Abstract
Humanized mice allow the development of human immune system in the host and facilitate in vivo human hematology and immunology research. Engraftment of human hematopoietic stem cell (HSC)/(HPC) into these host mice provides long-term multilineage hematopoiesis and generation of human immune responses against a variety of antigens including HIV.
Development of such mice has been mainly based on the recombination activating genes 1 and 2 (Rag1 and Rag2) deficient or severe combined immune deficiency (scid) mice, and the immunodeficiency had been considered responsible for the engraftment of human hematopoietic tissues. While some scid mice will spontaneously develop partial immune reactivity, display “leaky” phenotype, Rag1 or Rag2 deficient mice show a “nonleaky” phenotype. However, xenoengraftment of human hematopoietic tissue into the Rag1- or Rag2-based mice are not superior to scid-based mice. Furthermore, wild-type HSCs can significantly engraft into unconditioned scid mice, compared to Rag1 −/− mice, suggesting that immunodeficiency itself may not be the primary characteristic permitting engraftment in scid mice. We proposed that a defect in bone marrow (BM) hematopoietic niche occupancy of scid HSCs contributes to the conduciveness of engraftment by exogenous HSCs, including human HSCs.
In this chapter, we discuss the mechanism by which scid mice are more conductive to exogenous HSCs. We characterize the intrinsic properties of HSCs in scid mice and compare those with Rag1 −/− HSCs.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Manz MG. Human-hemato-lymphoid-system mice: opportunities and challenges. Immunity. 2007;26(5):537–41.
Wilson A, Laurenti E, Trumpp A. Balancing dormant and self-renewing hematopoietic stem cells. Curr Opin Genet Dev. 2009;19(5):461–8.
Orford KW, Scadden DT. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet. 2008;9(2):115–28.
Pietras EM, Warr MR, Passegue E. Cell cycle regulation in hematopoietic stem cells. J Cell Biol. 2011;195(5):709–20.
Rossi L, Lin KK, Boles NC, Yang L, King KY, Jeong M, et al. Less is more: unveiling the functional core of hematopoietic stem cells through knockout mice. Cell Stem Cell. 2012;11(3):302–17.
Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441(7092):475–82.
Yilmaz OH, Morrison SJ. The PI-3kinase pathway in hematopoietic stem cells and leukemia-initiating cells: a mechanistic difference between normal and cancer stem cells. Blood Cells Mol Dis. 2008;41(1):73–6.
Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, et al. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell. 2007;1(1):101–12.
Yalcin S, Zhang X, Luciano JP, Mungamuri SK, Marinkovic D, Vercherat C, et al. Foxo3 is essential for the regulation of ataxia telangiectasia mutated and oxidative stress-mediated homeostasis of hematopoietic stem cells. J Biol Chem. 2008;283(37):25692–705.
Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell. 2007;128(2):325–39.
Papayannopoulou T, Scadden DT. Stem-cell ecology and stem cells in motion. Blood. 2008;111(8):3923–30.
Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.
Ema H, Suda T. Two anatomically distinct niches regulate stem cell activity. Blood. 2012;120(11):2174–81.
Lo Celso C, Scadden DT. The haematopoietic stem cell niche at a glance. J Cell Sci. 2011;124(Pt 21):3529–35.
Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.
Broxmeyer HE. Chemokines in hematopoiesis. Curr Opin Hematol. 2008;15(1):49–58.
Lapidot T, Dar A, Kollet O. How do stem cells find their way home? Blood. 2005;106(6):1901–10.
Nie Y, Han YC, Zou YR. CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med. 2008;205(4):777–83.
Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–88.
Thoren LA, Liuba K, Bryder D, Nygren JM, Jensen CT, Qian H, et al. Kit regulates maintenance of quiescent hematopoietic stem cells. J Immunol. 2008;180(4):2045–53.
Geissler EN, Russell ES. Analysis of the hematopoietic effects of new dominant spotting (W) mutations of the mouse. I. Influence upon hematopoietic stem cells. Exp Hematol. 1983;11(6):452–60.
Sharma Y, Astle CM, Harrison DE. Heterozygous kit mutants with little or no apparent anemia exhibit large defects in overall hematopoietic stem cell function. Exp Hematol. 2007;35(2):214–20.
Bhattacharya D, Rossi DJ, Bryder D, Weissman IL. Purified hematopoietic stem cell engraftment of rare niches corrects severe lymphoid deficiencies without host conditioning. J Exp Med. 2006;203(1):73–85.
Czechowicz A, Kraft D, Weissman IL, Bhattacharya D. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science. 2007;318(5854):1296–9.
Xue X, Pech NK, Shelley WC, Srour EF, Yoder MC, Dinauer MC. Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice. Blood. 2010;116(24):5419–22.
Migliaccio AR, Carta C, Migliaccio G. In vivo expansion of purified hematopoietic stem cells transplanted in nonablated W/Wv mice. Exp Hematol. 1999;27(11):1655–66.
Fleischman RA. From white spots to stem cells: the role of the Kit receptor in mammalian development. Trends Genet. 1993;9(8):285–90.
Russell ES. Hereditary anemias of the mouse: a review for geneticists. Adv Genet. 1979;20:357–459.
Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457(7225):92–6.
Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D, et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457(7225):97–101.
Qing Y, Lin Y, Gerson SL. An intrinsic BM hematopoietic niche occupancy defect of HSC in scid mice facilitates exogenous HSC engraftment. Blood. 2012;119(7):1768–71.
Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010;79:181–211.
Antonchuk J, Hyland CD, Hilton DJ, Alexander WS. Synergistic effects on erythropoiesis, thrombopoiesis, and stem cell competitiveness in mice deficient in thrombopoietin and steel factor receptors. Blood. 2004;104(5):1306–13.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Qing, Y., Gerson, S. (2014). BM Hematopoietic Niche Occupancy Defect of HSC in Scid Mice. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_7
Download citation
DOI: https://doi.org/10.1007/978-1-4939-1655-9_7
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4939-1654-2
Online ISBN: 978-1-4939-1655-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)