Liver disease is a serious threat to human life and health. At present, the most effective treatment for end-stage liver disease and acute liver failure is orthotopic liver transplantation. In view of the shortage of donor liver and the expensive cost of treatment, cell therapy and stem cell technology have prompted researchers to gradually try to use human primary hepatocyte and hepatocyte-like cells instead of liver transplantation to treat liver disease. However, it is very difficult to culture human primary hepatocytes in vitro, which has always been a problem in the field.

On November 8th, Peng Luying research group of Tongji University School of Medicine, in close cooperation with Hui Lijian research group of Shanghai Research Institute of Biochemistry and Cell, Chinese Academy of Sciences, published an important research achievement titled In vitro expansion of primary human hepatocytes with efficient liver repopulation capacity in the internationally famous academic journal Cell Stem Cell.

The main innovation points of this research included:

1. A whole set of new human hepatocyte culture system in vitro was established, which could expand the primary human hepatocytes as much as 10000 times in vitro, and it was detected that multiple individuals of different races, genders and ages had similar proliferation ability in this culture system, which would provide sufficient cell sources for clinical treatment of hepatocytes.

2. The proliferating human hepatocytes (ProliHH) cultured in this system still retained the expression of some liver functional genes and maintained the function of some hepatocytes, and were in the dual phenotype state of co-expression of liver functional genes and liver precursor genes. Compared with liver precursor cells, the function of ProliHH in vitro and in vivo was more similar to that of human primary hepatocytes.

3. Using 3D culture to establish a new hepatic induction system, ProliHH could rapidly mature in vitro, which provided a very stable human hepatocyte research system for researchers studying drug metabolism in vitro, hepatophilic virus infection and some other directions.

4. The most important discovery was that, while ProliHH was transplanted into the liver of the immunodeficient mice who were Fah knockout. These cells showed the ability of integrating and regenerating similar to the primary human hepatocytes in vivo, and they could secrete up to Mg level of human albumin and showed the specific ability of human drug metabolism. The transplanted ProliHH showed a very similar therapeutic effect with primary hepatocytes in terms of reducing liver injury and improving survival rate of mice.

This research work effectively solved the problem of the source of human liver parenchymal cells, which would provide an ideal research system for the model construction and drug screening in vitro of liver diseases, and lay a solid foundation for the treatment of hepatocyte transplantation.

Zhang Kun, Ph.D. student from Peng Luying’s lab and Dr. Zhang Ludi from Hui Lijian’s lab were the co-first authors of this paper, and Prof. Hui Lijian, Prof. Peng Luying and Dr. Zhang Ludi were the co-corresponding authors of this paper.