Fang Yan1,2, Yi Wang1, Wencheng Zhang1, Mingyang Chang1, Zhiying He3, Jinbo Xu2, Changzhen Shang4, Tao Chen4, Jiang Liu5, Xin Wang6, Xuetao Pei7,8, Yunfang Wang1. 1. Stem Cell and Tissue Engineering Lab, Beijing Institute of Transfusion Medicine, Beijing, China. 2. Transfusion Immunology Lab, Beijing Institute of Transfusion Medicine, Beijing, China. 3. Department of Cell Biology, Second Military Medical University, Shanghai, China. 4. Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China. 5. CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. 6. Key Laboratory of National Education, Ministry for Mammalian Reproductive Biology and Biotechnology, Inner Mongolia University, Huhhot, China. 7. Stem Cell and Regenerative Medicine Lab, Beijing Institute of Transfusion Medicine, Beijing, China. 8. South China Research Center for Stem Cell & Regenerative Medicine, AMMS, Guangzhou, China.
Abstract
Maturation of hepatic cells can be gradually acquired through multiple stages of hepatic lineage specification, while it is unclear whether hepatitis C virus (HCV) infection is maturationally lineage-dependent. We investigated the susceptibility to HCV at multiple stages of human embryonic stem cells, definitive endodermal cells, hepatic stem cells, hepatoblasts (hHBs), and mature hepatocytes. Susceptibility to infection occurred initially at the stage of human hepatic stem cells; however, hHBs proved to have the highest permissiveness and infectivity compared with all other stages. The hHBs' susceptibility to HCV correlated with the translocation of occludin, an HCV receptor, from cytoplasm to plasma membrane of HBs. Vascular endothelial cell growth factor enhanced the HCV susceptibility of hHBs through rearrangement of occludin by dephosphorylation; this minimized hHB polarization and prevented hHBs from further maturation. The transcription profiles of different hepatic lineage stages indicated that expression of innate immune response genes was correlated with hepatic maturation; interferon β played an important role in protecting hHBs from HCV infection. HCV-infected hHBs were able to engraft and integrate into the livers of Fah-/- Rag2-/- mice and maintained an hHB phenotype for over 12 weeks during the time when HCV antigen was evident. After suppression of interferon β in hHBs, HCV infection was significantly enhanced in the engrafted humanized liver tissue of host mice. CONCLUSION: Human embryonic stem cell-derived hHBs are the optimal hosts for HCV infectivity; the realization that HCV entry and replication occur primarily at a particular hepatic lineage stage enables us to understand the HCV infection factors, life cycle, and infection dynamics that are facets of the pathogenesis as well as suggesting targets for anti-HCV treatment. (Hepatology 2017;66:717-735).
Maturation of hepatic cells can be gradually acquired through multiple stages of hepatic lineage specification, while it is unclear whether hepatitis C virus (HCV) infection is maturationally lineage-dependent. We investigated the susceptibility to HCV at multiple stages of human embryonic stem cells, definitive endodermal cells, hepatic stem cells, hepatoblasts (hHBs), and mature hepatocytes. Susceptibility to infection occurred initially at the stage of human hepatic stem cells; however, hHBs proved to have the highest permissiveness and infectivity compared with all other stages. The hHBs' susceptibility to HCV correlated with the translocation of occludin, an HCV receptor, from cytoplasm to plasma membrane of HBs. Vascular endothelial cell growth factor enhanced the HCV susceptibility of hHBs through rearrangement of occludin by dephosphorylation; this minimized hHB polarization and prevented hHBs from further maturation. The transcription profiles of different hepatic lineage stages indicated that expression of innate immune response genes was correlated with hepatic maturation; interferon β played an important role in protecting hHBs from HCV infection. HCV-infected hHBs were able to engraft and integrate into the livers of Fah-/- Rag2-/- mice and maintained an hHB phenotype for over 12 weeks during the time when HCV antigen was evident. After suppression of interferon β in hHBs, HCV infection was significantly enhanced in the engrafted humanized liver tissue of host mice. CONCLUSION:Human embryonic stem cell-derived hHBs are the optimal hosts for HCV infectivity; the realization that HCV entry and replication occur primarily at a particular hepatic lineage stage enables us to understand the HCV infection factors, life cycle, and infection dynamics that are facets of the pathogenesis as well as suggesting targets for anti-HCV treatment. (Hepatology 2017;66:717-735).
Authors: Shuyong Wang; Xuan Wang; Zuolong Tan; Yuxin Su; Juan Liu; Mingyang Chang; Fang Yan; Jie Chen; Tao Chen; Chuanjiang Li; Jie Hu; Yunfang Wang Journal: Cell Res Date: 2019-10-18 Impact factor: 25.617
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