Humanized NOD/SCID/IL2Rγ<sup>null</sup>Mice Transplanted with Hematopoietic Stem Cells under Nonmyeloablative Conditions Show Prolonged Life Spans and Allow Detailed Analysis of Human Immunodeficiency Virus Type 1 Pathogenesis

Watanabe, Sumio; Ohta, Shinrai; Yajima, Misako; Terashima, Kazuo; Ito, Mamoru; Mugishima, Hideo; Fujiwara, Shigeyoshi; Shimizu, Kazufumi; Honda, Mitsuo; Shimizu, Norio; Yamamoto, Naoki

doi:10.1128/jvi.01353-07

Cited by 78 publications

(80 citation statements)

References 24 publications

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“…Although no formal survival analysis was performed, we noted that the difference in survival became larger at later time points (Table S2). In line with a previous report, we found no NSG mice alive after 9 mo, impairing the value of this model for long-term studies (28). Our analysis of hematopoietic organs in the different strains of mice demonstrate increased numbers of human HSPCs in the bone marrow of hSIRPa-DKO mice compared with DKO mice.…”

Section: Discussionsupporting

confidence: 81%

“…S4 A and B). We were unable to analyze NSG mice at this late time point, because of a high mortality that became apparent beyond 6 mo (Table S2), which has also been reported previously (28). In the spleen, we observed a similar trend with cell numbers declining in all strains of mice from 3 to 6 mo ( Fig.…”

Section: Results Hsirpa Is Faithfully Expressed and Functional In Hsisupporting

confidence: 71%

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Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice

Strowig

Rongvaux

Rathinam

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

201

177

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Transplantation of human hematopoietic stem cells into severely immunocompromised newborn mice allows the development of a human hematopoietic and immune system in vivo. NOD/scid/γ c −/− (NSG) and BALB/c Rag2 −/− γ c −/− mice are the most commonly used mouse strains for this purpose and a number of studies have demonstrated the high value of these model systems in areas spanning from basic to translational research. However, limited cross-reactivity of many murine cytokines on human cells and residual host immune function against the xenogeneic grafts results in defective development and maintenance of human cells in vivo. Whereas NSG mice have higher levels of absolute human engraftment than similar mice on a BALB/c background, they have a shorter lifespan and NOD ES cells are unsuitable for the complex genetic engineering that is required to improve human hematopoiesis and immune responses by transgenesis or knockin of human genes. We have generated mice that faithfully express a transgene of human signal regulatory protein alpha (SIRPa), a receptor that negatively regulates phagocytosis, in Rag2 −/− γ c −/− mice on a mixed 129/BALB/c background, which can easily be genetically engineered. These mice allow significantly increased engraftment and maintenance of human hematopoietic cells reaching levels comparable to NSG mice. Furthermore, we found improved functionality of the human immune system in these mice. In summary, hSIRPa-transgenic Rag2 −/− γ c −/− mice represent a unique mouse strain supporting high levels of human cell engraftment, which can easily be genetically manipulated.

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Section: Discussionsupporting

confidence: 81%

Section: Results Hsirpa Is Faithfully Expressed and Functional In Hsisupporting

confidence: 71%

Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice

Strowig

Rongvaux

Rathinam

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

201

177

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“…26,62,63 This research is further accelerated through the use of HSC-transplanted immunodeficient mice, in which multilineage hematopoietic cells can be differentiated. [64][65][66][67] In this field, a unique model for HIV-1 [68][69][70] reported by Garcia's group at the University of North Carolina and termed bone marrow-liver-thymus (BLT) mice, has attracted attention. As the name suggests, this model is generated by transplantation of fetal bone marrow, liver and thymus into a subcutaneous region of the kidney.…”

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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“…These humanized NOG mice can be efficiently infected with human blood-borne pathogens such as human immunodeficiency virus type 1 (HIV-1) [3]. In addition, functional endometrium or ovary can be regenerated by transplantation of singly-dispersed cells or fragments of human organs into NOG mice [4,5].…”

Section: Introductionmentioning

confidence: 99%

In Vivo Bioluminescence Imaging of Pancreatic Cancer Xenografts in NOG Mice

Yoshimura¹,

Matsuda²,

Naito³

et al. 2013

J Carcinogene Mutagene

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Implantation of human tumors in immunodeficient mice and in vivo bioluminescence imaging are powerful tools for cancer research. In the present study, we established a novel cell line, PANC-luc5, from PANC-1 pancreatic carcinoma cells transfected with the luciferase gene. We confirmed the usefulness of this cell line by transplanting it into three mouse strains with different immunodeficiency statuses; BALB/cA Jcl-nu/nu (Nude), Crlj:SHO-Prkdc scid Hr hr (SHO), and NOD/Shi-scid, IL-2γ null (NOG) mice. NOG mice were also inoculated with PANC-luc5 cells in either the tail vein or abdominal cavity, and monitored with in vivo bioluminescence imaging. Our results show that PANC-luc5 tumors orthotopically transplanted into NOG mice grew steadily and progressed to metastases, but those in Nude and SHO mice remained their original size with no metastasis throughout the experimental period. In the orthotopic and experimental metastasis models, in vivo bioluminescence imaging was used successfully to visualize tumor growth and metastasis of PANC-luc5 cells in NOG mice. In conclusion, in vivo bioluminescence imaging using orthotopic, intravenous, and intraperitoneal implantation of PANC-luc5 cells into NOG mice can be used to study the mechanisms of metastasis and to develop anti-pancreatic cancer drugs.

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Humanized NOD/SCID/IL2Rγ^nullMice Transplanted with Hematopoietic Stem Cells under Nonmyeloablative Conditions Show Prolonged Life Spans and Allow Detailed Analysis of Human Immunodeficiency Virus Type 1 Pathogenesis

Cited by 78 publications

References 24 publications

Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice

Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice

Current advances in humanized mouse models

In Vivo Bioluminescence Imaging of Pancreatic Cancer Xenografts in NOG Mice

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Humanized NOD/SCID/IL2RγnullMice Transplanted with Hematopoietic Stem Cells under Nonmyeloablative Conditions Show Prolonged Life Spans and Allow Detailed Analysis of Human Immunodeficiency Virus Type 1 Pathogenesis

Cited by 78 publications

References 24 publications

Transgenic expression of human signal regulatory protein alpha in Rag2−/−γc−/−mice improves engraftment of human hematopoietic cells in humanized mice

Transgenic expression of human signal regulatory protein alpha in Rag2−/−γc−/−mice improves engraftment of human hematopoietic cells in humanized mice

Current advances in humanized mouse models

In Vivo Bioluminescence Imaging of Pancreatic Cancer Xenografts in NOG Mice

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Product

Resources

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Humanized NOD/SCID/IL2Rγ^nullMice Transplanted with Hematopoietic Stem Cells under Nonmyeloablative Conditions Show Prolonged Life Spans and Allow Detailed Analysis of Human Immunodeficiency Virus Type 1 Pathogenesis

Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice

Transgenic expression of human signal regulatory protein alpha in Rag2^−/−γ_c^−/−mice improves engraftment of human hematopoietic cells in humanized mice