人類脂肪幹細胞為HCV在體內感染的標的細胞

C型肝炎病毒（HCV）為透過血液或體液的傳染造成肝臟嚴重病變，並同時引發體內其他器官併發症，造成全球每年約350,000人死亡。根據世界衛生組織(WHO)，目前全球大約有1.7億人口感染HCV，但臨床使用的干擾素治療只能達50-90%的療效，且副作用更嚴重影響患者們身理及心理上極大的壓力。而受限於C型肝炎病毒無法在體外有效複製以及人工細胞株(cell line)無法確實代表體內感染情形，進而無法全盤了解C型肝炎病毒作用機轉。因此，仍未有有效的C型肝炎疫苗或是專一性的抗病毒藥物。目前已有其他研究團隊利用人類胚胎幹細胞(hESC)分化成肝臟細胞及誘導多功能性幹細胞，做為C型肝炎病毒複製的平台。而我們發現到，C型肝炎病人在臨床上比B型肝炎病人有明顯的脂肪堆積和脂肪肝，也有研究顯示脂肪代謝在C型肝炎病毒複製中扮演重要的角色。因此我們假設，人類脂肪幹細胞可以做為複製C型肝炎病毒的平台。而根據本實驗室研究團隊先前的研究，已經成功的培養脂肪幹細胞複製C型肝炎病毒，我們進而求證在臨床上是否也具有一致性。因此，在本篇的論文中，主要探討在HCV病人脂肪組織內，其脂肪幹細胞是否同時帶有C型肝炎病毒病原，進一步確認脂肪幹細胞和病毒之間的作用。我們首先利用雙染免疫組織染色(double immunohistochemistry staining) 來分析脂肪幹細胞表現分子DLK1是否存在於C型肝炎病人脂肪組織中，再進一步觀察HCV感染表現分子NS5A是否與脂肪幹細胞表現分子DLK1重疊。而其結果顯示，在C型肝炎病人的脂肪組織中，除了表現脂肪幹細胞之外，其脂肪幹細胞更帶有C型肝炎病毒，證實了HCV並不會單一感染攻擊肝臟細胞，更能感染脂肪幹細胞循環至全身其他器官，造成更進一步其他器官的破壞。我們希望在未來能更加了解C型肝炎和脂肪幹細胞兩者之間的作用，包括脂肪在肝臟內外的角色；以期許在未來不僅僅能進一步預防C型肝炎惡化，並能夠更了解C型肝炎作用機轉。

關鍵字

C型肝炎

並列摘要

Hepatitis C Virus (HCV) infection is mainly infected via blood transmission, resulting in several liver related diseases, such as hepatic cirrhosis or hepatocellular carcinoma. It has also been suggested with other extrahepatic manifestations and complications, mostly autoimmune disorders contributing to the poor progression of HCV infection, contributing to 350,000 deaths per year. According to WHO, there are about 170 million world population chronically infected with HCV. However, the current treatments, pegylated interferon and ribavirin, can only reach 50-80% response in patients, not to mention to the severe side effects. Unfortunately, we are still not able to understand the mechanism of HCV infection and replication entirely due to the lack of a sufficient and efficient platform for HCV prorogation in vitro. Therefore, still no vaccine or specific antiviral drugs have been developed to treat HCV infection. Some researchers use hepatocyte-like cells derived from human embryonic stem cells (hESC) or induced pluripotent stem cells (iPSC) as a replication platform for HCV. However, we noted a clinical feature in HCV patient that the HCV infected liver is surrounded by excessive fat as compared with HBV patients. Moreover, some studies have indicated that lipid metabolism plays an important role in the HCV replication mechanism. Thus, we hypothesized that human adipose stem cells (hADSCs) can also be used as an in vitro platform to propagate HCV. In our previous results, HCV from human serum has successfully infected the hADSCs and then replicate in vitro. Therefore, the purpose of this study is to verify whether the hADSCs cells, are the potential target for HCV infection by using double immunohistochemistry (IHC) staining in fat tissues of HCV patients. The results of IHC have identified preadipocty positive cells in HCV fat tissues, and those positive cells were also notably co-localized with HCV replication marker (hepatitis C NS-5 antigen). In addition, we also further performed the hADSCs infected with HCV serum. In conclusion, we believe hADSCs doesn’t only exit in the HCV fat tissues but also carry HCV circulating in our bodies and contributing to severe extrahepatic diseases. In our future work, we would like to focus more on the interaction between hADSCs and HCV, in order to prevent the severe progression of HCV also to develop more sufficient treatment.

並列關鍵字

HCV ； human adipose stem cells ； liver

參考文獻

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