Repopulation Efficiencies of Adult Hepatocytes, Fetal Liver Progenitor Cells, and Embryonic Stem Cell-Derived Hepatic Cells in Albumin-Promoter-Enhancer Urokinase-Type Plasminogen Activator Mice

Haridass, Dhivya; Yuan, Qing; Becker, Pablo D.; Cantz, Tobias; Iken, Marcus; Rothe, Michael; Narain, Nidhi; Bock, Michael; Nörder, Miriam; Legrand, Nicolas; Wedemeyer, Heiner; Weijer, Kees; Spits, Hergen; Manns, Michael P.; Cai, Jun; Deng, Hongkui; Santo, James P. Di; Guzmán, Carlos A.; Ott, Michael

doi:10.2353/ajpath.2009.090117

Cited by 102 publications

(85 citation statements)

References 48 publications

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“…Hu-liver mice provide a good infection model for viruses specific to hepatocytes, including hepatitis C and B viruses. [85][86][87] These models provide invaluable tools for analyzing the mechanisms of human infection and for developing chemotherapeutic agents such as antibodies.…”

Section: Infectious Diseasesmentioning

confidence: 99%

Current advances in humanized mouse models

et al. 2012

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Humanized mouse models that have received human cells or tissue transplants are extremely useful in basic and applied human disease research. Highly immunodeficient mice, which do not reject xenografts and support cell and tissue differentiation and growth, are indispensable for generating additional appropriate models. Since the early 2000s, a series of immunodeficient mice appropriate for generating humanized mice has been successively developed by introducing the IL-2Rc null gene (e.g., NOD/SCID/cc null and Rag2 null cc null mice). These strains show not only a high rate of human cell engraftment, but also generate well-differentiated multilineage human hematopoietic cells after human hematopoietic stem cell (HSC) transplantation. These humanized mice facilitate the analysis of human hematology and immunology in vivo. However, human hematopoietic cells developed from HSCs are not always phenotypically and functionally identical to those in humans. More recently, a new series of immunodeficient mice compensates for these disadvantages. These mice were generated by genetically introducing human cytokine genes into NOD/SCID/cc null and Rag2 null cc null mice. In this review, we describe the current knowledge of human hematopoietic cells developed in these mice. Various human disease mouse models using these humanized mice are summarized.

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Section: Infectious Diseasesmentioning

confidence: 99%

Current advances in humanized mouse models

et al. 2012

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“…The same holds true for the homozygous animals, where repopulation reached levels around 46%, in line with previously published data. 24 The transplantation of transduced or eGFP-transgenic hepatocytes into wild-type mice (n¼6 for both), which do not provide the graft with any selective advantage, led to repopulation efficiencies below 1% as expected (Supplementary Figure S10).…”

Section: Stable Gene Transfer Into Primary Mouse Hepatocytes M Rothe mentioning

confidence: 99%

“…24,[38][39][40] All animals had free access to food and water, and were handled in accordance with institutional guidelines. Hepatocytes were transduced overnight in adherence with HGM-E (10 ng ml À1 EGF) and detached from the culture plates by using Trypsin/EDTA as described above.…”

Section: Hepatocyte Transplantationmentioning

confidence: 99%

“…A total of 500 000 cells were transplanted intra-splenically into three hetero-and three homozygous alb-uPA-transgenic animals, which is a well-established murine liver repopulation model, at day 9 after birth. 24 In parallel, six uPA animals were transplanted with freshly isolated cells derived from an eGFP-transgenic mouse. 25 The animals were analyzed for repopulation efficiencies after 1 year by macroscopic examination of whole livers and fluorescence microscopy of paraffin sections.…”

Section: Stable Gene Transfer Into Primary Mouse Hepatocytes M Rothe mentioning

confidence: 99%

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Epidermal growth factor improves lentivirus vector gene transfer into primary mouse hepatocytes

et al. 2011

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Partial resistance of primary mouse hepatocytes to lentiviral (LV) vector transduction poses a challenge for ex vivo gene therapy protocols in models of monogenetic liver disease. We thus sought to optimize ex vivo LV gene transfer while preserving the hepatocyte integrity for subsequent transplantation into recipient animals. We found that culture media supplemented with epidermal growth factor (EGF) and, to a lesser extent, hepatocyte growth factor (HGF) markedly improved transduction efficacy at various multiplicities of infection. Up to 87% of primary hepatocytes were transduced in the presence of 10 ng EGF, compared with B30% in standard culture medium (SCMs). The increased number of transgene-expressing cells correlated with increased nuclear import and more integrated pro-viral copies per cell. Higher LV transduction efficacy was not associated with proliferation, as transduction capacity of gammaretroviral vectors remained low (o1%). Finally, we developed an LV transduction protocol for short-term (maximum 24 h) adherent hepatocyte cultures. LV-transduced hepatocytes showed liver repopulation capacities similar to freshly isolated hepatocytes in alb-uPA mouse recipients. Our findings highlight the importance of EGF for efficient LV transduction of primary hepatocytes in culture and should facilitate studies of LV gene transfer in mouse models of monogenetic liver disease.

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“…In this study we used a mouse model for the generation of human-mouse chimeric livers based on Rag2 -/-IL-2Rγ null mice with BALB/c background that are homozygously transgenic for albumin-promoter-enhancer driven urokinase-type plasminogen activator expression (AlbuPA tg+/+ ) (5)(6)(7)(8)(9). This BALB-RAG/ c -uPA mouse model is characterized by severe damage of the liver architecture, requiring transplantation of uPA-negative hepatocytes within 2-5 weeks after birth for survival.…”

Section: Introductionmentioning

confidence: 99%

170 Ectopic Expression of Murine Cd47 Minimizes Macrophage Rejection of Human Hepatocyte Xenografts in Immunodeficient Mice

Waern¹,

Yuan²,

Rüdrich³

et al. 2012

Journal of Hepatology

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Macrophages play an important role in the rejection of xenogeneic cells and therefore represent a major obstacle to generating chimeric mice with human xenografts that are useful tools for basic and preclinical medical research. The inhibitory SIRP receptor is a negative regulator of macrophage phagocytic activity and interacts in a species-specific fashion with its ligand CD47. Furthermore, SIRP polymorphism amongst laboratory mouse strains significantly affects the extent of human CD47-mediated toleration of human xenotransplants.Aiming to minimize macrophage activity and thus optimize human cell engraftment in immunodeficient mice, we lentivirally transduced murine CD47 (Cd47) into human liver cells.Human HepG2 liver cells expressing Cd47 were less frequently contacted and phagocytosed by murine RAW264.7 macrophages in vitro than their Cd47-negative counterparts. For the generation of human-mouse chimeric livers in immunodeficient BALB-RAG/ c -uPA mice, freshly thawed cryopreserved human hepatocytes were transduced with a lentiviral expression vector for Cd47 using a refined in vitro transduction protocol immediately before transplantation. In vivo, Cd47-positive human primary hepatocytes were selectively retained following engraftment in immunodeficient mice, leading to at least a doubling of liver repopulation efficiencies. Conclusion:We conclude that ectopic expression of murine Cd47 in human hepatocytes selectively favors engraftment upon transplantation into mice, a finding that should have a profound impact on the generation of robust humanized small animal models. Moreover, dominance of ectopically expressed murine Cd47 over endogenous human CD47 should also widen the spectrum of immunodeficient mouse strains suitable for humanization.

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Repopulation Efficiencies of Adult Hepatocytes, Fetal Liver Progenitor Cells, and Embryonic Stem Cell-Derived Hepatic Cells in Albumin-Promoter-Enhancer Urokinase-Type Plasminogen Activator Mice

Abstract: Fetal liver progenitor cell suspensions (FLPC) and hepatic precursor cells derived from embryonic stem cells (ES-HPC

Cited by 102 publications

References 48 publications

Current advances in humanized mouse models

Current advances in humanized mouse models

Epidermal growth factor improves lentivirus vector gene transfer into primary mouse hepatocytes

170 Ectopic Expression of Murine Cd47 Minimizes Macrophage Rejection of Human Hepatocyte Xenografts in Immunodeficient Mice

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