers is a major obstacle. Researchers are attempting to address this issue by using hepatocytes from animal donors (such as pigs) or human stem cells (such as iPSCs) to grow large numbers of fully functional hepatocytes. Clinical results in studies examining bio-artificial livers have been mixed, with some showing no benefits over current treatment methods. However, next generation technologies for growing cells in these bio-artificial livers may improve the quality of the cells, cell metabolic activity and overall effectiveness of these devices for treatment.

Tissue engineering the liver

Tissue engineering research is advancing technologies to bioengineer whole organs, including the liver. Bioengineering a liver is complex, requiring the ability to assemble extremely large numbers of functional hepatocytes into specific three-dimensional structures with other types of cells. Researchers have determined how to create scaffolds for hepatocytes to grow on and direct their general structure, but there are still substantial challenges.

Once again, the need for large numbers of human hepatocytes is a problem. Stem cells, particularly iPSCs, offer the potential for creating the large numbers of hepatocytes needed, but researchers must make sure that these cells show the correct metabolic activity, and will not continue to multiply once in the body. Unregulated growth of stem cell-made hepatocytes has potential to lead to tumours.

As well as the issue of cell numbers, researchers are still investigating how to create bioengineered tissue which incorporates vascular tissue and other cells types, which would be essential for the organs integration, functioning, and survival in the body.

Bioengineering the liver with stem cells is an ambitious goal but has the potential to avoid or solve many problems associated with other treatment methods. Such a technology would completely replace the damaged liver with a new liver, and potentially avoid attack by the immune system if made with iPSCs.

Find out more

European Association for the Study of the Liver (Information on EU Policy)

British Liver Trust (Information on treatment options, and support within the UK)

 

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