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J Exp Med. 1995 December 1; 182(6): 2037–2043.
PMCID: PMC2192238

Improved engraftment of human hematopoietic cells in severe combined immunodeficient (SCID) mice carrying human cytokine transgenes

Abstract

We have generated immunodeficient scid-/scid- (SCID)-transgenic mice expressing the genes for human interleukin 3, granulocyte/macrophage- colony stimulating factor, and stem cell factor. We have compared engraftment and differentiation of human hematopoietic cells in transgenic SCID mice with two strains of nontransgenic SCID mice. Human bone marrow cells carrying the CD34 antigen or human umbilical cord blood were injected into sublethally irradiated recipients. Human DNA was detected by polymerase chain reaction in peripheral blood and bone marrow of 14 of 28 transgenic SCID mice after transplantation, but in only 2 of 15 nontransgenic SCID littermates at a 10-fold lower level. Bone marrow cultures 8 wk after transplantation of cord blood gave rise to human burst-forming unit erythroid, colony-forming unit granulocyte/macrophage, or granulocyte/erythroid/macrophage/megakaryocyte colonies. Engraftment was observed for up to 6 mo in transgenic SCID mice, twice as long as nontransgenic littermates or previous studies in which transplanted SCID mice were given daily injections of growth factors. We conclude that the level and duration of engraftment of human cells in SCID mice can be improved by expression of human cytokine transgenes and that transgenic SCID mice are an efficient model system for the study of human hematopoiesis.

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Selected References

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  • Zanjani ED, Flake AW, Rice H, Hedrick M, Tavassoli M. Long-term repopulating ability of xenogeneic transplanted human fetal liver hematopoietic stem cells in sheep. J Clin Invest. 1994 Mar;93(3):1051–1055. [PMC free article] [PubMed]
  • Bosma GC, Custer RP, Bosma MJ. A severe combined immunodeficiency mutation in the mouse. Nature. 1983 Feb 10;301(5900):527–530. [PubMed]
  • Bosma MJ, Carroll AM. The SCID mouse mutant: definition, characterization, and potential uses. Annu Rev Immunol. 1991;9:323–350. [PubMed]
  • Kirchgessner CU, Patil CK, Evans JW, Cuomo CA, Fried LM, Carter T, Oettinger MA, Brown JM. DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science. 1995 Feb 24;267(5201):1178–1183. [PubMed]
  • Hendrickson EA, Qin XQ, Bump EA, Schatz DG, Oettinger M, Weaver DT. A link between double-strand break-related repair and V(D)J recombination: the scid mutation. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4061–4065. [PubMed]
  • Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature. 1988 Sep 15;335(6187):256–259. [PubMed]
  • McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL. The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988 Sep 23;241(4873):1632–1639. [PubMed]
  • McCune J, Kaneshima H, Krowka J, Namikawa R, Outzen H, Peault B, Rabin L, Shih CC, Yee E, Lieberman M, et al. The SCID-hu mouse: a small animal model for HIV infection and pathogenesis. Annu Rev Immunol. 1991;9:399–429. [PubMed]
  • Kamel-Reid S, Dick JE. Engraftment of immune-deficient mice with human hematopoietic stem cells. Science. 1988 Dec 23;242(4886):1706–1709. [PubMed]
  • 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 Feb 28;255(5048):1137–1141. [PubMed]
  • Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG, et al. Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell. 1986 Oct 10;47(1):3–10. [PubMed]
  • Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC, et al. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990 Oct 5;63(1):213–224. [PubMed]
  • Bernstein ID, Andrews RG, Zsebo KM. Recombinant human stem cell factor enhances the formation of colonies by CD34+ and CD34+lin- cells, and the generation of colony-forming cell progeny from CD34+lin- cells cultured with interleukin-3, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor. Blood. 1991 Jun 1;77(11):2316–2321. [PubMed]
  • Vormoor J, Lapidot T, Pflumio F, Risdon G, Patterson B, Broxmeyer HE, Dick JE. Immature human cord blood progenitors engraft and proliferate to high levels in severe combined immunodeficient mice. Blood. 1994 May 1;83(9):2489–2497. [PubMed]
  • Sorrentino BP, Brandt SJ, Bodine D, Gottesman M, Pastan I, Cline A, Nienhuis AW. Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1. Science. 1992 Jul 3;257(5066):99–103. [PubMed]
  • Warburton PE, Greig GM, Haaf T, Willard HF. PCR amplification of chromosome-specific alpha satellite DNA: definition of centromeric STS markers and polymorphic analysis. Genomics. 1991 Oct;11(2):324–333. [PubMed]
  • Carow CE, Harrington MA, Broxmeyer HE. Detection of human myeloid progenitor cells in a murine background. Exp Hematol. 1993 Jan;21(1):66–69. [PubMed]
  • Broxmeyer HE. Cord blood as an alternative source for stem and progenitor cell transplantation. Curr Opin Pediatr. 1995 Feb;7(1):47–55. [PubMed]
  • Orazi A, Braun SE, Broxmeyer HE. Commentary: Immunohistochemistry represents a useful tool to study human cell engraftment in SCID mice transplantation models. Blood Cells. 1994;20(2-3):323–330. [PubMed]
  • Larochelle A, Vormoor J, Lapidot T, Sher G, Furukawa T, Li Q, Shultz LD, Olivieri NF, Stamatoyannopoulos G, Dick JE. Engraftment of immune-deficient mice with primitive hematopoietic cells from beta-thalassemia and sickle cell anemia patients: implications for evaluating human gene therapy protocols. Hum Mol Genet. 1995 Feb;4(2):163–172. [PubMed]
  • Greiner DL, Shultz LD, Yates J, Appel MC, Perdrizet G, Hesselton RM, Schweitzer I, Beamer WG, Shultz KL, Pelsue SC, et al. Improved engraftment of human spleen cells in NOD/LtSz-scid/scid mice as compared with C.B-17-scid/scid mice. Am J Pathol. 1995 Apr;146(4):888–902. [PubMed]
  • Murphy WJ, Bennett M, Anver MR, Baseler M, Longo DL. Human-mouse lymphoid chimeras: host-vs.-graft and graft-vs.-host reactions. Eur J Immunol. 1992 Jun;22(6):1421–1427. [PubMed]
  • Leiter EH, Prochazka M, Coleman DL. The non-obese diabetic (NOD) mouse. Am J Pathol. 1987 Aug;128(2):380–383. [PubMed]
  • Shultz LD, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL, et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J Immunol. 1995 Jan 1;154(1):180–191. [PubMed]
  • Kyoizumi S, Baum CM, Kaneshima H, McCune JM, Yee EJ, Namikawa R. Implantation and maintenance of functional human bone marrow in SCID-hu mice. Blood. 1992 Apr 1;79(7):1704–1711. [PubMed]
  • Chen BP, Galy A, Kyoizumi S, Namikawa R, Scarborough J, Webb S, Ford B, Cen DZ, Chen SC. Engraftment of human hematopoietic precursor cells with secondary transfer potential in SCID-hu mice. Blood. 1994 Oct 15;84(8):2497–2505. [PubMed]
  • Dick JE, Lapidot T, Pflumio F. Transplantation of normal and leukemic human bone marrow into immune-deficient mice: development of animal models for human hematopoiesis. Immunol Rev. 1991 Dec;124:25–43. [PubMed]
  • Broxmeyer HE, Hangoc G, Cooper S, Ribeiro RC, Graves V, Yoder M, Wagner J, Vadhan-Raj S, Benninger L, Rubinstein P, et al. Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4109–4113. [PubMed]
  • Lu L, Xiao M, Shen RN, Grigsby S, Broxmeyer HE. Enrichment, characterization, and responsiveness of single primitive CD34 human umbilical cord blood hematopoietic progenitors with high proliferative and replating potential. Blood. 1993 Jan 1;81(1):41–48. [PubMed]
  • Moritz T, Keller DC, Williams DA. Human cord blood cells as targets for gene transfer: potential use in genetic therapies of severe combined immunodeficiency disease. J Exp Med. 1993 Aug 1;178(2):529–536. [PMC free article] [PubMed]
  • Lu L, Xiao M, Clapp DW, Li ZH, Broxmeyer HE. High efficiency retroviral mediated gene transduction into single isolated immature and replatable CD34(3+) hematopoietic stem/progenitor cells from human umbilical cord blood. J Exp Med. 1993 Dec 1;178(6):2089–2096. [PMC free article] [PubMed]
  • Nolta JA, Hanley MB, Kohn DB. Sustained human hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. Blood. 1994 May 15;83(10):3041–3051. [PubMed]

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