A chimeric humanized mouse model by engrafting the human induced pluripotent stem cell-derived hepatocyte-like cell for the chronic hepatitis B virus infection

Lunzhi Yuan, Xuan Liu, Liang Zhang, Xiaoling Li, Yali Zhang, Kun Wu, Yao Chen, Jiali Cao, Wangheng Hou, Jun Zhang, Hua Zhu, Quan Yuan, Qiyi Tang, Tong Cheng, Ningshao Xia

Research output: Contribution to journalArticle

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Abstract

Humanized mouse model generated by grafting primary human hepatocytes (PHHs) to immunodeficient mouse has contributed invaluably to understanding the pathogenesis of hepatitis B virus (HBV). However, the source of PHHs is limited, which necessitates the search for alternatives. Recently, hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs) have been used for in vitro HBV infection. Herein, we developed a robust human liver chimeric animal model to study in vivo HBV infection by engrafting the hiPSC-HLCs to Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice. After being optimized by a small molecule, XMU-MP-1, the hiPSC-HLCs engrafted FRGS (hHLC-FRGS) mice displayed approximately 40% liver chimerism at week 6 after engraftment and maintained at this level for at least 14 weeks. Viremia and HBV infection markers include antigens, RNA, DNA, and covalently closed circular DNA were detectable in HBV infected hHLC-FRGS mice. Furthermore, hiPSC-HLCs and hHLC-FRGS mice were successfully used to evaluate different antivirals. Therefore, we established a humanized mouse model for not only investigating HBV pathogenesis but also testing the effects of the anti-HBV drugs. Highlights: (1) The implanted hiPSC-HLCs established a long-term chimerism in FRGS mice liver. (2) hHLC-FRGS mice are adequate to support chronic HBV infection with a full viral life cycle. (3) hiPSC-HLCs and hHLC-FRGS mice are useful tools for evaluation of antivirals against HBV infection in vitro and in vivo. Research in Context To overcome the disadvantages of using primary human hepatocytes, we induced human pluripotent stem cells to hepatocyte-like cells (hiPSC-HLCs) that developed the capability to express important liver functional markers and critical host factors for HBV infection. The hiPSC-HLCs were permissive for the HBV infection and supported a full HBV replication. The hiPSC-HLCs were then engrafted to immunodeficient mouse to establish a chimeric liver mouse model, which was capable of supporting HBV infection in vivo and evaluating the effects of antiviral drugs. Our results shed light into improving the cellular and animal models for studying HBV and other hepatotropic viruses.

Original languageEnglish (US)
Article number908
JournalFrontiers in Microbiology
Volume9
Issue numberMAY
DOIs
StatePublished - May 8 2018

Fingerprint

Induced Pluripotent Stem Cells
Chronic Hepatitis B
Virus Diseases
Hepatitis B virus
Hepatocytes
Pluripotent Stem Cells
SCID Mice
Liver
Antiviral Agents
Chimerism
Animal Models
Circular DNA
Viremia
Differentiation Antigens
Virus Replication
Life Cycle Stages

All Science Journal Classification (ASJC) codes

  • Microbiology (medical)
  • Microbiology

Keywords

  • HHLC-FRGS
  • Hepatitis B virus
  • Hepatocyte-like cells
  • Infectious animal model
  • Liver humanized mouse
  • Stem cells

Cite this

Yuan, Lunzhi ; Liu, Xuan ; Zhang, Liang ; Li, Xiaoling ; Zhang, Yali ; Wu, Kun ; Chen, Yao ; Cao, Jiali ; Hou, Wangheng ; Zhang, Jun ; Zhu, Hua ; Yuan, Quan ; Tang, Qiyi ; Cheng, Tong ; Xia, Ningshao. / A chimeric humanized mouse model by engrafting the human induced pluripotent stem cell-derived hepatocyte-like cell for the chronic hepatitis B virus infection. In: Frontiers in Microbiology. 2018 ; Vol. 9, No. MAY.
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abstract = "Humanized mouse model generated by grafting primary human hepatocytes (PHHs) to immunodeficient mouse has contributed invaluably to understanding the pathogenesis of hepatitis B virus (HBV). However, the source of PHHs is limited, which necessitates the search for alternatives. Recently, hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs) have been used for in vitro HBV infection. Herein, we developed a robust human liver chimeric animal model to study in vivo HBV infection by engrafting the hiPSC-HLCs to Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice. After being optimized by a small molecule, XMU-MP-1, the hiPSC-HLCs engrafted FRGS (hHLC-FRGS) mice displayed approximately 40{\%} liver chimerism at week 6 after engraftment and maintained at this level for at least 14 weeks. Viremia and HBV infection markers include antigens, RNA, DNA, and covalently closed circular DNA were detectable in HBV infected hHLC-FRGS mice. Furthermore, hiPSC-HLCs and hHLC-FRGS mice were successfully used to evaluate different antivirals. Therefore, we established a humanized mouse model for not only investigating HBV pathogenesis but also testing the effects of the anti-HBV drugs. Highlights: (1) The implanted hiPSC-HLCs established a long-term chimerism in FRGS mice liver. (2) hHLC-FRGS mice are adequate to support chronic HBV infection with a full viral life cycle. (3) hiPSC-HLCs and hHLC-FRGS mice are useful tools for evaluation of antivirals against HBV infection in vitro and in vivo. Research in Context To overcome the disadvantages of using primary human hepatocytes, we induced human pluripotent stem cells to hepatocyte-like cells (hiPSC-HLCs) that developed the capability to express important liver functional markers and critical host factors for HBV infection. The hiPSC-HLCs were permissive for the HBV infection and supported a full HBV replication. The hiPSC-HLCs were then engrafted to immunodeficient mouse to establish a chimeric liver mouse model, which was capable of supporting HBV infection in vivo and evaluating the effects of antiviral drugs. Our results shed light into improving the cellular and animal models for studying HBV and other hepatotropic viruses.",
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author = "Lunzhi Yuan and Xuan Liu and Liang Zhang and Xiaoling Li and Yali Zhang and Kun Wu and Yao Chen and Jiali Cao and Wangheng Hou and Jun Zhang and Hua Zhu and Quan Yuan and Qiyi Tang and Tong Cheng and Ningshao Xia",
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Yuan, L, Liu, X, Zhang, L, Li, X, Zhang, Y, Wu, K, Chen, Y, Cao, J, Hou, W, Zhang, J, Zhu, H, Yuan, Q, Tang, Q, Cheng, T & Xia, N 2018, 'A chimeric humanized mouse model by engrafting the human induced pluripotent stem cell-derived hepatocyte-like cell for the chronic hepatitis B virus infection', Frontiers in Microbiology, vol. 9, no. MAY, 908. https://doi.org/10.3389/fmicb.2018.00908

A chimeric humanized mouse model by engrafting the human induced pluripotent stem cell-derived hepatocyte-like cell for the chronic hepatitis B virus infection. / Yuan, Lunzhi; Liu, Xuan; Zhang, Liang; Li, Xiaoling; Zhang, Yali; Wu, Kun; Chen, Yao; Cao, Jiali; Hou, Wangheng; Zhang, Jun; Zhu, Hua; Yuan, Quan; Tang, Qiyi; Cheng, Tong; Xia, Ningshao.

In: Frontiers in Microbiology, Vol. 9, No. MAY, 908, 08.05.2018.

Research output: Contribution to journalArticle

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T1 - A chimeric humanized mouse model by engrafting the human induced pluripotent stem cell-derived hepatocyte-like cell for the chronic hepatitis B virus infection

AU - Yuan, Lunzhi

AU - Liu, Xuan

AU - Zhang, Liang

AU - Li, Xiaoling

AU - Zhang, Yali

AU - Wu, Kun

AU - Chen, Yao

AU - Cao, Jiali

AU - Hou, Wangheng

AU - Zhang, Jun

AU - Zhu, Hua

AU - Yuan, Quan

AU - Tang, Qiyi

AU - Cheng, Tong

AU - Xia, Ningshao

PY - 2018/5/8

Y1 - 2018/5/8

N2 - Humanized mouse model generated by grafting primary human hepatocytes (PHHs) to immunodeficient mouse has contributed invaluably to understanding the pathogenesis of hepatitis B virus (HBV). However, the source of PHHs is limited, which necessitates the search for alternatives. Recently, hepatocyte-like cells (HLCs) generated from human induced pluripotent stem cells (hiPSCs) have been used for in vitro HBV infection. Herein, we developed a robust human liver chimeric animal model to study in vivo HBV infection by engrafting the hiPSC-HLCs to Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice. After being optimized by a small molecule, XMU-MP-1, the hiPSC-HLCs engrafted FRGS (hHLC-FRGS) mice displayed approximately 40% liver chimerism at week 6 after engraftment and maintained at this level for at least 14 weeks. Viremia and HBV infection markers include antigens, RNA, DNA, and covalently closed circular DNA were detectable in HBV infected hHLC-FRGS mice. Furthermore, hiPSC-HLCs and hHLC-FRGS mice were successfully used to evaluate different antivirals. Therefore, we established a humanized mouse model for not only investigating HBV pathogenesis but also testing the effects of the anti-HBV drugs. Highlights: (1) The implanted hiPSC-HLCs established a long-term chimerism in FRGS mice liver. (2) hHLC-FRGS mice are adequate to support chronic HBV infection with a full viral life cycle. (3) hiPSC-HLCs and hHLC-FRGS mice are useful tools for evaluation of antivirals against HBV infection in vitro and in vivo. Research in Context To overcome the disadvantages of using primary human hepatocytes, we induced human pluripotent stem cells to hepatocyte-like cells (hiPSC-HLCs) that developed the capability to express important liver functional markers and critical host factors for HBV infection. The hiPSC-HLCs were permissive for the HBV infection and supported a full HBV replication. The hiPSC-HLCs were then engrafted to immunodeficient mouse to establish a chimeric liver mouse model, which was capable of supporting HBV infection in vivo and evaluating the effects of antiviral drugs. Our results shed light into improving the cellular and animal models for studying HBV and other hepatotropic viruses.

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KW - HHLC-FRGS

KW - Hepatitis B virus

KW - Hepatocyte-like cells

KW - Infectious animal model

KW - Liver humanized mouse

KW - Stem cells

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