摘要
某些重大疾病的研究需要在体内探究免疫系统对病原体感染、转化以及破坏过的局部组织产生免疫应答的过程,而直接对疾病个体进行深入研究却存在一定风险,MHC分子限制性的嵌合体小鼠将是一个最实用的模型。目前认为造血干细胞能在免疫缺陷或是致死照射的小鼠体内发育分化成免疫系统,常见的受体鼠有NOD-scid Il2r γ-/-(NSG)小鼠及BALB/c背景的Rag2-/-Il2r γ-/-小鼠。同样,外源肝细胞或是胚胎干细胞也可以在某些特殊的受体小鼠体内扩增成为肝脏嵌合小鼠,比如尿激酶型血纤维蛋白溶酶原激活剂转基因小鼠模型(uPA模型)及延胡索酰乙酰乙酸脱氢酶缺陷小鼠模型(FAH模型)。然而,上述两种模型都不是研究免疫系统与病原体感染组织相互作用的最佳模型。
人体生物学的研究受限于伦理因素及技术难度,人源化小鼠的发展却为其提供了便利。免疫系统人源化(HIS)小鼠在研究人类免疫反应及嗜人免疫系统病原菌感染方面表现出极大的应用前景；而肝脏人源化小鼠也在人类嗜肝病原菌感染研究和抗肝炎病毒药物的临床评判方面发挥了重要的作用。但是,进一步研究某些特殊疾病(如HBV,HCV感染引发的肝炎以及疟疾的肝脏阶段)的病理发生,免疫关系,以及发病机制需要一种更好的小鼠模型,即免疫系统和病原体靶向组织同时实现人源化,并能通过MHC分子相互识别。最近,研究者们建立了AFC8-hu HSC/Hep小鼠模型,他们从15-18周的胎肝组织中分离得到肝脏祖细胞,并跟CD34+人造血干细胞一起转输给BALB/c背景的Rag2-/-Il2r γ-/-小鼠,从而成功建立了免疫系统和肝脏同时人源化的小鼠模型。尽管该模型能较好满足研究的需要,但是胎肝组织的获取难度限制了该模型的广泛应用。
近年来,也有报道称通过骨髓转输的方法,造血干细胞能在体内转化成肝细胞。在本论文中,我们用延胡索酰乙酰乙酸脱氢酶缺陷的小鼠进行骨髓重建,以探求造血干细胞能否在受体小鼠体内同时发育成免疫系统和肝脏细胞。该模型的成功建立将极大地促进疾病状态下免疫系统与肝细胞的相互作用的研究。
本研究中,我们首先通过体重监测,血清ALT检测,以及肝损伤的观测等手段观察了FAH缺陷鼠在NTBC停药后的生长情况；接着,我们将小鼠肝细胞或人源肝细胞系转入FAH缺陷鼠体内,观察外源肝细胞能否成功植入受体鼠肝脏并实现扩增；然后,我们尝试运用同基因,异基因,甚至异种骨髓移植的方法在FAH缺陷鼠体内实现免疫系统及肝脏的双重建。在转输骨髓后,给受体鼠停止NTBC用药,并观察其体重及血清ALT变化。为评判免疫系统的重建,我们每两周检测一次外周血。重建8周后,我们分离检测嵌合鼠的骨髓,胸腺,外周血,肝脏以及淋巴结中供体淋巴细胞分布情况,并用组织学染色的方法分析小鼠脾脏和淋巴结中的免疫重建状况。与此同时,我们给嵌合鼠免疫HBV疫苗或是OVA蛋白,然后用RIA或ELISA的方法检测小鼠血清中特异抗体的产生情况。为评价肝细胞的重建,我们分离停药后长期存活鼠的肝细胞并用流式分析表型。同时,我们也用H&E染色及免疫组化来分析肝组织切片。通过上述实验,我们取得了以下一些主要结果：
1.FAH小鼠在NTBC停药后自发肝损伤
首先,我们对比了FAH缺陷鼠在NTBC停药与不停药时的生长情况。我们发现,停药后缺陷鼠的体重逐渐下降,当体重损失达到30%时,小鼠就会死亡。血清ALT也在逐周增加提示肝损伤在逐渐加重。分离停药鼠的肝细胞体外培养,发现停药后肝细胞更易凋亡。肝脏组织病理学分析发现淋巴细胞浸润到肝脏局部,进一步研究发现,T,B淋巴细胞都可能参与了停药后小鼠肝损伤的过程。总之,上述结果表明,NTBC能够保护FAH缺陷鼠免于肝损伤,NTBC的撤除可作为启动FAH缺陷鼠肝细胞坏死的开关。
2.外源肝细胞向FAH移植后的体内扩增
接着,我们将新鲜分离的EGFP-Tg鼠的肝细胞转入FAH缺陷鼠体内,然后给小鼠停药。与不转输的停药对照组相比,转输组小鼠的体重及血清ALT水平能较快的恢复到正常水平,并且转输组小鼠的存活时间大大延长。同时,我们在转输鼠的肝脏内检测到EGFP阳性的供体肝细胞,它们能提供FAH来恢复受体鼠的肝脏功能。但是,当我们用人源肝细胞系L02细胞进行转输时,受体小鼠会发生肝脏肿瘤而死亡。我们在小鼠的肝脏中观察到许多肿瘤结节,可能是L02细胞系在体内扩增太快导致的。
3.同基因骨髓移植后FAH小鼠体内免疫系统及肝脏的双重建
接下来,我们将同基因型的骨髓细胞转入到FAH小鼠体内观察重建情况。我们选取了两种供体小鼠,分别是EGFP-Tg小鼠和HBs-Tg小鼠。我们在转输28天后给小鼠停药,结果发现,绝大部分骨髓转输小鼠在停药后能存活至少5个月以上。骨髓转输小鼠表现出稳定的造血重建能力,髓系及淋巴系的造血发育都和正常供体鼠一样。嵌合鼠外周血中NK,B,CD4T,CD8T细胞的数量也能逐渐发育正常,8周后受体鼠各脏器中免疫细胞就能重建完全,脾脏及淋巴结的组织学染色也进一步证明免疫重建的成功。为检测重建免疫系统的功能,我们用HBV疫苗免疫小鼠2次,结果发现,所有嵌合鼠都能产生跟供体鼠相类似的HBV特异性的抗体。我们用停药后长期存活的嵌合小鼠来评判肝细胞重建状况。肝组织染色结果发现供体来源的肝细胞成簇存在,进一步用流式分析肝细胞的表型发现髓样单个核细胞(CD45+F4/80+Gr-1+CD11b+CD11c-)可能是体内骨髓来源肝细胞的前体。综上结果可知,同基因型小鼠来源的造血干细胞是能够在FAH缺陷鼠体内同时重建免疫系统及肝脏系统的。
4.异基因骨髓移植后FAH小鼠体内免疫系统及肝脏的双重建
确定同基因型的骨髓能在FAH缺陷鼠体内成功实现免疫系统及肝细胞的双重建之后,我们又进行了异基因型的骨髓移植。我们同样选取了两种供体小鼠,分别是C3H/HeJ小鼠(H-2k)and HBV-Tg小鼠(H-2d)。大约60%的异基因骨髓移植小鼠能在停药后存活5个月以上。通过检测嵌合鼠外周血单个核细胞的比例,我们发现NK,B,CD4T,CD8T淋巴细胞能逐渐发育正常,脾脏及淋巴结的组织学染色也进一步证明免疫系统重建成功。跟供体鼠相似,嵌合鼠在OVA蛋白免疫后能产生OVA特异性的抗体。同时,从嵌合鼠中分离出的肝细胞部分表达供体鼠MHC-I类分子,并且这种肝细胞也表达受体鼠的MHC-I分子及CD45抗原,提示骨髓来源的肝细胞可能与受体原有的肝细胞发生了细胞融合。
5.异种骨髓移植后FAH小鼠体内免疫系统及肝脏的双重建
接下来,我们想探明异种骨髓细胞能否在FAH缺陷鼠体内实现免疫系统及肝脏的双重建。我们将S.D.大鼠(RT1A,Fah+/+)的骨髓细胞转入FAH缺陷鼠体内,结果发现约有50%的嵌合鼠停药后能存活5个月以上,血清转氨酶也维持在正常水平。嵌合小鼠表现出稳定的造血重建能力,髓系及淋巴系的造血发育也很正常,外周血中供体来源的单个核细胞(RT1A+)比例接近100%。嵌合鼠外周血中NK,B,CD4T,CD8T淋巴细胞逐渐发育正常,8周后受体鼠各脏器中T细胞比例接近于供体大鼠。与此同时,从嵌合鼠中分离出的肝细胞部分表达大鼠RT1A分子,肝脏组织学分析也显示FAH阳性肝细胞成团分布。总之,异种来源的造血干细胞同样能在FAH缺陷鼠体内完成双重建。
6.人源造血干细胞转输后FAH-rag2双缺陷小鼠体内免疫系统及肝脏的双重建
基于之前同基因,异基因,异种骨髓转输所取得的结果,我们将纯化的人脐血干细胞转入FAH-rag2双缺陷小鼠体内。结果发现,停药后转输鼠体重先是由于亚致死照射下降10%左右,然后迅速恢复正常并稳步上升。血清ALT也一直维持在较低水平,暗示着人源造血干细胞的移植部分恢复了嵌合鼠体内的肝脏功能。同时我们注意到,与非转输对照鼠相比,大多数嵌合鼠的存活时间更长。另外,嵌合鼠的肝脏功能恢复与人造血干细胞的植入程度有关,比较不同的受体小鼠,我们发现FRG受体鼠在接受转输后存活时间长于FAH单缺陷鼠。我们也确实在FRG受体鼠体内检测到更多的人源细胞。肝脏H&E染色能检测到人源肝细胞,它的细胞更大,嗜酸性染色较浅。由于B6背景的小鼠HSC植入较少,我们在肝组织中只检测到少量FAH阳性的人源肝细胞。总之,人源HSC转输后,受体鼠肝脏内确实有部分肝细胞被人源肝细胞取代,它们产生FAH来减轻肝损伤。
小结：本研究主要发现来自一个个体的造血干细胞能在免疫缺陷或是照射过的FAH缺陷鼠体内成功发育分化成免疫细胞和肝细胞。我们第一次比较系统地逐步通过同基因,异基因,异种骨髓移植,证明了单种造血干细胞可以在小鼠体内实现免疫系统及肝细胞的双重建。同时,我们也发现给FAH-rag2双缺陷小鼠转输人源造血干细胞能部分恢复受体小鼠的肝脏功能。上述结果提示,将来运用更加适合人源化构建的免疫缺陷型FAH小鼠,如Fah-/-NSG小鼠,有可能构建出一种更理想的人源化小鼠,这种小鼠具备免疫系统及肝细胞的双重人源化,并具备HLA分子识别的一致性。尽管我们的模型还有许多有待改进的地方,但我们相信这种双重建小鼠模型将给临床前检测及免疫系统与病变器官的相互作用研究提供更好的机会!
A MHC-restricted chimeras mouse will be a most practical tool for studying donor's immune response against donor's non-immune cells from organ with pathogen infection, transformation and damage in recipient mice, without putting individuals at risk. It was extensively accepted hematopoietic stem cells (HSC) may engraft and develop into immune system in lethal irradiated or immunodeficient mice, such as NOD-scid112r γ-/-(NSG) recipients or BALB/c-Rag2-/-Il2r γ-/-recipients. Liver chimeric mice were also reproted to be developed by exogenous hepatocytes or embryonic stem cells transplantation, like the uroplasminogen-activator (uPA) transgenic model or fumarylacetoacetate hydrolase (FAH) deficient model. However, neither of the chimeric mice are suitable for further investigation of the interaction between the immune system and pathogen infected organs.
Development of humanized mice provides insights into in vivo human biology that would be severely limited by ethical and/or technical constraints. Human immune system (HIS) mice are already established, showing a potential as the available model for the study of human immune response and human lymphotropic pathogens in mice, and human liver chimeric mice were developed for study of human hepatotropic pathogens or preclinical evaluation of anti-hepatitis virus drug candidates. However, further investigation of the pathology, immune correlates, and mechanisms of highly specialized pathogens like HBV, HCV and malaria (at liver stage) needs an excellent mouse model engrafted with MHC-restricted human immune system and pathogen-targeting organs. Recently, AFC8-hu HSC/Hep mice model was developed by meeting this requirement through co-implantation of human CD34+HSCs and hepatocyte progenitor cells from a15-18weeks old fetal liver tissue into BALB/c-Rag2-/-Il2r γ-/-mice. Although this approach successfully provides immune system and liver cells together in recipients, its extensive utilization is limited by obtaining human fetal liver tissues.
It was recently reported that HSC may also differentiate into hepatocytes in bone marrow transplanted (BMT) mice. Here, using a strain of mice deficient in tyrosine catabolic enzyme fumarylacetoacetate hydrolase (fah-/-), we tried to see whether donor's HSC may concurrently differentiate into immune cells and hepatocytes in recipient, which will greatly benefit exploiting the donor's MHC-restricted interaction between immune cells and hepatocytes.
In this study, we firstly assessed the bodyweight, serum ALT and liver failure in fah-/-mice after NTBC withdrawal. Then, we transplanted mouse or human hepatocytes into fah-/-mice or FRG mice to see whether exogenous hepatocytes could repopulate in the recipient liver. After that, we tried to established chimeric mice model with a dual immunologic and hepatic reconstitution by syngeneic, allogeneic or even xenogeneic bone marrow transplantation. Bodyweight and serum ALT was measured in BMT animals after NTBC withdrawal. To confirm immunologic reconstitution in recipients, PBMC subset were monitored every two weeks in BMT mice, and the mononuclear cells from bone marrow, thymus, spleen, blood, liver and lymph node were detected using flow cytometry after8weeks rebuild time. The histopathology of spleen and lymph node was aslo assessed by H&E staining and immunohistochemistry (IHC). Further more, BMT mice were immunized by HBV vaccine or OVA protain, and antigen-specific antibody was examined by RIA or ELISA. To evaluate the hepatic reconstitution, hepatocytes from long-term survivors were isolated and analyzed using flow cytometry. Liver histology of sections of BMT mice was aslo detected by H&E staining and IHC. The major results of our studies are shown as follows:
1. Fah-/-mice suffer from progressive liver failure after NTBC withdrawal.
Firstly, we compared the life status of fah-/-mice with or without NTBC. We found that the body weight of fah-/-mice reduced gradually and finally died when the loss of bodyweight exceed30%when NTBC was off. Serun ALT increased week by week indicated progressive liver failure in these mice. Hepatocytes from fah-/-mice without NTBC feeding were more prone to apoptosis. Liver histology of these mice also showed lymphocytes inflitration, and further analysis shown that T, B lymphocytes may play a important role in the progressive liver failure. Together, these results implied that NTBC protect fah-/-mice from death of liver injury, and NTBC cut off could be a switch to initiate hepatocytes necrosis in fah-/-mice.
2. Liver repopulation with exogenous hepatocytes in fah-/-mice.
Next, we transplanted fresh isolated hepatocytes (EGFP-positive) into fah-/- mice, then we stopped NTBC feeding. In contrast to congtrol fah-/-mice, the body weight and serum ALT from recipient mice with hepatocytes transplantation could soon recovered to normal. Transplanted mice survived far more longer than control mice after NTBC withdrawal. We also detected EGFP-positive hepatocytes in these mice, and such hepatocytes could provide FAH to to restore liver function in recipient. However, when we changed the donor cells to human hepatocytes cell line (LO2), the recipient mice died of hepatoma. The uncontrolled expansion of LO2cells in the liver maybe cause the death, because we found many tumor nodules in the liver from LO2transplanted mice.
3. A dual immunologic and hepatic reconstitution in recipient fah-/-mice after syn-BMT
Further, we transplanted syngeneic bone marrow cells into fah-/-/129SvvJ (haplotype H-2b) recipients. We choose two different mice as donor, EGFP-Tg mice and HBs-Tg mice. Most BMT mice survived at least5months after NTBC withdrawal beginning at day28. Surviving recipients also show stable mutilineage hematopoietic reconstitution after syn-BMT. And there was little difference in myeloid and lymphoid development between chimeras and donor mice. NK, B, CD4and CD8T cells could reconstitute normally in chimeras' peripheral blood, and there was a similar ratio of T cells in all immune organs of recipient mice to that of donor mice. Spleen and inguinal lymph node histology of serial sections further confirmed successful immunologic reconstitution in BMT mice. To directly test the immune response after reconstitution, mice were immunized2times with HBV vaccine. All recipient mice produced specific anti-HBsAg antibodies in serum, similar to the donor mice. To evaluate the hepatic reconstitution, long-term survivors were sacrificed and analyzed. Liver histology showed that donor-derived hepatocytes (FAH-positive) were organized in a cell cluster. Further study demonstrated that myelomonocytic cells (CD45+F4/80+Gr-1+CD11b+CD11c-) were the progenitors for the bone marrow-derived hepatocytes. Together, these data imply that HSC from a syngeneic mouse may concurrently reconstitute immunologic and hepatic system in recipient fah-/-mice.
4. A dual immunologic and hepatic reconstitution in recipient fah-/-mice after allo-BMT.
After successful liver and immune reconstitution after syn-BMT in fah-/-mice, we carried out allo-BMT. We also choose two allogeneic mice as donor, C3H/HeJ mice (haplotype H-2k) and HBV-Tg mice (haplotype H-2d). About60%of BMT mice survived at least5months after NTBC withdrawal. We monitored PBMC subset from BMT mice, and found contents of NK, B, CD4and CD8T cells became normal in chimeras. Meanwhile, spleen and inguinal lymph node histology of serial sections further confirmed successful immunologic reconstitution in BMT mice. BMT mice produced specific anti-OVA antibodies in serum, similar to donor mice after immunization with OVA protein. Meanwhile, hepatocytes from BMT mice partially expressed donor MHC class Ⅰ antigen, and such hepatocytes were partially positive for recipient MHC class Ⅰ antigen and CD45antigen, implying cellular fusion between donor BMC and resident hepatocytes.
5. A dual immunologic and hepatic reconstitution in recipient fah-/-mice after xeno-BMT.
We next attempted to define whether xenogeneic HSC could successfully reconstitute immunologic and hepatic system in fah-/-mice. We transplanted S.D. rat (RT1A,fah+/+) bone marrow into fah-/-/129SvJ (haplotype H-2b) recipients. About50%of BMT mice survived at least5months after NTBC withdrawal, and serum ALT almost kept in a normal level. Surviving recipients also show stable mutilineage hematopoietic reconstitution after Xeno-BMT. Nearly100%of the PBMCs from the chimeras were RT1A+similar to donor cells, and there was little difference in contents of myeloid and lymphoid cells between chimeras and recipient mice. NK, CD4and CD8T cells could reconstitute normally in chimeras'peripheral blood, and there was a similar ratio of T cells in all immune organs of recipient mice to that of donor rat. Meanwhile, hepatocytes from Rat-BMT mice were partially positive for donor MHC class I antigen (RT1A+), implying the generation of bone marrow derived hepotocytes. Liver histology also showed that FAH-positive cells were organized in a cell cluster. Altogether, HSC from xenogeneic donor could indeed reconstitute immunologic and hepatic system in fah-/-mice.
6. Immunologic and hepatic reconstitution in recipient fah-/-rag2-/-mice after human HSC transplantation.
Based on the inspiring results from syn/allo/xeno-BMT, we then transplanted purified human hematopoietic stem cells (CD34+cord blood cells) into immunodeficient fah-/-/129SvJ.B6recipients (fah-/-rag2-/-). After NTBC withdrawal, the body weight of most chimeras was about10%loss at the beginning because of sub lethal irradiation, but soon they recovered and kept getting on body weight gradually. Serum ALT from these mice also kept in a normal level, implying that human HSC transplantation partially restored liver function in chimeras. Meanwhile, most chimeras survived longer than no cell transferred mice. Additionally, the liver function restoration was relative to the engraftment of human HSC. We compared different recipient mice, and found that chimeras in fah-/-rag2-/-112r γ-/-mice survived better than that in fah-/-mice, and we indeed detected the most human cells in these mice. H&E staining of the liver section clearly distinguished human hepatocyte clusters, which were larger and less eosinophilic and hence appear paler than mouse cells. Since the poor engraftment of human HSC in B6recipients (fah-/-rag2-/-), we could only detected few FAH-positive hepatocytes in liver tissue. Thus, after HSC transplantation, recipient mice could be partially repopulated with human origin hepatocytes, which provided FAH to alleviate live injury.
Conclusion:The major finding of the current study was that HSCs from one individual were successfully differentiated into both immune cells and hepatocytes by using an irradiated or imunodeficient fah-/-mouse. We, for the first time, developed a mouse model with immune and liver reconstitution from one donor's HSCs, which was carried out by systematically performing syngeneic, allogeneic or even xenogeneic BMT. We further showed that the purified human hematopoietic stem cells transplantation could partially restore liver function in fah-rag2double knockout mice. These finding indicated that a better humanized mouse model, with a HLA-identity between human immune cells and human hepatocytes, would be developed by using a more imunodeficient fah-/-mouse, such as fah-/-NSG in future. Although further improvements of our model need to be done, we expect that such model provide a new opportunity to perform pre-clinical testing and to investigate many human biological processes which are happened between donor immune cells and organs with MHC-identity.
引文
Arsov, T., Silva, D.G., O'Bryan, M.K., Sainsbury, A., Lee, N.J., Kennedy, C., Manji, S.S., Nelms, K., Liu, C., Vinuesa, C.G., et al. (2006). Fat aussie--a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis. Mol Endocrinol 20,1610-1622.
Azuma, H., Paulk, N., Ranade, A., Dorrell, C., Al-Dhalimy, M., Ellis, E., Strom, S., Kay, M.A., Finegold, M., and Grompe, M. (2007). Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/I12rg-/- mice. Nat Biotechnol 25,903-910.
Baenziger, S., Tussiwand, R., Schlaepfer, E., Mazzucchelli, L., Heikenwalder, M., Kurrer, M.O., Behnke, S., Frey, J., Oxenius, A., Joller, H., et al. (2006). Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2-/-gamma c-/- mice. Proceedings of the National Academy of Sciences of the United States of America 103,15951-15956.
Barker, L.F., Chisari, F.V., McGrath, P.P., Dalgard, D.W., Kirschstein, R.L., Almeida, J.D., Edington, T.S., Sharp, D.G., and Peterson, M.R. (1973). Transmission of type B viral hepatitis to chimpanzees. The Journal of infectious diseases 127,648-662.
Baron, J.L., Gardiner, L., Nishimura, S., Shinkai, K., Locksley, R., and Ganem, D. (2002). Activation of a nonclassical NKT cell subset in a transgenic mouse model of hepatitis B virus infection. Immunity 16,583-594.
Barth, H., Robinet, E., Liang, T.J., and Baumert, T.F. (2008). Mouse models for the study of HCV infection and virus-host interactions. Journal of hepatology 49,134-142.
Bataller, R., and Brenner, D.A. (2005). Liver fibrosis. The Journal of clinical investigation 115, 209-218.
Bente, D.A., Melkus, M.W., Garcia, J.V., and Rico-Hesse, R. (2005). Dengue fever in humanized NOD/SCID mice. Journal of virology 79,13797-13799.
Berges, B.K., Wheat, W.H., Palmer, B.E., Connick, E., and Akkina, R. (2006). HIV-1 infection and CD4 T cell depletion in the humanized Rag2-/-gamma c-/- (RAG-hu) mouse model. Retrovirology 3,76.
Bosma, G.C., Custer, R.P., and Bosma, M.J. (1983). A severe combined immunodeficiency mutation in the mouse. Nature 301,527-530.
Cai, J., Zhao, Y., Liu, Y., Ye, F., Song, Z., Qin, H., Meng, S., Chen, Y, Zhou, R., Song, X., et al. (2007). Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45,1229-1239.
Camargo, F.D., Finegold, M., and Goodell, M.A. (2004). Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. The Journal of clinical investigation 113, 1266-1270.
Cao, X., Shores, E.W., Hu-Li, J., Anver, M.R., Kelsall, B.L., Russell, S.M., Drago, J., Noguchi, M., Grinberg, A., Bloom, E.T., et al. (1995). Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2,223-238.
Chen, Q., Khoury, M., and Chen, J. (2009). Expression of human cytokines dramatically improves reconstitution of specific human-blood lineage cells in humanized mice. Proceedings of the National Academy of Sciences of the United States of America 106, 21783-21788.
Chen, Y., Wei, H., Sun, R., Dong, Z., Zhang, J., and Tian, Z. (2007). Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells. Hepatology 46,706-715.
Chisari, F.V., Pinkert, C.A., Milich, D.R., Filippi, P., McLachlan, A., Palmiter, R.D., and Brinster, R.L. (1985). A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science 230,1157-1160.
Constandinou, C., Henderson, N., and Iredale, J.P. (2005). Modeling liver fibrosis in rodents. Methods in molecular medicine 117,237-250.
Cullen, J.M., Sandgren, E.P., Brinster, R.L., and Maronpot, R.R. (1993). Histologic characterization of hepatic carcinogenesis in transgenic mice expressing SV40 T-antigens. Veterinary pathology 30,111-118.
de Lima, V.M., Oliveira, C.P., Alves, V.A., Chammas, M.C., Oliveira, E.P., Stefano, J.T., de Mello, E.S., Cerri, G.G., Carrilho, F.J., and Caldwell, S.H. (2008). A rodent model of NASH with cirrhosis, oval cell proliferation and hepatocellular carcinoma. Journal of hepatology 49,1055-1061.
Deng, Q.G., She, H., Cheng, J.H., French, S.W., Koop, D.R., Xiong, S., and Tsukamoto, H. (2005). Steatohepatitis induced by intragastric overfeeding in mice. Hepatology 42, 905-914.
DiSanto, J.P., Muller, W., Guy-Grand, D., Fischer, A., and Rajewsky, K. (1995). Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proceedings of the National Academy of Sciences of the United States of America 92, 377-381.
Domenicali, M., Caraceni, P., Giannone, F, Baldassarre, M., Lucchetti, G., Quarta, C., Patti, C., Catani, L., Nanni, C., Lemoli, R.M., et al. (2009). A novel model of CC14-induced cirrhosis with ascites in the mouse. Journal of hepatology 51,991-999.
Dong, Z., Wei, H., Sun, R., Hu, Z., Gao, B., and Tian, Z. (2004). Involvement of natural killer cells in PolyI:C-induced liver injury. Journal of hepatology 41,966-973.
Droetto, S., Viale, A., Primo, L., Jordaney, N., Bruno, S., Pagano, M., Piacibello, W., Bussolino, F., and Aglietta, M. (2004). Vasculogenic potential of long term repopulating cord blood progenitors. The FASEB journal:official publication of the Federation of American Societies for Experimental Biology 18,1273-1275.
El-Serag, H.B., and Rudolph, K.L. (2007). Hepatocellular carcinoma:epidemiology and molecular carcinogenesis. Gastroenterology 132,2557-2576.
Espejel, S., Roll, G.R., McLaughlin, K.J., Lee, A.Y., Zhang, J.Y., Laird, D.J., Okita, K., Yamanaka, S., and Willenbring, H. (2010). Induced pluripotent stem cell-derived hepatocytes have the functional and proliferative capabilities needed for liver regeneration in mice. The Journal of clinical investigation 120,3120-3126.
Farazi, P.A., and DePinho, R.A. (2006). Hepatocellular carcinoma pathogenesis:from genes to environment. Nature reviews Cancer 6,674-687.
Farber, E., Solt, D., Cameron, R., Laishes, B., Ogawa, K., and Medline, A. (1977). Newer insights into the pathogenesis of liver cancer. The American journal of pathology 89, 477-482.
Friedman, S.L. (2008). Mechanisms of hepatic fibrogenesis. Gastroenterology 134,1655-1669.
Gao, B., Jeong, W.I., and Tian, Z. (2008). Liver:An organ with predominant innate immunity. Hepatology 47,729-736.
Georgiev, P., Jochum, W., Heinrich, S., Jang, J.H., Nocito, A., Dahm, F., and Clavien, P.A. (2008). Characterization of time-related changes after experimental bile duct ligation. The British journal of surgery 95,646-656.
Gershwin, M.E., Mackay, I.R., Sturgess, A., and Coppel, R.L. (1987). Identification and specificity of a cDNA encoding the 70 kd mitochondrial antigen recognized in primary biliary cirrhosis. J Immunol 138,3525-3531.
Grompe, M., al-Dhalimy, M., Finegold, M., Ou, C.N., Burlingame, T., Kennaway, N.G., and Soriano, P. (1993). Loss of fumarylacetoacetate hydrolase is responsible for the neonatal hepatic dysfunction phenotype of lethal albino mice. Genes & development 7,2298-2307.
Grompe, M., Lindstedt, S., al-Dhalimy, M., Kennaway, N.G., Papaconstantinou, J., Torres-Ramos, C.A., Ou, C.N., and Finegold, M. (1995). Pharmacological correction of neonatal lethal hepatic dysfunction in a murine model of hereditary tyrosinaemia type I. Nature genetics 10, 453-460.
Guidotti, L.G., Matzke, B., Schaller, H., and Chisari, F.V. (1995). High-level hepatitis B virus replication in transgenic mice. Journal of virology 69,6158-6169.
Guirado, E., Amat, I., Gil, O., Diaz, J., Arcos, V., Caceres, N., Ausina, V., and Cardona, P.J. (2006). Passive serum therapy with polyclonal antibodies against Mycobacterium tuberculosis protects against post-chemotherapy relapse of tuberculosis infection in SCID mice. Microbes and infection/Institut Pasteur 8,1252-1259.
Gunawan, B.K., Liu, Z.X., Han, D., Hanawa, N., Gaarde, W.A., and Kaplowitz, N. (2006). c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity. Gastroenterology 131,165-178.
Harada, N., Miyoshi, H., Murai, N., Oshima, H., Tamai, Y., Oshima, M., and Taketo, M.M. (2002). Lack of tumorigenesis in the mouse liver after adenovirus-mediated expression of a dominant stable mutant of beta-catenin. Cancer research 62,1971-1977.
Heindryckx, F., Colle, I., and Van Vlierberghe, H. (2009). Experimental mouse models for hepatocellular carcinoma research. International journal of experimental pathology 90, 367-386.
Hou, X., Zhou, R., Wei, H., Sun, R., and Tian, Z. (2009). NKG2D-retinoic acid early inducible-1 recognition between natural killer cells and Kupffer cells in a novel murine natural killer cell-dependent fulminant hepatitis. Hepatology 49,940-949.
Hu, Z., Van Rooijen, N., and Yang, Y.G. (2011). Macrophages prevent human red blood cell reconstitution in immunodeficient mice. Blood 118,5938-5946.
Huang, L.R., Wu, H.L., Chen, P.J., and Chen, D.S. (2006). An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America 103,17862-17867.
Huang, P., He, Z., Ji, S., Sun, H., Xiang, D., Liu, C., Hu, Y, Wang, X., and Hui, L. (2011). Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475,386-389.
Irie, J., Wu, Y., Wicker, L.S., Rainbow, D., Nalesnik, M.A., Hirsch, R., Peterson, L.B., Leung, P.S., Cheng, C., Mackay, I.R., et al. (2006). NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis. The Journal of experimental medicine 203,1209-1219.
Ishikawa, F., Shimazu, H., Shultz, L.D., Fukata, M., Nakamura, R., Lyons, B., Shimoda, K., Shimoda, S., Kanemaru, T., Nakamura, K., et al. (2006). Purified human hematopoietic stem cells contribute to the generation of cardiomyocytes through cell fusion. The FASEB journal:official publication of the Federation of American Societies for Experimental Biology 20,950-952.
Ishikawa, F., Yasukawa, M., Lyons, B., Yoshida, S., Miyamoto, T., Yoshimoto, G, Watanabe, T., Akashi, K., Shultz, L.D., and Harada, M. (2005). Development of functional human blood and immune systems in NOD/SCID/IL2 receptor{gamma} chain(null) mice. Blood 106, 1565-1573.
Ishikawa, F., Yasukawa, M., Yoshida, S., Nakamura, K., Nagatoshi, Y., Kanemaru, T., Shimoda, K., Shimoda, S., Miyamoto, T., Okamura, J., et al. (2004). Human cord blood- and bone marrow-derived CD34+ cells regenerate gastrointestinal epithelial cells. The FASEB journal:official publication of the Federation of American Societies for Experimental Biology 18,1958-1960.
Islas-Ohlmayer, M., Padgett-Thomas, A., Domiati-Saad, R., Melkus, M.W., Cravens, P.D., Martin Mdel, P., Netto, G, and Garcia, J.V. (2004). Experimental infection of NOD/SCID mice reconstituted with human CD34+ cells with Epstein-Barr virus. Journal of virology 78, 13891-13900.
Ito, M., Hiramatsu, H., Kobayashi, K., Suzue, K., Kawahata, M., Hioki, K., Ueyama, Y., Koyanagi, Y, Sugamura, K., Tsuji, K., et al. (2002). NOD/SCID/gamma(c)(null) mouse:an excellent recipient mouse model for engraftment of human cells. Blood 100,3175-3182.
Jacobs, H., Krimpenfort, P., Haks, M., Allen, J., Blom, B., Demolliere, C., Kruisbeek, A., Spits, H., and Berns, A. (1999). PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chain-mutant mice and permits thymocyte maturation in Rag- but not CD3gamma-deficient mice. The Journal of experimental medicine 190,1059-1068.
Jiang, W., Sun, R., Wei, H., and Tian, Z. (2005). Toll-like receptor 3 ligand attenuates LPS-induced liver injury by down-regulation of toll-like receptor 4 expression on macrophages. Proceedings of the National Academy of Sciences of the United States of America 102,17077-17082.
Katoh, M., Sawada, T., Soeno, Y, Nakajima, M., Tateno, C., Yoshizato, K., and Yokoi, T. (2007). In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. Journal of pharmaceutical sciences 96,428-437.
Koarada, S., Wu, Y., Fertig, N., Sass, D.A., Nalesnik, M., Todd, J A., Lyons, P.A., Fenyk-Melody, J., Rainbow, D.B., Wicker, L.S., et al. (2004). Genetic control of autoimmunity:protection from diabetes, but spontaneous autoimmune biliary disease in a nonobese diabetic congenic strain. J Immunol 173,2315-2323.
Kodama, Y., Kisseleva, T., Iwaisako, K., Miura, K., Taura, K., De Minicis, S., Osterreicher, C.H., Schnabl, B., Seki, E., and Brenner, D.A. (2009). c-Jun N-terminal kinase-1 from hematopoietic cells mediates progression from hepatic steatosis to steatohepatitis and fibrosis in mice. Gastroenterology 137,1467-1477 e1465.
Kremsdorf, D., and Brezillon, N. (2007). New animal models for hepatitis C viral infection and pathogenesis studies. World journal of gastroenterology:WJG 13,2427-2435.
Kuhla, A., Eipel, C., Siebert, N., Abshagen, K., Menger, M.D., and Vollmar, B. (2008). Hepatocellular apoptosis is mediated by TNFalpha-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure. Apoptosis:an international journal on programmed cell death 13,1427-1438.
Lagasse, E., Connors, H., Al-Dhalimy, M., Reitsma, M., Dohse, M., Osborne, L., Wang, X., Finegold, M., Weissman, I.L., and Grompe, M. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nature medicine 6,1229-1234.
Lapidot, T., Pflumio, F., Doedens, M., Murdoch, B., Williams, D.E., and Dick, J.E. (1992). Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255,1137-1141.
Leclercq, I.A., Farrell, G.C., Field, J., Bell, D.R., Gonzalez, F.J., and Robertson, G.R. (2000). CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. The Journal of clinical investigation 105,1067-1075.
Lee, J.S., Chu, I.S., Mikaelyan, A., Calvisi, D.F., Heo, J., Reddy, J.K., and Thorgeirsson, S.S. (2004). Application of comparative functional genomics to identify best-fit mouse models to study human cancer. Nature genetics 36,1306-1311.
Legrand, N., Huntington, N.D., Nagasawa, M., Bakker, A.Q., Schotte, R., Strick-Marchand, H., de Geus, S.J., Pouw, S.M., Bohne, M., Voordouw, A., et al. (2011). Functional CD47/signal regulatory protein alpha (SIRP(alpha)) interaction is required for optimal human T- and natural killer- (NK) cell homeostasis in vivo. Proceedings of the National Academy of Sciences of the United States of America 108,13224-13229.
Legrand, N., Ploss, A., Balling, R., Becker, P.D., Borsotti, C., Brezillon, N., Debarry, J., de Jong, Y., Deng, H., Di Santo, J.P., et al. (2009). Humanized mice for modeling human infectious disease:challenges, progress, and outlook. Cell host & microbe 6,5-9.
Levrero, M. (2006). Viral hepatitis and liver cancer:the case of hepatitis C. Oncogene 25, 3834-3847.
Lieber, C.S., Jones, D.P., and Decarli, L.M. (1965). Effects of Prolonged Ethanol Intake: Production of Fatty Liver Despite Adequate Diets. The Journal of clinical investigation 44, 1009-1021.
Lootens, L., Meuleman, P., Pozo, O.J., Van Eenoo, P., Leroux-Roels, G., and Delbeke, F.T. (2009). uPA+/+-SCID mouse with humanized liver as a model for in vivo metabolism of exogenous steroids:methandienone as a case study. Clinical chemistry 55,1783-1793.
Ma, N., Ladilov, Y., Kaminski, A., Piechaczek, C., Choi, Y.H., Li, W., Steinhoff, G, and Stamm, C. (2006). Umbilical cord blood cell transplantation for myocardial regeneration. Transplantation proceedings 38,771-773.
Magness, S.T., Bataller, R., Yang, L., and Brenner, D.A. (2004). A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 40, 1151-1159.
Makino, H., Togo, S., Kubota, T., Morioka, D., Morita, T., Kobayashi, T., Tanaka, K., Shimizu, T., Matsuo, K., Nagashima, Y, et al. (2005). A good model of hepatic failure after excessive hepatectomy in mice. The Journal of surgical research 127,171-176.
Manz, M.G. (2007). Human-hemato-lymphoid-system mice:opportunities and challenges. Immunity 26,537-541.
Mason, W.S., Seal, G, and Summers, J. (1980). Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus. Journal of virology 36,829-836.
McCune, J., Kaneshima, H., Krowka, J., Namikawa, R., Outzen, H., Peault, B., Rabin, L., Shih, C.C., Yee, E., Lieberman, M., et al. (1991). The SCID-hu mouse:a small animal model for HIV infection and pathogenesis. Annu Rev Immunol 9,399-429.
McCune, J.M., Namikawa, R., Kaneshima, H., Shultz, L.D., Lieberman, M., and Weissman, I.L. (1988). The SCID-hu mouse:murine model for the analysis of human hematolymphoid differentiation and function. Science 241,1632-1639.
McGlynn, K.A., Hunter, K., LeVoyer, T., Roush, J., Wise, P., Michielli, R.A., Shen, F.M., Evans, A.A., London, W.T., and Buetow, K.H. (2003). Susceptibility to aflatoxin B1-related primary hepatocellular carcinoma in mice and humans. Cancer research 63,4594-4601.
Melkus, M.W., Estes, J.D., Padgett-Thomas, A., Gatlin, J., Denton, P.W., Othieno, F.A., Wege, A.K., Haase, A.T., and Garcia, J.V. (2006). Humanized mice mount specific adaptive and innate immune responses to EBV and TSST-1. Nature medicine 12,1316-1322.
Mercer, D.F., Schiller, D.E., Elliott, J.F., Douglas, D.N., Hao, C., Rinfret, A., Addison, W.R., Fischer, K.P., Churchill, T.A., Lakey, J.R., et al. (2001). Hepatitis C virus replication in mice with chimeric human livers. Nature medicine 7,927-933.
Merle, P., Kim, M., Herrmann, M., Gupte, A., Lefrancois, L., Califano, S., Trepo, C., Tanaka, S., Vitvitski, L., de la Monte, S., et al. (2005). Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. Journal of hepatology 43,854-862.
Miyazawa, Y, Tsutsui, H., Mizuhara, H., Fujiwara, H., and Kaneda, K. (1998). Involvement of intrasinusoidal hemostasis in the development of concanavalin A-induced hepatic injury in mice. Hepatology 27,497-506.
Mombaerts, P., Iacomini, J., Johnson, R.S., Herrup, K., Tonegawa, S., and Papaioannou, V.E. (1992). RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68,869-877.
Mosier, D.E., Gulizia, R.J., Baird, S.M., and Wilson, D.B. (1988). Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 335, 256-259.
Nakagawa, S., Umehara, T., Matsuda, C., Kuge, S., Sudoh, M., and Kohara, M. (2007). Hsp90 inhibitors suppress HCV replication in replicon cells and humanized liver mice. Biochemical and biophysical research communications 353,882-888.
Namisaki, T., Yoshiji, H., Kojima, H., Yoshii, J., Ikenaka, Y., Noguchi, R., Sakurai, S., Yanase, K., Kitade, M., Yamazaki, M., et al. (2006). Salvage effect of the vascular endothelial growth factor on chemically induced acute severe liver injury in rats. Journal of hepatology 44, 568-575.
Nelson, F.K., Greiner, D.L., Shultz, L.D., and Rajan, T.V. (1991). The immunodeficient scid mouse as a model for human lymphatic filariasis. The Journal of experimental medicine 173, 659-663.
Newell, P., Villanueva, A., Friedman, S.L., Koike, K., and Llovet, J.M. (2008). Experimental models of hepatocellular carcinoma. Journal of hepatology 48,858-879.
Newsome, P.N., Plevris, J.N., Nelson, L.J., and Hayes, P.C. (2000). Animal models of fulminant hepatic failure:a critical evaluation. Liver transplantation:official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 6,21-31.
Nicholes, K., Guillet, S., Tomlinson, E., Hillan, K., Wright, B., Frantz, G.D., Pham, T.A., Dillard-Telm, L., Tsai, S.P., Stephan, J.P., et al. (2002). A mouse model of hepatocellular carcinoma:ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. The American journal of pathology 160,2295-2307.
Nishimura, M., Yoshitsugu, H., Yokoi, T., Tateno, C., Kataoka, M., Horie, T., Yoshizato, K., and Naito, S. (2005). Evaluation of mRNA expression of human drug-metabolizing enzymes and transporters in chimeric mouse with humanized liver. Xenobiotica; the fate of foreign compounds in biological systems 35,877-890.
Oertelt, S., Lian, Z.X., Cheng, C.M., Chuang, Y.H., Padgett, K.A., He, X.S., Ridgway, W.M., Ansari, A.A., Coppel, R.L., Li, M.O., et al. (2006). Anti-mitochondrial antibodies and primary biliary cirrhosis in TGF-beta receptor Ⅱ dominant-negative mice. J Immunol 177, 1655-1660.
Ohbo, K., Suda, T., Hashiyama, M., Mantani, A., Ikebe, M., Miyakawa, K., Moriyama, M., Nakamura, M., Katsuki, M., Takahashi, K., et al. (1996). Modulation of hematopoiesis in mice with a truncated mutant of the interleukin-2 receptor gamma chain. Blood 87, 956-967.
Olleros, M.L., Vesin, D., Fotio, A.L., Santiago-Raber, M.L., Tauzin, S., Szymkowski, D.E., and Garcia, I. (2010). Soluble TNF, but not membrane TNF, is critical in LPS-induced hepatitis. Journal of hepatology 53,1059-1068.
Pflumio, F., Izac, B., Katz, A., Shultz, L.D., Vainchenker, W., and Coulombel, L. (1996). Phenotype and function of human hematopoietic cells engrafting immune-deficient CB17-severe combined immunodeficiency mice and nonobese diabetic-severe combined immunodeficiency mice after transplantation of human cord blood mononuclear cells. Blood 88,3731-3740.
Ploss, A., Evans, M.J., Gaysinskaya, V.A., Panis, M., You, H., de Jong, Y.P., and Rice, C.M. (2009). Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457,882-886.
Ploss, A., and Rice, C.M. (2009). Towards a small animal model for hepatitis C. EMBO reports 10,1220-1227.
Poirier, L.A. (1975). Hepatocarcinogenesis by diethylnitrosamine in rats fed high dietary levels of lipotropes. Journal of the National Cancer Institute 54,137-140.
Protzer, U., Maini, M.K., and Knolle, P.A. (2012). Living in the liver:hepatic infections. Nat Rev Immunol 12,201-213.
Quintana-Bustamante, O., Alvarez-Barrientos, A., Kofman, A.V., Fabregat, I., Bueren, J.A., Theise, N.D., and Segovia, J.C. (2006). Hematopoietic mobilization in mice increases the presence of bone marrow-derived hepatocytes via in vivo cell fusion. Hepatology 43, 108-116.
Ramadori, G, Moriconi, F., Malik, I., and Dudas, J. (2008). Physiology and pathophysiology of liver inflammation, damage and repair. Journal of physiology and pharmacology:an official journal of the Polish Physiological Society 59 Suppl 1,107-117.
Reddy, J.K., Rao, S., and Moody, D.E. (1976). Hepatocellular carcinomas in acatalasemic mice treated with nafenopin, a hypolipidemic peroxisome proliferator. Cancer research 36, 1211-1217.
Sakai, H., Park, S.S., and Kikkawa, Y. (1992). Differential oxidase activity of hepatic and pulmonary microsomal cytochrome P-450 isozymes after treatment with cytochrome P-450 inducers. Biochemical and biophysical research communications 187,1262-1269.
Salas, J.T., Banales, J.M., Sarvide, S., Recalde, S., Ferrer, A., Uriarte, I., Oude Elferink, R.P., Prieto, J., and Medina, J.F. (2008). Ae2a,b-deficient mice develop antimitochondrial antibodies and other features resembling primary biliary cirrhosis. Gastroenterology 134, 1482-1493.
Salguero Palacios, R., Roderfeld, M., Hemmann, S., Rath, T., Atanasova, S., Tschuschner, A., Gressner, O.A., Weiskirchen, R., Graf, J., and Roeb, E. (2008). Activation of hepatic stellate cells is associated with cytokine expression in thioacetamide-induced hepatic fibrosis in mice. Laboratory investigation; a journal of technical methods and pathology 88, 1192-1203.
Sasaki, K., Ichikawa, H., Takei, S., No, H.S., Tomotsune, D., Kano, Y., Yokoyama, T., Sirasawa, S., Mogi, A., Yoshie, S., et al. (2009). Hepatocyte differentiation from human ES cells using the simple embryoid body formation method and the staged-additional cocktail. TheScientificWorldJournal 9,884-890.
Shafritz, D.A. (2007). A human hepatocyte factory. Nat Biotechnol 25,871-872.
Shavinskaya, A., Boulant, S., Penin, F., McLauchlan, J., and Bartenschlager, R. (2007). The lipid droplet binding domain of hepatitis C virus core protein is a major determinant for efficient virus assembly. The Journal of biological chemistry 282,37158-37169.
Shinkai, Y, Rathbun, G, Lam, K.P., Oltz, E.M., Stewart, V., Mendelsohn, M., Charron, J., Datta, M., Young, F., Stall, A.M., et al. (1992). RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68,855-867.
Shultz, L.D., Ishikawa, F., and Greiner, D.L. (2007). Humanized mice in translational biomedical research. Nat Rev Immunol 7,118-130.
Shultz, L.D., Lyons, B.L., Burzenski, L.M., Gott, B., Chen, X., Chaleff, S., Kotb, M., Gillies, S.D., King, M., Mangada, J., et al. (2005). Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol 174,6477-6489.
Shultz, L.D., Saito, Y., Najima, Y, Tanaka, S., Ochi, T., Tomizawa, M., Doi, T., Sone, A., Suzuki, N., Fujiwara, H., et al. (2010). Generation of functional human T-cell subsets with HLA-restricted immune responses in HLA class I expressing NOD/SCID/IL2r gamma(null) humanized mice. Proceedings of the National Academy of Sciences of the United States of America 107,13022-13027.
Song, X., Guo, Y., Duo, S., Che, J., Wu, C., Ochiya, T., Ding, M., and Deng, H. (2009). A mouse model of inducible liver injury caused by tet-on regulated urokinase for studies of hepatocyte transplantation. The American journal of pathology 175,1975-1983.
Starkel, P., and Leclercq, I.A. (2011). Animal models for the study of hepatic fibrosis. Best practice & research Clinical gastroenterology 25,319-333.
Strowig, T., Rongvaux, A., Rathinam, C., Takizawa, H., Borsotti, C., Philbrick, W., Eynon, E.E., Manz, M.G., and Flavell, R.A. (2011). Transgenic expression of human signal regulatory protein alpha in Rag2-/-gamma(c)-/ -mice improves engraftment of human hematopoietic cells in humanized mice. Proceedings of the National Academy of Sciences of the United States of America 108,13218-13223.
Sugamura, K., Asao, H., Kondo, M., Tanaka, N., Ishii, N., Ohbo, K., Nakamura, M., and Takeshita, T. (1996). The interleukin-2 receptor gamma chain:its role in the multiple cytokine receptor complexes and T cell development in XSCID. Annu Rev Immunol 14, 179-205.
Summers, J., Smolec, J.M., and Snyder, R. (1978). A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proceedings of the National Academy of Sciences of the United States of America 75,4533-4537.
Sun, R., Jaruga, B., Kulkarni, S., Sun, H., and Gao, B. (2005). IL-6 modulates hepatocyte proliferation via induction of HGF/p21cip1:regulation by SOCS3. Biochemical and biophysical research communications 335,1943-1949.
Suzuki, A., McCall, S., Choi, S.S., Sicklick, J.K., Huang, J., Qi, Y., Zdanowicz, M., Camp, T., Li, Y.X., and Diehl, A.M. (2006). Interleukin-15 increases hepatic regenerative activity. Journal of hepatology 45,410-418.
Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., Tsukamoto, Y., Iso, H., Fujimori, Y., Stern, D.M., et al. (2004). Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. The Journal of clinical investigation 114,330-338.
Tateno, C., Yoshizane, Y., Saito, N., Kataoka, M., Utoh, R., Yamasaki, C., Tachibana, A., Soeno, Y., Asahina, K., Hino, H., et al. (2004). Near completely humanized liver in mice shows human-type metabolic responses to drugs. The American journal of pathology 165, 901-912.
Tonjes, R.R., Lohler, J., O'Sullivan, J.F., Kay, G.F., Schmidt, G.H., Dalemans, W., Pavirani, A., and Paul, D. (1995). Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice. Oncogene 10,765-768.
Torrente, Y., Belicchi, M., Sampaolesi, M., Pisati, F., Meregalli, M., D'Antona, G, Tonlorenzi, R., Porretti, L., Gavina, M., Mamchaoui, K., et al. (2004). Human circulating AC133(+) stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. The Journal of clinical investigation 114,182-195.
Traggiai, E., Chicha, L., Mazzucchelli, L., Bronz, L., Piffaretti, J.C., Lanzavecchia, A., and Manz, M.G. (2004). Development of a human adaptive immune system in cord blood cell-transplanted mice. Science 304,104-107.
Turrini, P., Sasso, R., Germoni, S., Marcucci, I., Celluci, A., Di Marco, A., Marra, E., Paonessa, G, Eutropi, A., Laufer, R., et al. (2006). Development of humanized mice for the study of hepatitis C virus infection. Transplantation proceedings 38,1181-1184.
Vassilopoulos, G, Wang, P.R., and Russell, D.W. (2003). Transplanted bone marrow regenerates liver by cell fusion. Nature 422,901-904.
Vesselinovitch, S.D., and Mihailovich, N. (1983). Kinetics of diethylnitrosamine hepatocarcinogenesis in the infant mouse. Cancer research 43,4253-4259.
Wakabayashi, K., Lian, Z.X., Moritoki, Y., Lan, R.Y., Tsuneyama, K., Chuang, Y.H., Yang, G.X., Ridgway, W., Ueno, Y, Ansari, A.A., et al. (2006). IL-2 receptor alpha(-/-) mice and the development of primary biliary cirrhosis. Hepatology 44,1240-1249.
Walters, K.A., Joyce, M.A., Thompson, J.C., Smith, M.W., Yeh, M.M., Proll, S., Zhu, L.F., Gao, T.J., Kneteman, N.M., Tyrrell, D.L., et al. (2006). Host-specific response to HCV infection in the chimeric SCID-beige/Alb-uPA mouse model:role of the innate antiviral immune response. PLoS pathogens 2, e59.
Wang, J., Sun, R., Wei, H., Dong, Z., Gao, B., and Tian, Z. (2006). Poly I:C prevents T cell-mediated hepatitis via an NK-dependent mechanism. Journal of hepatology 44, 446-454.
Wang, X., Willenbring, H., Akkari, Y., Torimaru, Y., Foster, M., Al-Dhalimy, M., Lagasse, E., Finegold, M., Olson, S., and Grompe, M. (2003). Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422,897-901.
Washburn, M.L., Bility, M.T., Zhang, L., Kovalev, G.I., Buntzman, A., Frelinger, J.A., Barry, W., Ploss, A., Rice, C.M., and Su, L. (2011). A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 140,1334-1344.
Watanabe, S., Terashima, K., Ohta, S., Horibata, S., Yajima, M., Shiozawa, Y., Dewan, M.Z., Yu, Z., Ito, M., Morio, T., et al. (2007). Hematopoietic stem cell-engrafted NOD/SCID/IL2Rgamma null mice develop human lymphoid systems and induce long-lasting HIV-1 infection with specific humoral immune responses. Blood 109,212-218.
Weisburger, E.K. (1977). Carcinogenicity studies on halogenated hydrocarbons. Environmental health perspectives 21,7-16.
Willenbring, H., Bailey, A.S., Foster, M., Akkari, Y., Dorrell, C., Olson, S., Finegold, M., Fleming, W.H., and Grompe, M. (2004). Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nature medicine 10,744-748.
Yoshitsugu, H., Nishimura, M., Tateno, C., Kataoka, M., Takahashi, E., Soeno, Y., Yoshizato, K., Yokoi, T., and Naito, S. (2006). Evaluation of human CYP1A2 and CYP3A4 mRNA expression in hepatocytes from chimeric mice with humanized liver. Drug metabolism and pharmacokinetics 21,465-474.