Transplanting liver stem cells: a future dream for both children and dogs with hereditary diseases

As a paediatrician in the Wilhelmina Children’s Hospital (WKZ) in Utrecht, Sabine Fuchs sees many children with metabolic illnesses. In most of these cases, their liver isn’t working properly. But for many of these children a liver transplant is not an option. Together with veterinarian and scientist Hedwig Kruitwagen of the Faculty of Veterinary Medicine, Fuchs is trying to improve the medical possibilities for liver patients. As part of their research, the duo carried out a liver stem cell transplantation in six dogs suffering from ‘copper accumulation’ in the liver. Two researchers talk about their shared dream of helping both dogs and people with liver diseases.

Kinderarts Sabine Fuchs voelt aan de pols van een kind dat in een ziekenhuisbed ligt.
Paediatrician Sabine Fuchs: ‘There is still no treatment available for many children, they die at a young age

Kruitwagen: ‘There are around 7500 dogs in the Netherlands with some form of liver disease. Thirty percent of those dogs have problems with copper accumulation caused by a hereditary defect. Their bodies are unable to eliminate copper and so it accumulates in the liver. After a few years, the liver contains so much copper that it becomes inflamed and no longer works properly. Without treatment these dogs don’t survive.’

Comparable metabolic diseases occur in children too, says Fuchs. ‘There are more than ten thousand families in the Netherlands in which one or more children suffer from a metabolic disease. There is still no treatment available for many of these children. They become mentally and physically handicapped and die at a young age. I want to do something about this.’

There are more than ten thousand families in the Netherlands in which one or more children suffer from a metabolic disease.

Sabine Fuchs, paediatrician
Wilhelmina Children's Hospital

Advantages

The potential treatment that Fuchs and Kruitwagen are now researching, transplantation of liver stem cells, could possibly replace transplantation of liver tissue in the future. This would bring many advantages for children. Fuchs explains: ‘First of all, there’s a waiting list for new livers. Many patients have to wait until their health deteriorates before they become eligible for a new liver. That’s terrible. Some children are not eligible for a new liver because they also have problems in other organs, or are actually already too ill. We can grow large numbers of liver stem cells in the lab. In that case, availability would no longer present a problem. Another big advantage would be that we can administer stem cells through a blood vessel, instead of in a major surgery. This means that many more patients could be considered for treatment.’

 

Dierenarts en wetenschapper Hedwig Kruitwagen aan het werk in het laboratorium
Veterinarian and scientist Hedwig Kruitwagen

Improving transplantation efficiency

However, the transplantation of stem cells is currently not efficient enough to allow treatment, as shown by Fuchs’ and Kruitwagen’s work. Kruitwagen continues: ‘Together with a colleague at the Faculty of Veterinary Medicine, molecular biologist Bart Spee, we transplanted around a billion healthy stem cells into the livers of six dogs. That’s one percent of the total number of cells in a dog liver. We hoped that the healthy stem cells would divide, and that they would outgrow the diseased cells.’ Unfortunately for the researchers, that didn’t happen. After two years, they found only a small proportion of the transplanted cells still surviving in the liver. ‘This was a setback’, recounts Fuchs. ‘The transplantation efficiency still needs to be dramatically improved. That’s our biggest goal.’ However, she does stress that it’s not necessary to achieve a 100 percent recovery of the liver. ‘When it comes to metabolic diseases, such as the illness affecting these six dogs, you often need just five to ten percent of liver function in order to treat the patients’ symptoms, so we could treat the disease by just replacing a small part of the liver cells.’

Portret van het gezicht van hondpatient Aagje
Aagje is one of the six dogs in whom the stem cell transplantation was successful.

Five years

Nonetheless, the fact that the transplantation of the stem cells succeeded in the six dogs is a good step forward in itself. Kruitwagen explains: ‘We took a small biopsy from the dogs’ livers. In the lab we selected the stem cells, corrected the genetic defect in these and stimulated them to multiply very often. When we had around a billion healthy cells, we put the cells back in the liver of the same dog.’ The transplantation succeeded and proved to be healthy: no complications occurred. ‘If we can manage to increase the efficiency in the future, then we could also translate this technique into human medicine. Dogs resemble children in terms of body weight and liver function.’ Fuchs feels confident about the method. ‘I really believe that it should be possible. The collaboration in regenerative medicine between researchers in the fields of human and veterinary medicine enables fantastic cross-fertilisation. I hope that we can treat the first patient with a liver stem cell transplantation in five years from now.’

 

The dog liver stem cell transplantation project was co-financed by ZonMW ( 116004121), under responsibility  of  Dr Louis C. Penning of the faculty of Veterinary Sciences.