Break through the bottleneck! Chinese scientists successfully established a model of hepatitis B virus infection

The medical network said on May 6 that many people are familiar with hepatitis B. According to statistics, there are about 400 million liver disease patients in China, accounting for 40% of global liver patients. About 120 million of them carry hepatitis B virus. No effective cure has yet been found.
Recently, a research paper published in the journal Science by Deng Hongkui Research Group of Peking University, Lu Shichun Research Group of the People's Liberation Army General Hospital and Yuan Zhenghong's research group of Fudan University brought hope of liver disease treatment. Studies have shown that scientists have for the first time demonstrated that a small chemical molecule can regulate cellular signaling pathways and help achieve long-term maintenance of functional hepatocytes in vitro. In addition, the study also demonstrated that hepatocytes support long-term persistent infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) in vitro. This study provides the possibility to prepare a large number of functional mature cells and their applications.
Pain points in liver disease research
Liver diseases have not yet found an effective cure. The main reason is that liver disease research has been lacking in good in vitro models.
Originally, human liver primary cells (PHHs) were ideal experimental models. However, functional hepatocytes are very fragile and will quickly dedifferentiate and lose normal function once they leave the microenvironment.
In addition, due to the lack of suitable culture conditions and microenvironment, functional cells induced to differentiate by stem cells in vitro are difficult to truly mature and maintain their function for a long time. Therefore, how to induce the acquisition of functionally mature cells and maintain their functionality in vitro is a key bottleneck in regenerative medicine.
In the past few decades, scientists from all over the world have been trying to explore and try to change culture materials and culture methods. But unfortunately, there is no simple, efficient and relatively stable functional cell culture system.
Small molecules have a big effect
Professor Deng Hongkui and his team found that five chemical small molecule combinations (5 compounds, 5C) can help long-term maintenance of hepatocyte function in vitro. The 5C combination inhibits the dedifferentiation of hepatocytes, so that the overall gene expression of hepatocytes in vitro is highly similar to that of hepatocytes in vivo, and can maintain normal hepatocyte function such as albumin secretion, urea synthesis, and drug metabolism for a long time.
Compared to traditional genetic methods, chemical small molecules can achieve fine regulation of multiple signal pathway targets. The chemical small molecule induced reprogramming has been paid attention to since the beginning of the world. Compared with the traditional transgenic method-mediated reprogramming, chemical small molecules can not only avoid the risk of endogenous gene modification, but also have cell membrane penetration. Sex, reversibility, controllability and ease of manufacture.
This study shows that the advantages of chemical small molecules in fine-tuning cell fate and function, this method also provides a new way for the long-term maintenance of other types of cells in vitro.
Establishment of hepatitis B virus infection model
After discovering that the 5C combination has the effect of inhibiting cell differentiation, the Deng Hongkui research team and the Lu Shichun research group of the PLA General Hospital and the Yuan Zhenghong research group of Fudan University successfully established the first hepatitis B virus infection model. Continue to high-level expression of hepatitis B surface antigen, e antigen, synthetic hepatitis B virus DNA and other infection indicators, especially long-term stable production of cccDNA necessary for hepatitis B virus replication.
The establishment of this model is of great significance for the in-depth study and drug development of hepatitis B virus. Because hepatitis B virus invades liver cells, it forms a viral replication template cccDNA that is difficult to remove. There are no drugs targeting this virus to replicate key targets.
In contrast, the discovery of hepatitis C virus, although later than hepatitis B virus, has been successfully screened and obtained for the treatment of hepatitis C based on an effective in vitro viral infection model. Hepatocytes under 5C culture conditions support the high-efficiency infection of hepatitis B virus and can produce cccDNA for a long time, which can be used as an ideal drug screening model, which brings hope for curing hepatitis B.
Wen Yumei, an academician of the Chinese Academy of Engineering, pointed out that this method of long-term culture of human liver primary cells by using only five chemical small molecules is easy to implement, and is highly suitable for high-throughput screening of drugs, providing more treatment for liver diseases. It is of great practical significance for simple research tools.
Reference materials:
[1] Long-term functional maintenance of primary human hepatocytes in vitro
[2] Deng Hongkui research team and collaborators published a paper in Science to report a new method for long-term maintenance of functional mature cells in vitro.
　 [3] My scientist successfully established a model of hepatitis B virus infection

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