Generation of Humanized Liver Mouse Model by Transplant of Patient-Derived Fresh Human Hepatocytes

Kim, M.; Choi, Bomi; Joo, Sanghoon; Lee, H.; Lee, J.-H.; Lee, K.W.; Lee, S.; Park, J.B.; Lee, S.-K.; Kim, Seung Ju

doi:10.1016/j.transproceed.2013.11.098

Cited by 11 publications

(5 citation statements)

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“…Since growth factors, cytokines, and chemokines could have species-specificity, PDX mouse models might not be the best model to investigate interactions between the tumor and its microenvironment. In this regard, a chimeric mouse model with a humanized liver would provide a better human tissue microenvironment for the implanted human tumors to the liver [ 43 ]. Another major challenge to the PDX approach is the lack of tumor-immune system interactions.…”

Section: Discussionmentioning

confidence: 99%

Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis

et al. 2017

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BackgroundMetastatic uveal melanoma is a highly fatal disease; most patients die from their hepatic metastasis within 1 year. A major drawback in the development of new treatments for metastatic uveal melanoma is the difficulty in obtaining appropriate cell lines and the lack of appropriate animal models. Patient-derived xenograft (PDX) tumor models, bearing ectopically implanted tumors at a subcutaneous site, have been developed. However, these ectopically implanted PDX models have obstacles to translational research, including a low engraftment rate, slow tumor growth, and biological changes after multiple passages due to the different microenvironment. To overcome these limitations, we developed a new method to directly transplant biopsy specimens to the liver of immunocompromised mice.ResultsBy using two metastatic uveal melanoma cell lines, we demonstrated that the liver provides a more suitable microenvironment for tumor growth compared to subcutaneous sites and that surgical orthotopic implantation (SOI) of tumor pieces allows the creation of a liver tumor in immunocompromised mice. Subsequently, 10 of 12 hepatic metastasis specimens from patients were successfully xenografted into the immunocompromised mice (83.3% success rate) using SOI, including 8 of 10 needle biopsy specimens (80%). Additionally, four cryopreserved PDX tumors were re-implanted to new mice and re-establishment of PDX tumors was confirmed in all four mice. The serially passaged xenograft tumors as well as the re-implanted tumors after cryopreservation were similar to the original patient tumors in histologic, genomic, and proteomic expression profiles. CT imaging was effective for detecting and monitoring PDX tumors in the liver of living mice. The expression of Ki67 in original patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDX mice.ConclusionsSurgical orthotopic implantation of hepatic metastasis from uveal melanoma is highly successful in the establishment of orthotopic PDX models, enhancing their practical utility for research applications. By using CT scan, tumor growth can be monitored, which is beneficial to evaluate treatment effects in interventional studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1247-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis

et al. 2017

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“…The recent TK-NOG chimeric model may be a better option than hFRGN mice for control of the level of humanization in the mouse liver (Kim et al, 2014). However, the same disrupted signaling between the murine intestine and human hepatocytes and mouse nonparenchymal cells in TK-NOG mouse would also exist.…”

Section: Discussionmentioning

confidence: 99%

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Chow

Quach

Zhang

et al. 2016

J Pharmacol Exp Ther

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The humanized liver mouse model is being exploited increasingly for human drug metabolism studies. However, its model stability, intercommunication between human hepatocytes and mouse nonparenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expressions have not been investigated. We examined these issues in FRGN [fumarylacetoacetate hydrolase (Fah2/2), recombination activating gene 2 (Rag22/2), and interleukin 2 receptor subunit gamma (IL-2rg 2/2) triple knockout] on nonobese diabetic (NOD) background] and chimeric mice: mFRGN and hFRGN (repopulated with mouse or human hepatocytes, respectively). hFRGN mice showed markedly higher levels of liver cholesterol, biliary bilirubin, and bile acids (liver, bile, and plasma; mainly human forms, but also murine bile acids) but lower transforming growth factor beta receptor 2 (TGFBR2) mRNA expression levels (10%) in human hepatocytes and other proliferative markers in mouse nonparenchymal cells (Tgf-b1) and cholangiocytes [plasma membrane-bound, G protein-coupled receptor for bile acids (Tgr5)], suggestive of irregular regeneration processes in hFRGN livers. Changes in gene expression in murine intestine, kidney, and brain of hFRGN mice, in particular, induction of intestinal farnesoid X receptor (Fxr) genes: fibroblast growth factor 15 (Fgf15), mouse ileal bile acid binding protein (Ibabp), small heterodimer partner (Shp), and the organic solute transporter alpha (Osta), were observed. Proteomics revealed persistence of remnant murine proteins (cyotchrome P450 7a-hydroxylase (Cyp7a1) and other enzymes and transporters) in hFRGN livers and suggest the likelihood of mouse activity. When compared with normal human liver tissue, hFRGN livers showed lower SHP mRNA and higher CYP7A1 (300%) protein expression, consequences of tb-and ta-muricholic acid-mediated inhibition of the FXR-SHP cascade and miscommunication between intestinal Fgf15 and human liver fibroblast growth factor receptor 4 (FGFR4), as confirmed by the unchanged hepatic pERK/total ERK ratio. Dysregulation of hepatocyte proliferation and bile acid homeostasis in hFRGN livers led to hepatotoxicity, gallbladder distension, liver deformity, and other extrahepatic changes, making questionable the use of the preparation for drug metabolism studies.

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“…Previous studies indicated that GCV injection induced liver injury in TK‐NOG mice 16 . To evaluate the liver injury in replaced mice after GCV injection, we measured the ALT levels in the serum and examined the histology of the liver tissues.…”

Section: Resultsmentioning

confidence: 99%

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice

Kanbe

Ishikawa

Hara

et al. 2020

J of Gastro and Hepatol

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Background and Aim The chronicity of hepatitis B virus (HBV) infection is the result of impaired HBV‐specific immune responses that cannot eliminate or cure the infected hepatocytes efficiently. Previous studies have used immunodeficient mice such as herpes simplex virus type 1 thymidine kinase NOD/Scid/IL2Rrnull (HSV‐TK‐NOG) mice. However, it is difficult to analyze the immune response in the previous models. In the present study, we established a novel HBV infection model using herpes simplex virus type 1 thymidine kinase (HSV‐TK) mice in which the host immune system was not impaired. Methods Herpes simplex virus type 1 thymidine kinase mice were injected intraperitoneally with ganciclovir (GCV). Seven days after GCV injection, GCV‐treated mice were transplanted with 1 × 106 hepatocytes from HBV‐transgenic (HBV‐Tg) mice. Results Serum alanine aminotransferase levels in HSV‐TK mice increased 1 and 2 weeks after GCV injection. The number and viability of hepatocytes from the whole liver of HBV‐Tg mice significantly increased using digestion medium containing liberase. Hepatitis B surface antigen (HBsAg)‐positive areas in the liver tissue were observed for at least 20 weeks after HBsAg‐positive hepatocyte transplantation. In addition, we measured HBsAg in the serum after transplantation. HBsAg levels in HBV‐Tg hepatocyte‐replaced mice increased 4 weeks after transplantation. Furthermore, we examined the immune response in HSV‐TK mice. The increase in hepatitis B surface antibody levels in replaced mice was maintained for 20 weeks. Also, interferon‐γ‐producing cells were increased in non‐replaced mice. Conclusions A novel HBV infection mouse model will help to understand the mechanisms of HBV tolerance similar to human chronic HBV‐infected patients and can be used to develop a new strategy to treat chronic HBV infection.

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Generation of Humanized Liver Mouse Model by Transplant of Patient-Derived Fresh Human Hepatocytes

Cited by 11 publications

References 11 publications

Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis

Establishment of an orthotopic patient-derived xenograft mouse model using uveal melanoma hepatic metastasis

Disrupted Murine Gut–to–Human Liver Signaling Alters Bile Acid Homeostasis in Humanized Mouse Liver Models

Novel hepatitis B virus infection mouse model using herpes simplex virus type 1 thymidine kinase transgenic mice

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