Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells.
Humanized mice efficiently engrafted with fetal hepatoblasts and syngeneic immune cells develop human monocytes and NK cells.
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DOI：
10.1016/j.jhep.2016.04.022
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发表时间：
2016-08
影响因子：
25.7
通讯作者：
de Jong YP
中科院分区：
文献类型：
--
作者：
Billerbeck E;Mommersteeg MC;Shlomai A;Xiao JW;Andrus L;Bhatta A;Vercauteren K;Michailidis E;Dorner M;Krishnan A;Charlton MR;Chiriboga L;Rice CM;de Jong YP
人肝嵌合小鼠是人肝炎病毒感染（包括B和C型肝炎病毒感染）的有用模型。独立地，用来自胎肝的CD 34+造血干细胞（HSC）重建的免疫缺陷小鼠可靠地发育人类T和B淋巴细胞。结合这些系统长期以来一直受到人类胎儿成肝细胞的肝脏重建效率低下的阻碍。我们的研究旨在增强肝母细胞的植入，以建立具有同基因人类肝脏和免疫细胞的小鼠模型。检测了人抑癌素-M给药对胎儿肝母细胞植入免疫缺陷fah−/−小鼠的影响。然后用同基因人成肝细胞和HSC移植小鼠，之后通过流式细胞术分析人白细胞嵌合体和功能性，并用HBV攻击小鼠。在免疫缺陷fah−/−小鼠中，添加人抑瘤素-M可使人肝母细胞植入增强5-100倍。与单独移植HSC的小鼠（主要发育人T和B淋巴细胞）相比，共移植同基因成肝细胞的小鼠也含有生理水平的人单核细胞和自然杀伤细胞。感染HBV后，这些小鼠表现出快速和持续的病毒血症。我们的研究提供了一种新的小鼠模型，具有改进的人胎儿肝母细胞植入和扩展的人免疫细胞库。随着进一步的改进，该模型可能成为有用的研究人类对病毒性肝炎的免疫。重要的人类病原体如B型肝炎病毒、C型肝炎病毒和人类免疫缺陷病毒仅感染人类细胞，这使得用于研究这些病原体的小鼠模型的开发复杂化。使小鼠对人类病原体具有宽容性的一种方法是将人类细胞移植到免疫受损的小鼠中。例如，人类肝细胞的移植将允许这些所谓的“肝嵌合体小鼠”感染B型肝炎病毒和C型肝炎病毒。将人免疫细胞共移植到肝脏嵌合小鼠中将进一步允许研究人对B型肝炎病毒或丙型肝炎病毒的免疫应答。然而，对于免疫学研究来说，移植的人类肝脏和免疫细胞来自同一个人类供体至关重要。在我们的研究中，我们描述了人胎肝细胞和来自同一供体的免疫细胞在小鼠体内的有效植入。我们发现，肝脏共移植导致了人类免疫细胞库的扩大，包括肝脏中的单核细胞和自然杀伤细胞。我们进一步证明，这些小鼠可以感染B型肝炎病毒，导致自然杀伤细胞的扩增。总之，我们已经开发了一种新的小鼠模型，可以用于研究人类对人类肝脏病原体的免疫反应。
Human liver chimeric mice are useful models of human hepatitis virus infection, including hepatitis B and C virus infections. Independently, immunodeficient mice reconstituted with CD34+ hematopoietic stem cells (HSC) derived from fetal liver reliably develop human T and B lymphocytes. Combining these systems has long been hampered by inefficient liver reconstitution of human fetal hepatoblasts. Our study aimed to enhance hepatoblast engraftment in order to create a mouse model with syngeneic human liver and immune cells. The effects of human oncostatin-M administration on fetal hepatoblast engraftment into immunodeficient fah−/− mice was tested. Mice were then transplanted with syngeneic human hepatoblasts and HSC after which human leukocyte chimerism and functionality were analyzed by flow cytometry, and mice were challenged with HBV. Addition of human oncostatin-M enhanced human hepatoblast engraftment in immunodeficient fah−/− mice by 5–100 fold. In contrast to mice singly engrafted with HSC, which predominantly developed human T and B lymphocytes, mice co-transplanted with syngeneic hepatoblasts also contained physiological levels of human monocytes and natural killer cells. Upon infection with HBV, these mice displayed rapid and sustained viremia. Our study provides a new mouse model with improved human fetal hepatoblast engraftment and an expanded human immune cell repertoire. With further improvements, this model may become useful for studying human immunity against viral hepatitis. Important human pathogens such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus only infect human cells which complicates the development of mouse models for the study of these pathogens. One way to make mice permissive for human pathogens is the transplantation of human cells into immune-compromised mice. For instance, the transplantation of human liver cells will allow the infection of these so-called “liver chimeric mice” with hepatitis B virus and hepatitis C virus. The co-transplantation of human immune cells into liver chimeric mice will further allow the study of human immune responses to hepatitis B virus or hepatitis C virus. However, for immunological studies it will be crucial that the transplanted human liver and immune cells are derived from the same human donor. In our study we describe the efficient engraftment of human fetal liver cells and immune cells derived from the same donor into mice. We show that liver co-engraftment resulted in an expanded human immune cell repertoire, including monocytes and natural killer cells in the liver. We further demonstrate that these mice could be infected with hepatitis B virus, which lead to an expansion of natural killer cells. In conclusion we have developed a new mouse model that could be useful to study human immune responses to human liver pathogens.