Closing in on Pluripotent Stem Cell Therapies for Liver Diseases

October 9, 2020

The liver, our largest internal organ, plays vital roles in food metabolism, energy storage, and elimination of toxins. Liver disorders kill more than two million people per year, representing a significant global health challenge. In addition, liver failure is the end stage of many life-threatening diseases, such as alcoholic hepatitis, Hepatitis B infection, and liver cancer. In such conditions, liver failure results from the widespread death of the major cell type of the liver, the hepatocyte.

Organ transplantation is the only available therapeutic option for people with end-stage liver disease. However, because of difficulties in finding immune-matched donors, only around 10 percent of patients requiring a transplant receive a new functional liver, and many patients die before a suitable donor can be found. Researchers are looking to the potential of stem cell research to provide novel treatments to patients who do not have access to a liver transplant.

Pluripotent stem cells can become any cell type in the body. These stem cells can be grown in the lab in large numbers and can be transformed into functional cells with the goal that they will be able to integrate into a human organ and successfully carry out physiological activities or even potentially replace the need for donated organs for transplantation.

Scientists have been working towards the production of functional liver cells for more than 20 years. After great effort, scientists determined how to mimic the various stages of embryonic liver development in the laboratory to produce stem cell-derived hepatocytes that are comparable to normal liver cells, in terms of food metabolism, energy storage, and elimination of toxins. Scientists are studying whether these stem cell-derived liver cells can safely be transplanted into a patient or used to create an artificial liver that would function outside of the body.  

Recently, a group led by Mureo Kasahara at the National Center for Child Health and Development in Japan treated a six-day-old baby with pluripotent stem cell-derived hepatocytes for the first time. This newborn suffered a rare genetic urea cycle disorder where the liver cannot eliminate ammonia, resulting in the accumulation of this toxic compound in the baby’s blood. This disease normally requires a liver transplantation, but this complex surgery is too dangerous until about three to six months.

To “bridge” the patient until the time when the baby could safely receive a liver transplant, doctors decided to try a novel stem cell treatment. Doctors injected stem cell-derived hepatocytes into the baby’s liver with the hope of providing temporary support until a transplant was feasible. Strikingly, after the stem cell treatment, the level of ammonia in the blood stabilized, allowing the baby to survive until five months of age. The baby then received a successful liver transplant from the father and is now healthy and home from the hospital. While further studies are required to test the safety and efficacy of this procedure, it is a promising finding that the transplanted stem cell-derived hepatocytes appeared to bridge the baby’s liver function until transplantation was possible.

Researchers also are exploring ways that stem cell-derived liver cells might help patients through external devices. As an alternative to transplantation, stem cell-derived hepatocytes can be used to create a dialysis-like device that treats liver disease by clearing blood toxins. Such a machine, also known as a bioartificial liver, may ease the symptoms of liver failure and prolong the time until a liver transplant is needed.

“We are currently using these stem cell-derived hepatocytes to devise a bioartificial liver system to treat liver failure patients,” said Dr Xiaolei Shi, chief hepatobiliary surgeon at the Drum Tower Hospital of Nanjing University, China.

Shi and colleagues used stem cell-derived hepatocytes to make “mini liver tissues,” called hepatic spheroids. In pre-clinical studies, these spheroids were used to create a bioartificial liver that was able to rescue pigs from severe liver failure. This is a significant result because pigs are comparable in size and weight to humans and therefore offer insight into how these machines may function in human patients. This research is important pre-clinical support for going forward with clinical trials in humans, which will thoroughly test whether the bioartificial liver is safe and effective for treating liver disease.

While there has been significant progress, challenges remain. There are ongoing concerns whether stem cell therapy might form tumors following transplantation. External devices, however, physically separate stem cell derivatives from the patient, which could circumvent certain safety issues as the cells can easily be removed if issues arise.

Recent advances shed light on the ways that stem cell-derived liver cells might be used to help patients with various types of liver diseases. Ongoing research will continue to explore how pluripotent cell therapies can safely be used to help treat millions suffering worldwide.


Blog by guest contributor S.C. Jacky Sun, PhD candidate in the labs of Ed Stanley and Andrew Elefanty at the Murdoch Children’s Research Institute, Melbourne.