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Related Collections Hematopoiesis and Stem Cells Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, Vol. 95 No. 10 (May 15), 2000: pp. 3102-3105 HEMATOPOIESIS 2 Microglobulin-deficient (B2mnull) NOD/SCID mice are excellent recipients for studying human stem cell function Orit Kollet, Amnon Peled, Tamara Byk, Herzl Ben-Hur, Dale Greiner, Leonard Shultz, and Tsvee Lapidot From the Department of Immunology, The Weizmann Institute and the Department of Obstetrics and Gynecology, Kaplan Hospital, Rehovot, Israel; the University of Massachusetts, Worcester MA; and The Jackson Laboratory, Bar Harbor, ME.     Abstract Top Abstract Introduction Materials and methods Results and discussion References Human SCID repopulating cells (SRC) are defined based on their functional ability to repopulate the bone marrow of NOD/SCID mice with both myeloid and lymphoid cell populations. The frequency of SRC in umbilical cord blood cells is 1 in 9.3 × 105 mononuclear cells. We report that as few as 8 × 104 human cord blood mononuclear cells transplanted into NOD/SCID/B2mnull mice resulted in mutlilineage differentiation in the murine bone marrow, revealing a more than 11-fold higher SRC frequency than in NOD/SCID mice. Moreover, as few as 2 to 5 × 103 CD34+ cells recovered from the bone marrow of primary transplanted NOD/SCID mice were sufficient for engrafting secondary NOD/SCID/B2mnull mice with SRC, suggesting SRC self-renewal. Thus, by using NOD/SCID/B2mnull mice as recipients, we established a functional assay for human stem cells capable of engrafting the bone marrow of primary and secondary transplanted immune-deficient mice with SRC, providing a model that better resembles autologous stem cell transplantation. (Blood. 2000;95:3102-3105) © 2000 by The American Society of Hematology.     Introduction Top Abstract Introduction Materials and methods Results and discussion References Blood-forming hematopoietic stem cells are defined in repopulation assays based on their functional ability to home to the bone marrow microenvironment and to repopulate transplanted recipients durably with both myeloid and lymphoid cell populations.1 We and others2-5 developed functional in vivo assays for primitive human cells by transplanting them into sublethally irradiated immune-deficient C.B-17-Prkdcscid (SCID) and, more recently, into NOD/LtSz-Prkdcscid (NOD/SCID) mice, with reduced residual immunity. An alternative approach for reducing innate immunity of the host, used by other investigators,6,7 was to treat these mice with anti-natural killer cell antibodies before transplantation with or without irradiation, resulting in improved engraftment. Quesenberry et al8,9 demonstrated that total body irradiation is not a prerequisite for stem cell engraftment in transplanted murine recipients by multiple daily injections of human or mouse donor cells into nonirradiated hosts. Recently, we demonstrated that total body irradiation of NOD/SCID or normal mice induces SDF-1 secretion in a time-dependent manner, mostly by osteoblast cells in the bone marrow.10 This SDF-1 gradient attracts primitive human CXCR4+ cells, increasing their homing to the bone marrow,11 resulting in higher levels of engraftment compared to nonirradiated recipients.10 The NOD/SCID mouse model is widely used to study many aspects of normal and leukemic human hematopoiesis, such as development,12,13 ex vivo expansion,14-17 gene transfer,3,18 mobilization,19 and interactions with the bone marrow stroma.20 More important, this model was used to identify and to characterize the human SCID repopulating cell (SRC) based on its functional ability to repopulate the murine bone marrow with multilineage myeloid and lymphoid cell populations. The cell surface phenotype of SRC was found to be CD34+CD385; however, CD34CD38, or CD34+CD38+ cells, also have limited engraftment capacities in transplanted NOD/SCID mice.15,21 NOD/SCID mice were also used to compare the frequencies of SRC in cord blood, bone marrow, and mobilized peripheral blood cells evaluating their multilineage repopulating potential.22 The frequency of SRC in cord blood mononuclear cells (MNC) was determined by detecting more than 0.1% human DNA in the bone marrow of transplanted mice with limiting dilution assays, and it was found to be 1 in 9.3 × 105 MNC.22 The frequency of competitive repopulating unit , a primitive human cell population that includes CD34+CD38+ cells and is also capable of engrafting NOD/SCID mice, was found to be 1 in 6 × 105 cord blood MNC.15 The recently developed 2 microglobulin knockout NOD/ LtSz-SCID B2mnull mice (NOD/SCID/B2mnull) have reduced innate immunity because of lack of natural killer (NK) cell activity.23 Recently, we reported that SRC are true stem cells capable of high levels of multilineage repopulation of both primary transplanted NOD/SCID and secondary transplanted NOD/SCID/B2mnull mice.24 The cell surface phenotype of human SRC is CD38/lowCXCR4+, and their engraftment is dependent on the chemokine SDF-1.24 We report here that NOD/SCID/B2mnull mice are better recipients than NOD/SCID mice for studying human stem cell function because they provide a model that better resembles autologous stem cell transplantation.     Materials and methods Top Abstract Introduction Materials and methods Results and discussion References Human cell preparation Human cord blood MNC from full-term deliveries was isolated by standard separation on Ficoll-Hypaque (Pharmacia Biotech, Uppsala, Sweden). Enrichment of CD34+ cells was performed using a MACS separation kit (Miltenyi Biotech, Bergisch Gladbach, Germany) as previously described.17,24 All procedures were approved by the human experimentation and ethics committees of the Weizmann Institute of Science. Mice NOD/SCID mice and NOD/SCID 2 microglobulin knockout mice, NOD/SCID/B2mnull,23 were bred and maintained under defined flora conditions at the Weizmann Institute in sterile intraventilated cages (IVC; Techniplast, Buguggiate, Italy). NOD/SCID mice were delivered by cesarean section and foster nursed on pathogen-free foster mice with defined flora. NOD/SCID/B2mnull were not rederived and carried the opportunistic pathogens, Pasteurella pneumotropica and Trichomonas. These mice received antibiotics (1.4 mg Ciprofloxacin; Bayer, Leverkusen, Germany) per 100 mL acidified autoclaved water during experiments to reduce the mortality from infections. In addition, NOD/SCID/B2mnull mice are prone to development of thymic lymphomas compared with NOD/SCID mice23; however, because young adult (8-week-old) mice were used as recipients, thymic lymphomas, which usually develop later, were rare. Data from rare events of mice having thymic lymphoma during the experiment course were excluded. NOD/SCID/B2mnull mice exhibit increased iron accumulation in the liver23; nevertheless, the increased levels of human SRC engraftment in NOD/SCID/B2mnull mice appears to be a consequence of reduced innate immunity rather than an indirect effect of hematochromatosis. Treatment of NOD/SCID mice with antimouse IL-2 receptor antibody reduced their NK cell activity and increased the engraftment of human peripheral blood mononuclear cells to levels seen in NOD/SCID/B2mnull mice (data not shown). The overall survival of irradiated and transplanted NOD/SCID/B2mnull mice over the course of the experiments was 75% ± 25%. NOD/SCID mice were irradiated with 375 cGy at 67 cGy/min from a 60Co source, whereas NOD/SCID/B2mnull mice were irradiated with 350 cGy because of their increased sensitivity to ionizing radiation.25 Within 24 hours, mice were transplanted intravenously with human cells as previously described17,24 and were killed 1 month later. All the experiments were approved by the animal care committee of the Weizmann Institute. Human cell detection Progenitor cells were assayed in semisolid cultures selective for human hematopoietic colonies.17,24 Human cells in the marrow of engrafted mice were detected by flow cytometry using human specific monoclonal antibodies (mAb): anti-CD45 fluorescein isothiocyanate (FITC; Immuno Quality Products, Groningen, The Netherlands); anti-CD19, -CD33, -CD38, and -CD56 phycoerythrin (Coulter, Miami FL), and anti-CD34 FITC (Becton Dickinson, San Jose, CA).17,24 For human NK cell induction, bone marrow cells from engrafted mice were cultured for 10 days in RPMI supplemented with 10% fetal calf serum in the presence of human stem cell factor and IL-15 (100 ng/mL; R&D Systems, Minneapolis, MN).17,24 Human DNA analysis The levels of human DNA in the marrow of transplanted mice were detected by Southern blot using a human-specific chromosome 17  satellite probe as previously described.17,24 Frequency analysis NOD/SCID/B2mnull mice were transplanted with cord blood MNC in a cell dose ranging from 1.25 × 104 to 2.5 × 105 cells per mouse. One month after transplantation, mice were killed and human DNA in the murine bone marrow was determined. A mouse was scored positive if 0.1% or more human DNA was detected by Southern blot. Data were analyzed by applying Poisson statistics to the single-hit model, and the frequency was calculated using the maximum likelihood estimator.22     Results and discussion Top Abstract Introduction Materials and methods Results and discussion References Increased frequency of cord blood cells capable of engrafting NOD/SCID/B2mnull compared to NOD/SCID mice To evaluate the frequency of cord blood cells capable of engrafting NOD/SCID/B2mnull mice, these mice were transplanted with cord blood MNC in a limiting dilution assay. Mice were scored as positive for engraftment when more than 0.1% human DNA was detected in the murine bone marrow because this method is human specific and very sensitive. Statistical analysis was performed on pooled data from 5 independent experiments with pooled cord blood cells from multiple donors (Table 1), and the frequency of human cells capable of engraftment was calculated as described.22 The frequency of cord blood MNC capable of engrafting NOD/SCID/B2mnull mice, as determined by human DNA measurements, was found to be 1 in 3.6 × 104 MNC (95% CI, 1 in 2 × 104 to 1 in 6.3 × 104) compared to 1 in 9.3 × 105 previously shown for NOD/SCID mice.22                                View this table: [in this window] [in a new window]   Table 1. Limiting dilution assay Higher levels of human cell engraftment in NOD/SCID/B2mnull compared to NOD/SCID mice The level of hematopoietic repopulation is a critical parameter in stem cell transplantation. Therefore, we compared the engraftment levels obtained in transplanted mice of both strains. Transplantation of 8 × 104 cord blood CD34+-enriched cells into NOD/SCID mice and 4 × 104 cord blood CD34+ cells into NOD/SCID/B2mnull mice resulted in significantly higher levels of engraftment in NOD/SCID/B2mnull than in NOD/SCID mice (Figure 1A). The incidence of immature human progenitor cells in the bone marrow of NOD/SCID/B2mnull mice was also higher than in the bone marrow of NOD/SCID mice (Figure 1B). Differential scoring of colonies revealed more colony-forming units (CFU) of granulocyte-macrophage (CFU-GM, 3-fold), immature erythroid (BFU-E, 6-fold) and the most primitive granulocyte-erythroid-macrophage-megakaryocyte (CFU-GEMM, 12-fold) in NOD/SCID/B2mnull than in NOD/SCID mice (Figure 1B). Furthermore, as few as 1 × 103 CD34+ cells transplanted into NOD/SCID/B2mnull mice were successfully engrafted, resulting in 0.1% to 1% human DNA in the bone marrow of transplanted mice (Figure 1C, lanes 1-3), whereas NOD/SCID mice could not be engrafted by such low cell doses (Figure 1C, lanes 4-6). Similarly, human bone marrow or mobilized peripheral blood cells engrafted NOD/SCID/B2mnull mice with significantly higher levels than NOD/SCID mice (data not shown). View larger version (60K): [in this window] [in a new window]   Fig 1. Higher levels of human cell engraftment in NOD/SCID/B2mnull mice. (A) Summary of engraftment levels in mice transplanted with enriched cord blood CD34+ cells. Similar percentage of human engraftment was detected by either Southern blot with human-specific  satellite probe (open circles) or by flow cytometry using human-specific anti CD45 mAb (filled circles). NOD/SCID mice were transplanted with 8 × 104 cells per mouse and NOD/SCID/B2mnull mice with 4 × 104 cells per mouse, in 5 independent experiments. (B) Bone marrow cells of mice presented in A were assayed for colony formation in semisolid culture selective for the growth of human colonies. Data shown are mean ± SE of 5 experiments. (C) Human DNA in the bone marrow of primary NOD/SCID/B2mnull mice transplanted with 103 CD34+ cells (lanes 1-3) and NOD/SCID mice transplanted with 104 CD34+ cells (lanes 4-6). Secondary NOD/SCID/B2mnull recipients were transplanted with 2 to 5 × 103 human CD34+ cells that were recovered from engrafted primary NOD/SCID mice (lanes 7, 8). (D) NOD/SCID mice were transplanted with 12.5 × 104 cord blood MNC per mouse (DI) and NOD/SCID/B2mnull mice with 8 × 104 or 5 × 104 cord blood MNC per mouse (DII and DVI, respectively). Bone marrow cells from transplanted mice were analyzed 1 month later for the presence of human CD45+ cells (R2). Human lineage-specific mAb were used to detect lymphoid CD45+CD19+ (DII, DVI, R1), myeloid CD45+CD33+ (DIII), and immature CD34+CD38/low (DIV) progenitor cells in the marrow of engrafted NOD/SCID/B2mnull mice. Lymphoid CD45+CD56+ NK cell differentiation was induced in vitro before analysis (DV). A representative mouse out of 9 in 3 different experiments is shown. Multilineage differentiation by SRC in transplanted NOD/SCID/B2mnull mice Stem cells are defined by their capability to repopulate the bone marrow of transplanted mice with multilineage differentiation. Therefore, the lymphoid and myeloid differentiation capacity of SRC in the bone marrow of NOD/SCID/B2mnull mice was of interest. When 12.5 × 104 cord blood MNC were transplanted into NOD/SCID mice, we could not detect by flow cytometry any lymphoid, myeloid, or other human cells in the murine bone marrow (Figure 1DI, R2). In contrast, as few as 8 × 104 cord blood MNC successfully engrafted NOD/SCID/B2mnull mice in 3 of 3 experiments (Figure 1DII, R2). In these experiments, multilineage differentiation of human SRC was observed in the bone marrow of transplanted NOD/SCID/B2mnull mice, which included lymphoid CD45+CD19+ cells (Figure 1DII R1) and myeloid CD45+CD33+ cells (DIII) as well as primitive CD34+CD38-/low cells (DIV). Cells recovered from the marrow of these mice could also differentiate into lymphoid CD45+CD56+ NK cells (Figure 1DV). These results, obtained with the transplantation of 8 × 104 MNC, indicated more than 11-fold higher frequency of human SRC detected in NOD/SCID/B2mnull mice compared with 1 in 9.3 × 105 previously shown for NOD/SCID mice.22 In another set of experiments, 33% of NOD/SCID/B2mnull mice transplanted with as few as 5 × 104 cord blood MNC were also successfully engrafted with SRC, which differentiated into multilineage lymphoid cells (Figure 1DVI) and myeloid cells (data not shown). Engraftment in secondary transplanted NOD/SCID/B2mnull mice The ability of hematopoietic stem cells to self-renew, that is, to maintain undifferentiated cells by proliferation and in parallel to produce mature cells by multilineage differentiation, can only be assayed by serial transplantations. In this assay, stem cells that gave rise to multilineage hematopoiesis in primary recipients were also capable of repeating this process in secondary transplanted recipients. Recently, we successfully used NOD/SCID/B2mnull as secondary recipients after primary NOD/SCID mice transplantation with 1 to 2 × 105 cord blood CD34+-enriched cells.24 Each NOD/SCID/B2mnull mouse was transplanted with bone marrow cells recovered from 1 primary transplanted NOD/SCID mouse after in vitro CXCR4 up-regulation by stimulation with stem cell factor and IL-6 for 40 hours. These secondarily transplanted mice had higher levels of multilineage human engraftment, even though only approximately 33% of the total bone marrow cells from a primary transplanted NOD/SCID mouse was transplanted into a secondary NOD/SCID/B2mnull recipient.24 As few as 2 to 5 × 103 human CD34+ cells in the bone marrow recovered from primary transplanted NOD/SCID mice were sufficient to engraft secondarily transplanted NOD/SCID/B2mnull mice (Figure 1C, lanes 7, 8) with multilineage SRC engraftment (data not shown). Taken together, we found that NOD/SCID/B2mnull mice are superior recipients for human stem cell transplantation than NOD/SCID mice because of their reduced innate immunity, resulting in higher levels of engraftment with primitive progenitors and multilineage differentiation. Moreover, by using NOD/SCID/B2mnull mice as recipients, the frequency of human SRC was more than 11-fold higher than with NOD/SCID mice. Finally, as few as 2 to 5 × 103 CD34+ cells recovered from the bone marrow of primary transplanted NOD/SCID mice were sufficient for consecutive multilineage engraftment with SRC in secondarily transplanted NOD/SCID/B2mnull mice, suggesting human stem cell self-renewal in the murine bone marrow. We therefore conclude that NOD/SCID/B2mnull mice are better recipients for studying human stem cell function and provide a model that better resembles autologous stem cell transplantation. Recently, Arevalo et al26 crossed the nude mutation onto the NOD/SCID strain to generate better recipients for human hematopoiesis. The resultant nude athymic NOD/SCID/NUDE mouse has a longer lifespan because of the lack of thymic lymphoma development. Similarly, crossing the B2mnull mutation with the newly developed NOD/LtSz-Rag1null strain27 may presumably reduce the radiosensitivity determined by defective DNA repair because of the scid mutation, reduce the incidences of malignant spontaneous thymic lymphomas, and create better recipients for human stem cell transplantation.     Footnotes Submitted November 5, 1999; accepted January 10, 2000. Supported in part by grants from the Israel Academy of Science (T.L.), a research grant from the Israel Cancer Research Fund (T.L.), the Godfrey Foundation (A.P), a Germany MINERVA Grant (O.K), the Hood Foundation (D.G.), and National Institutes of Health grants A130 389 (L.S.) and DK57 199 (D.G., L.S.). Reprints: Tsvee Lapidot, Incumbent of the Pauline Recanati Career Development Chair of Immunology, Department of Immunology, The Weizmann Institute of Science, Rehovot 76,100, Israel; e-mail: litsvee{at}wicc.weizmann.ac.il. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.     References Top Abstract Introduction Materials and methods Results and discussion References 1. Moore MA. Stem cell proliferation: ex vivo and in vivo observations. Stem Cells. 1997;15(suppl 1):239-248discussion 248-251. 2. Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE, Dick JE. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science. 1992;255:1137-1141[Abstract/Free Full Text]. 3. Larochelle A, Vormoor J, Hanenberg H, et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mice using retroviral gene marking and cell purification: implications for gene therapy. Nat Med. 1996;2:1329-1337[Medline] [Order article via Infotrieve]. 4. Cashman JD, Lapidot T, Wang JC, et al. Kinetic evidence of the regeneration of multilineage hematopoiesis from primitive cells in normal human bone marrow transplanted into immunodeficient mice. Blood. 1997;89:4307-4316[Abstract/Free Full Text]. 5. Bhatia M, Wang JCY, Kapp U, Bonnet D, Dick JE. Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci U S A. 1997;94:5320-5325[Abstract/Free Full Text]. 6. Lee LA, Sergio JJ, Sykes M. Natural killer cells weakly resist engraftment of allogeneic, long- term, multilineage-repopulating hematopoietic stem cells. Transplantation. 1996;61:125-132[Medline] [Order article via Infotrieve]. 7. Chargui J, Moya MJ, Sanhadji K, Blanc-Brunat N, Touraine JL. Anti-NK antibodies injected into recipient mice enhance engraftment and chimerism after allogeneic transplantation of fetal liver stem cells. Thymus. 1997;24:233-246[Medline] [Order article via Infotrieve]. 8. Lowry PA, Shultz LD, Greiner DL, et al. Improved engraftment of human cord blood stem cells in NOD/LtSz- scid/scid mice after irradiation or multiple-day injections into unirradiated recipients. Biol Blood Marrow Transplant. 1996;2:15-23[Medline] [Order article via Infotrieve]. 9. Quesenberry PJ, Ramshaw H, Crittenden RB, et al. Engraftment of normal murine marrow into nonmyeloablated host mice. Blood Cells. 1994;20:348-350[Medline] [Order article via Infotrieve]. 10. Lapidot T, Ponomaryov T, Petit I, et al. The chemokine SDF-1 is produced in the bone marrow mainly by osteoblast, bone forming cells: increased production following total body irradiation, and cyclophosphamide [abstract]. Blood. 1999;94:606a. 11. Kollet O, Peled A, Lapidot T. Exclusive homing of human CD38-/lowCXCR4+ stem cells to the spleen and bone marrow of immune deficient mice within 1-16 hours [abstract]. Blood. 1999;94:391. 12. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730-737[Medline] [Order article via Infotrieve]. 13. Robin C, Pflumio F, Vainchenker W, Coulombel L. Identification of lymphomyeloid primitive progenitor cells in fresh human cord blood and in the marrow of nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice transplanted with human CD34(+) cord blood cells. J Exp Med. 1999;189:1601-1610[Abstract/Free Full Text]. 14. Bhatia M, Bonnet D, Kapp U, Wang JC, Murdoch B, Dick JE. Quantitative analysis reveals expansion of human hematopoietic repopulating cells after short-term ex vivo culture. J Exp Med. 1997;186:619-624[Abstract/Free Full Text]. 15. Conneally E, Cashman J, Petzer A, Eaves C. Expansion in vitro of transplantable human cord blood stem cells demonstrated using a quantitative assay of their lympho-myeloid repopulating activity in nonobese diabetic-scid/scid mice. Proc Natl Acad Sci U S A. 1997;94:9836-9841[Abstract/Free Full Text]. 16. Piacibello W, Sanavio F, Severino A, et al. Engraftment in nonobese diabetic severe combined immunodeficient mice of human CD34(+) cord blood cells after ex vivo expansion: evidence for the amplification and self-renewal of repopulating stem cells. Blood. 1999;93:3736-3749[Abstract/Free Full Text]. 17. Kollet O, Aviram R, Chebath J, et al. The soluble interleukin-6 (IL-6) receptor/IL-6 fusion protein enhances in vitro maintenance and proliferation of human CD34(+)CD38(-/low) cells capable of repopulating severe combined immunodeficiency mice. Blood. 1999;94:923-931[Abstract/Free Full Text]. 18. Hennemann B, Conneally E, Pawliuk R, et al. Optimization of retroviral-mediated gene transfer to human NOD/SCID mouse repopulating cord blood cells through a systematic analysis of protocol variables. Exp Hematol. 1999;27:817-825[Medline] [Order article via Infotrieve]. 19. van der Loo JC, Hanenberg H, Cooper RJ, Luo FY, Lazaridis EN, Williams DA. Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse as a model system to study the engraftment and mobilization of human peripheral blood stem cells. Blood. 1998;92:2556-2570[Abstract/Free Full Text]. 20. Gan OI, Murdoch B, Larochelle A, Dick JE. Differential maintenance of primitive human SCID-repopulating cells, clonogenic progenitors, and long-term culture-initiating cells after incubation on human bone marrow stromal cells. Blood. 1997;90:641-650[Abstract/Free Full Text]. 21. Bhatia M, Bonnet D, Murdoch B, Gan OI, Dick JE. A newly discovered class of human hematopoietic cells with SCID-repopulating activity [in process citation]. Nat Med. 1998;4:1038-1045[Medline] [Order article via Infotrieve]. 22. Wang JC, Doedens M, Dick JE. Primitive human hematopoietic cells are enriched in cord blood compared with adult bone marrow or mobilized peripheral blood as measured by the quantitative in vivo SCID-repopulating cell assay. Blood. 1997;89:3919-3924[Abstract/Free Full Text]. 23. Christianson SW, Greiner DL, Hesselton RA, et al. Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. J Immunol. 1997;158:3578-3586[Abstract]. 24. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845-848[Abstract/Free Full Text]. 25. Greiner DL, Hesselton RA, Shultz LD. SCID mouse models of human stem cell engraftment. Stem Cells. 1998;16:166-177[Abstract/Free Full Text]. 26. Arevalo JMG, Ertl DC, Dao MA, Shultz LD, Nolta JA. A new immunodeficient mouse strain: the nude NOD/SCID mouse, for human hematopoietic cell xenotransplantation. [abstract] Blood. 1999;94:129a. 27. Shultz LD, Lang PA, Christianson SW, et al. NOD/LtSz-Rag1null mice: an immunodeficient and radioresistant model for engraftment of human hematolymphoid cells, HIV infection, and adoptive transfer of NOD mouse diabetogenic T cells. J Immunol. 2000;164:2496[Abstract/Free Full Text]. © 2000 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. V. Rosland, A. Svendsen, A. Torsvik, E. Sobala, E. McCormack, H. Immervoll, J. Mysliwietz, J.-C. Tonn, R. Goldbrunner, P. E. Lonning, et al. Long-term Cultures of Bone Marrow-Derived Human Mesenchymal Stem Cells Frequently Undergo Spontaneous Malignant Transformation Cancer Res., July 1, 2009; 69(13): 5331 - 5339. [Abstract] [Full Text] [PDF] B. M. Carreno, J. R. Garbow, G. R. 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Borok Retention of human bone marrow-derived cells in murine lungs following bleomycin-induced lung injury Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L285 - L292. [Abstract] [Full Text] [PDF] D. J. Maxwell, J. Bonde, D. A. Hess, S. A. Hohm, R. Lahey, P. Zhou, M. H. Creer, D. Piwnica-Worms, and J. A. Nolta Fluorophore-Conjugated Iron Oxide Nanoparticle Labeling and Analysis of Engrafting Human Hematopoietic Stem Cells Stem Cells, February 1, 2008; 26(2): 517 - 524. [Abstract] [Full Text] [PDF] S. Watanabe, S. Ohta, M. Yajima, K. Terashima, M. Ito, H. Mugishima, S. Fujiwara, K. Shimizu, M. Honda, N. Shimizu, et al. Humanized NOD/SCID/IL2R{gamma}null Mice Transplanted with Hematopoietic Stem Cells under Nonmyeloablative Conditions Show Prolonged Life Spans and Allow Detailed Analysis of Human Immunodeficiency Virus Type 1 Pathogenesis J. Virol., December 1, 2007; 81(23): 13259 - 13264. [Abstract] [Full Text] [PDF] A. Rizo, E. Vellenga, G. de Haan, and J. J. 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Lapidot, A. Dar, and O. Kollet How do stem cells find their way home? Blood, September 15, 2005; 106(6): 1901 - 1910. [Abstract] [Full Text] [PDF] F. Ishikawa, M. Yasukawa, B. Lyons, S. Yoshida, T. Miyamoto, G. Yoshimoto, T. Watanabe, K. Akashi, L. D. Shultz, and M. Harada Development of functional human blood and immune systems in NOD/SCID/IL2 receptor {gamma} chainnull mice Blood, September 1, 2005; 106(5): 1565 - 1573. [Abstract] [Full Text] [PDF] J. L. McKenzie, O. I. Gan, M. Doedens, and J. E. Dick Human short-term repopulating stem cells are efficiently detected following intrafemoral transplantation into NOD/SCID recipients depleted of CD122+ cells Blood, August 15, 2005; 106(4): 1259 - 1261. [Abstract] [Full Text] [PDF] L. D. Shultz, B. L. Lyons, L. M. Burzenski, B. Gott, X. Chen, S. Chaleff, M. Kotb, S. D. Gillies, M. King, J. Mangada, et al. Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2R{gamma}null Mice Engrafted with Mobilized Human Hemopoietic Stem Cells J. Immunol., May 15, 2005; 174(10): 6477 - 6489. [Abstract] [Full Text] [PDF] T. Byk, J. Kahn, O. Kollet, I. Petit, S. Samira, S. Shivtiel, H. Ben-Hur, A. Peled, W. Piacibello, and T. Lapidot Cycling G1 CD34+/CD38+ Cells Potentiate the Motility and Engraftment of Quiescent G0 CD34+/CD38-/low Severe Combined Immunodeficiency Repopulating Cells Stem Cells, April 1, 2005; 23(4): 561 - 574. [Abstract] [Full Text] [PDF] K. Chadwick, F. Shojaei, L. Gallacher, and M. Bhatia Smad7 alters cell fate decisions of human hematopoietic repopulating cells Blood, March 1, 2005; 105(5): 1905 - 1915. [Abstract] [Full Text] [PDF] G. R. Kolar, T. Yokota, M. I. D. Rossi, S. K. Nath, and J. D. Capra Human fetal, cord blood, and adult lymphocyte progenitors have similar potential for generating B cells with a diverse immunoglobulin repertoire Blood, November 1, 2004; 104(9): 2981 - 2987. [Abstract] [Full Text] [PDF] E. Thanopoulou, J. Cashman, T. Kakagianne, A. Eaves, N. Zoumbos, and C. Eaves Engraftment of NOD/SCID-{beta}2 microglobulin null mice with multilineage neoplastic cells from patients with myelodysplastic syndrome Blood, June 1, 2004; 103(11): 4285 - 4293. [Abstract] [Full Text] [PDF] A. Spiegel, O. Kollet, A. Peled, L. Abel, A. Nagler, B. Bielorai, G. Rechavi, J. Vormoor, and T. Lapidot Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling Blood, April 15, 2004; 103(8): 2900 - 2907. [Abstract] [Full Text] [PDF] E. Traggiai, L. Chicha, L. Mazzucchelli, L. Bronz, J.-C. Piffaretti, A. Lanzavecchia, and M. G. Manz Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice Science, April 2, 2004; 304(5667): 104 - 107. [Abstract] [Full Text] [PDF] N. Kambe, H. Hiramatsu, M. Shimonaka, H. Fujino, R. Nishikomori, T. Heike, M. Ito, K. Kobayashi, Y. Ueyama, N. Matsuyoshi, et al. Development of both human connective tissue-type and mucosal-type mast cells in mice from hematopoietic stem cells with identical distribution pattern to human body Blood, February 1, 2004; 103(3): 860 - 867. [Abstract] [Full Text] [PDF] J. Nolta Improved method to bridge mouse and man Blood, January 15, 2004; 103(2): 370 - 371. [Full Text] [PDF] A. K. Palucka, J. Gatlin, J. P. Blanck, M. W. Melkus, S. Clayton, H. Ueno, E. T. Kraus, P. Cravens, L. Bennett, A. Padgett-Thomas, et al. Human dendritic cell subsets in NOD/SCID mice engrafted with CD34+ hematopoietic progenitors Blood, November 1, 2003; 102(9): 3302 - 3310. [Abstract] [Full Text] [PDF] S. Brenner, N. L. Whiting-Theobald, G. F. Linton, K. L. Holmes, M. Anderson-Cohen, P. F. Kelly, E. F. Vanin, A. M. Pilon, D. M. Bodine, M. E. Horwitz, et al. Concentrated RD114-pseudotyped MFGS-gp91phox vector achieves high levels of functional correction of the chronic granulomatous disease oxidase defect in NOD/SCID/{beta}2-microglobulin-/- repopulating mobilized human peripheral blood CD34+ cells Blood, October 15, 2003; 102(8): 2789 - 2797. [Abstract] [Full Text] [PDF] H. Hiramatsu, R. Nishikomori, T. Heike, M. Ito, K. Kobayashi, K. Katamura, and T. Nakahata Complete reconstitution of human lymphocytes from cord blood CD34+ cells using the NOD/SCID/{gamma}cnull mice model Blood, August 1, 2003; 102(3): 873 - 880. [Abstract] [Full Text] [PDF] X. Wang, S. Ge, G. McNamara, Q.-L. Hao, G. M. Crooks, and J. A. Nolta Albumin-expressing hepatocyte-like cells develop in the livers of immune-deficient mice that received transplants of highly purified human hematopoietic stem cells Blood, May 15, 2003; 101(10): 4201 - 4208. [Abstract] [Full Text] [PDF] M. Ito, H. Hiramatsu, K. Kobayashi, K. Suzue, M. Kawahata, K. Hioki, Y. Ueyama, Y. Koyanagi, K. Sugamura, K. Tsuji, et al. NOD/SCID/gamma cnull mouse: an excellent recipient mouse model for engraftment of human cells Blood, October 16, 2002; 100(9): 3175 - 3182. [Abstract] [Full Text] [PDF] T. C. C. Kerre, G. De Smet, M. De Smedt, F. Offner, J. De Bosscher, J. Plum, and B. Vandekerckhove Both CD34+38+ and CD34+38- Cells Home Specifically to the Bone Marrow of NOD/LtSZ scid/scid Mice but Show Different Kinetics in Expansion J. Immunol., October 1, 2001; 167(7): 3692 - 3698. [Abstract] [Full Text] [PDF] O. Kollet, A. Spiegel, A. Peled, I. Petit, T. Byk, R. Hershkoviz, E. Guetta, G. Barkai, A. Nagler, and T. Lapidot Rapid and efficient homing of human CD34+CD38{-}/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice Blood, May 15, 2001; 97(10): 3283 - 3291. 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