NOD/LtSz-Rag1 null Pfp null mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment

Shultz, Leonard D.; Banuelos, Scott J.; Lyons, Bonnie L.; Samuels, Rebecca; Burzenski, Lisa M.; Gott, Bruce; Lang, Pamela A.; Leif, Jean; Appel, Michael C.; Rossini, Aldo A.; Greiner, Dale L.

doi:10.1097/01.tp.0000083041.44829.2c

Cited by 64 publications

(57 citation statements)

References 23 publications

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“…7,8 NOD/SCID/b2m null and NOD/ Rag1 null Pfp null mice were subsequently derived from NOD/SCID and NOD/Rag1 null mice. 9,10 Since the early 2000s, immunodeficient mice appropriate for generating humanized mice have been successively developed by introducing the mutant IL2rc gene into NOD/SCID and RAG1/2 null mice by backcross mating, thus resulting in NOD/SCID/cc null mice 11,12 and Rag1/2 null cc null mice. [13][14][15][16] These mice show multiple immunodeficiencies, including defects in T, B and natural killer (NK) cells, and reduced macrophage (Mw) and dendritic cell (DC) function.…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

Current advances in humanized mouse models

et al. 2012

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“…[5][6][7][8] Elimination of the lymphoid system is the first step to achieving reconstitution of human hematopoiesis. To deplete T and B cells, the scid mutation in the Prkdc gene [9][10][11] or disruption of the recombination activating gene 1 or 2 (Rag1 and Rag2) 12,13 has been introduced into various mouse strains. In addition, to deplete natural killer (NK) cells or their functions, the IL-2 receptor common ␥ chain subunit (Il2rg) [14][15][16] or beta-2-microglobulin (B2m) [17][18][19] is disrupted.…”

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Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Yamauchi

Takenaka

Urata

et al. 2013

Blood

121

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Key Points• NOD-specific Sirpa polymorphism is the genetic determinant of highly efficient xenograft activity in NOD-based immunodeficient mouse models.Current mouse lines efficient for human cell xenotransplantation are backcrossed into NOD mice to introduce its multiple immunodeficient phenotypes. Our positional genetic study has located the NOD-specific polymorphic Sirpa as a molecule responsible for its high xenograft efficiency: it recognizes human CD47 and the resultant signaling may cause NOD macrophages not to engulf human grafts. In the present study, we established C57BL/6.Rag2 nullIl2rgnull mice harboring NOD-Sirpa (BRGS). BRGS mice engrafted human hematopoiesis with an efficiency that was equal to or even better than that of the NOD.Rag1 nullIl2rgnull strain, one of the best xenograft models. Consequently, BRGS mice are free from other NOD-related abnormalities; for example, they have normalized C5 function that enables the evaluation of complement-dependent cytotoxicity of antibodies against human grafts in the humanized mouse model. Our data show that efficient human cell engraftment found in NOD-based models is mounted solely by their polymorphic Sirpa. The simplified BRGS line should be very useful in future studies of human stem cell biology. (Blood. 2013;121(8):1316-1325) IntroductionImmunodeficient mice are widely used to reconstitute human hematopoiesis by xenotransplantation of hematopoietic stem cells (HSCs). 1,2 This "humanized" mouse model provides a powerful tool with which to evaluate the biologic properties of human HSCs and progenitors in vivo. 3,4 Such xenotransplantation systems have also been used to study human cancer stem cells. [5][6][7][8] Elimination of the lymphoid system is the first step to achieving reconstitution of human hematopoiesis. To deplete T and B cells, the scid mutation in the Prkdc gene [9][10][11] or disruption of the recombination activating gene 1 or 2 (Rag1 and Rag2) 12,13 has been introduced into various mouse strains. In addition, to deplete natural killer (NK) cells or their functions, the IL-2 receptor common ␥ chain subunit (Il2rg) [14][15][16] or beta-2-microglobulin (B2m) [17][18][19] is disrupted.However, depletion of lymphoid cells is not sufficient and it has been shown empirically that additional strain-specific factors modulate human hematopoietic engraftment in the xenotransplantation setting. For example, within the SCID strain, the SCID with the NOD background was the gold standard for the xenotransplantation assay based on its high efficiency. 11 In fact, recent studies have shown that among the lymphoid-depleted mouse strains, the NOD-scid Il2rg null (NSG/NOG) 14,15 and NOD.Rag1 null Il2rg null (NOD-RG) 20 strains are the most efficient; the BALB/c.Rag2 null Il2rg null (BALB-RG) strain is the next efficient 21,22 ; and the C57BL/6 strains with scid, 23 Rag2 null , Rag2 null B2m null , Rag2 null Prf null , 24 or Rag2 null Jak3 null25 mutations are unable to reconstitute human hematopoiesis. The NOD strain has multiple immune deficiencies, ...

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“…Lacking mature B and T cells, NOD.scid mice are both insulitisand diabetes-free throughout life. However, because of a high incidence of thymic lymphomas, the mean lifespan is relatively short [13,23,24] . Accordingly, while the unique immune defects provide an excellent in vivo environment for hematopoietic investigation extending to effects within the marrow compartment, this model may not be suitable for assessing bone material properties.…”

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Diabetes-related impairment in bone strength is established early in the life course

Casazza

Hanks²,

Clines³

et al. 2013

WJD

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AIM:To evaluate properties of bone quantity/quality using young non-obese Type 1 (T1D)-diabetic (NOD) prone and syngenic non-diabetic (NOD.scid ) mice. METHODS:Quantitative bone assessment of tibia was conducted using dual-energy X-ray absorptiometry (DXA) for the evaluation of body mass, bone mineral content, body fat mass and lean mass. Qualitative assessment was accomplished by three-point breakage for assessment of force to failure and micro-computed tomography for evaluation of trabecular and cortical properties of bone. In addition, fasting blood was evaluated prior to sacrifice at week eleven and fifteen to evaluate and compare glucose homeostasis between the strains of mice. RESULTS:Our findings support a perturbation in the relationship between bone quantity, quality, and subsequently, the association between structure and strength. There were no differences in DXA-assessed body composition (body fat, % fat mass and lean mass) and bone composition (bone mineral content and bone mineral density) between strains. However, relative to NOD.scid , NOD mice had lower trabecular bone volume, relative trabecular bone volume, trabecular number and trabecular total material density (P < 0.05). Conversely, NOD mice had greater cortical total mean volume (P < 0.05). General linear models analysis adjusted for body weight revealed a significant contribution of T1D to bone health as early as 5 wk. CONCLUSION:It is well-established that diabetes is a significant risk factor for increased fractures, although the underlying mechanisms are not fully understood. Investigation of bone parameters encompassing strength and structure early in the life course will facilitate the elucidation of the pathogenesis of impaired bone integrity.

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NOD/LtSz-Rag1 null Pfp null mice: a new model system with increased levels of human peripheral leukocyte and hematopoietic stem-cell engraftment

Abstract: NOD/LtSz-Rag1nullPfpnull mice are devoid of mature B cell, T cell, and NK cell cytotoxic activity, engraft at high levels with human PBMC, and hematopoietic progenitor cells and provide a new NK cell-deficient model for human hematolymphoid cell engraftment.

Cited by 64 publications

References 23 publications

Current advances in humanized mouse models

Current advances in humanized mouse models

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Diabetes-related impairment in bone strength is established early in the life course

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