Regulation of Hematopoietic Stem Cells in the Osteoblastic Niche

  • Fumio Aria
  • Toshio Suda
Part of the Advances in Experimental Medicine and Biology book series (volume 602)

Tissue stem cells are characterized by their abilities to self-renew and to produce numerous differentiated daughter cells. These two special properties enable stem cells to play a central role in maintaining tissues. Many adult tissue stem cells, including hematopoietic system, skin epidermis, gastrointestinal epithelium, brain, and lung were identified (Fuchs, Tumbar, and Guasch 2004; Moore and Lemischka 2006). The activity of tissue stem cells is crucial for supplying the mature cells in normal tissue turnover. It now clear that the stem cell niche regulates the stem cell-specific properties, including self-renewal activity, multi-potentiality, and relative quiescence (Suda, Arai, and Hirao 2005; Adams and Scadden 2006; Wilson and Trumpp 2006). Interaction of stem cells with stem cell niches is critical for maintaining the stem cell properties, including self-renewal capacity and the ability of differentiation into single or multiple lineages.

Hematopoietic stem cells (HSCs) are responsible for blood cell production throughout the lifetime of individual. BM HSCs are best-characterized stem cells. A small subset of HSCs is isolated by cell surface markers (Spangrude, Heimfeld, and Weissman 1988; Osawa, Hanada, Hamada, et al. 1996). These HSCs differentiate into myeloid cells, B cells, and T cells in the presence of various cytokines (Akashi, Traver, Miyamoto, and Weissman 2000). It has been reported that single purified HSC is able to reconstitute lethally irradiated mice (Osawa, Hanada, Hamada, et al.; Matsuzaki, Kinjo, Mulligan, et al. 2004). In contrast to the identification of HSCs, the localization of HSCs in situ and structure of HSC niche had not been solved. Recently, long-term bone marrow (BM) repopulating (LTR) HSCs have been found in BM trabecular bone surface, and it was clarified that an osteoblastic (OB) cell is a critical component for sustaining HSCs (Calvi, Adams, Weibrecht, et al. 2003; Zhang, Niu, Ye, et al. 2003). Long-term label retaining cell (LRC) study showed that 89 % of CD45+Lin- LRCs attached to the endosteal surface (Zhang, Niu, Ye, et al. 2003). It suggests that quiescent/slow-dividing HSCs exclusively located in the osteoblastic niche. HSCs keep a balance between quiescence and cell division/proliferation in the osteoblastic niche (Arai, Hirao, Ohmura, et al. 2004). The specific properties of HSC are controlled dynamically by the signalings of receptor/ligand and cell adhesion molecules produced by osteoblastic niche cells (Suda, Arai, and Hirao 2005; Wilson and Trumpp 2006).

We described here the characterization of HSC and their niche, and the environmental regulation of HSCs in the niche.


Ataxia Telangiectasia Mutate Stem Cell Niche Adult Bone Marrow Tie2 Receptor Tissue Stem Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Adams, G.B., and D.T. Scadden. 2006. The hematopoietic stem cell in its place. Nat Immunol 7(4): 333–337.CrossRefPubMedGoogle Scholar
  2. 2.
    Akashi, K., D. Traver, T. Miyamoto, and I.L. Weissman. 2000. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404(6774): 193–197.CrossRefPubMedGoogle Scholar
  3. 3.
    Allsopp, R.C., G.B. Morin, R. DePinho, C.B. Harley, and I.L. Weissman. 2003. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102(2): 517–520.CrossRefPubMedGoogle Scholar
  4. 4.
    Arai, F., O. Ohneda, T. Miyamoto, X.Q. Zhang, and T. Suda. 2002. Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation. J Exp Med 195(12): 1549–1563.CrossRefPubMedGoogle Scholar
  5. 5.
    Arai, F., A. Hirao, M. Ohmura, H. Sato, S. Matsuoka, K. Takubo, K. Ito, G.Y. Koh, and T. Suda. 2004. Tie2/Angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118(2): 149–161.CrossRefPubMedGoogle Scholar
  6. 6.
    Blanpain, C., W.E. Lowry, A. Geoghegan, L. Polak, and E. Fuchs. 2004. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118(5): 635–648.CrossRefPubMedGoogle Scholar
  7. 7.
    Calvi, L.M., G.B. Adams, K.W. Weibrecht, J.M. Weber, D.P. Olson, M.C. Knight, R.P. Martin, E. Schipani, P. Divieti, F.R. Bringhurst, L.A. Milner, H.M. Kronenberg, and D.T. Scadden. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425(6960): 841–846.CrossRefPubMedGoogle Scholar
  8. 8.
    Cheng, T., N. Rodrigues, H. Shen, Y. Yang, D. Dombkowski, M. Sykes, and D.T. Scadden. 2000. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science 287(5459): 1804–1808.CrossRefPubMedGoogle Scholar
  9. 9.
    Davis, S., T.H. Aldrich, P.F. Jones, A. Acheson, D.L. Compton, V. Jain, T.E. Ryan, J. Bruno, C. Radziejewski, P.C. Maisonpierre, and G.D. Yancopoulos. 1996. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87(7): 1161–1169.CrossRefPubMedGoogle Scholar
  10. 10.
    Dumont, D.J., T.P. Yamaguchi, R.A. Conlon, J. Rossant, and M.L. Breitman. 1992. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene 7(8): 1471–1480.PubMedGoogle Scholar
  11. 11.
    Dumont, D.J., G. Gradwohl, G.H. Fong, M.C. Puri, M. Gertsenstein, A. Auerbach, and M.L. Breitman. 1994. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8(16): 1897–1909.CrossRefPubMedGoogle Scholar
  12. 12.
    Ema, H., H. Takano, K. Sudo, and H. Nakauchi. 2000. In vitro self-renewal division of hematopoietic stem cells. J Exp Med 192(9): 1281–1288.CrossRefPubMedGoogle Scholar
  13. 13.
    Fuchs, E., T. Tumbar, and G. Guasch. 2004. Socializing with the neighbors: stem cells and their niche. Cell 116(6): 769–778.CrossRefPubMedGoogle Scholar
  14. 14.
    Goodell, M.A., K. Brose, G. Paradis, A.S. Conner, and R.C. Mulligan. 1996. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 183(4): 1797–1806.CrossRefPubMedGoogle Scholar
  15. 15.
    Goodell, M.A., M. Rosenzweig, H. Kim, D.F. Marks, M. DeMaria, G. Paradis, S.A. Grupp, C.A. Sieff, R.C. Mulligan, and R.P. Johnson. 1997. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 3(12): 1337–1345.CrossRefPubMedGoogle Scholar
  16. 16.
    Hüttmann, A., S.L. Liu, A.W. Boyd, and C.L. Li. 2001. Functional heterogeneity within rhodamine123(lo) Hoechst33342(lo/sp) primitive hemopoietic stem cells revealed by pyronin Y. Exp Hematol 29(9): 1109–1116.CrossRefPubMedGoogle Scholar
  17. 17.
    Ito, K., A. Hirao, F. Arai, S. Matsuoka, K. Takubo, I. Hamaguchi, K. Nomiyama, K. Hosokawa, K. Sakurada, N. Nakagata, Y. Ikeda, T.W. Mak, and T. Suda. 2004. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431(7011): 997–1002.CrossRefPubMedGoogle Scholar
  18. 18.
    Ito, K., A. Hirao, F. Arai, K. Takubo, S. Matsuoka, K. Miyamoto, M. Ohmura, K. Naka, K. Hosokawa, Y. Ikeda, and T. Suda. 2006. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 12(4): 446–451.CrossRefPubMedGoogle Scholar
  19. 19.
    Iwama, A., I. Hamaguchi, M. Hashiyama, Y. Murayama, K. Yasunaga, and T. Suda. 1993. Molecular cloning and characterization of mouse TIE and TEK receptor tyrosine kinase genes and their expression in hematopoietic stem cells. Biochem Biophys Res Commun 195(1): 301–309.CrossRefPubMedGoogle Scholar
  20. 20.
    Kapuscinski, J., and Z. Darzynkiewicz. 1987. Interactions of pyronin Y(G) with nucleic acids. Cytometry 8(2): 129–137.CrossRefPubMedGoogle Scholar
  21. 21.
    Lin, H. 2002. The stem-cell niche theory: lessons from flies. Nat Rev Genet 3(12): 931–940.CrossRefPubMedGoogle Scholar
  22. 22.
    Matsuzaki, Y., K. Kinjo, R.C. Mulligan, and H. Okano. 2004. Unexpectedly efficient homing capacity of purified murine hematopoietic stem cells. Immunity 20(1): 87–93.CrossRefPubMedGoogle Scholar
  23. 23.
    Moore, K.A., and I.R. Lemischka. 2006. Stem cells and their niches. Science 311(5769): 1880–1885.CrossRefPubMedGoogle Scholar
  24. 24.
    Murphy, M.J., A. Wilson, and A. Trumpp. 2005. More than just proliferation: Myc function in stem cells. Trends Cell Biol 15(3): 128–137.CrossRefPubMedGoogle Scholar
  25. 25.
    Nilsson, S.K., H.M. Johnston, and J.A. Coverdale. 2001. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97(8): 2293–2299.CrossRefPubMedGoogle Scholar
  26. 26.
    Osawa, M., K. Hanada, H. Hamada, and H. Nakauchi. 1996. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273(5272): 242–245.CrossRefPubMedGoogle Scholar
  27. 27.
    Partanen, J., E. Armstrong, T.P. Makela, J. Korhonen, M. Sandberg, R. Renkonen, S. Knuutila, K. Huebner, and K. Alitalo. 1992. A novel endothelial cell surface receptor tyrosine kinase with extracellular epidermal growth factor homology domains. Mol Cell Biol 12(4): 1698–1707.PubMedGoogle Scholar
  28. 28.
    Partanen, J., M.C. Puri, L. Schwartz, K.D. Fischer, A. Bernstein, and J. Rossant. 1996. Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development. Development 122(10): 3013–3021.PubMedGoogle Scholar
  29. 29.
    Puri, M.C., and A. Bernstein. 2003. Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci USA 100(22): 12753–12758.CrossRefPubMedGoogle Scholar
  30. 30.
    Rodewald, H.R., and T.N. Sato. 1996. Tie1 a receptor tyrosine kinase essential for vascular endothelial cell integrity, is not critical for the development of hematopoietic cells. Oncogene 12(2): 397–404.PubMedGoogle Scholar
  31. 31.
    Sato, T.N., Y. Tozawa, U. Deutsch, K. Wolburg-Buchholz, Y. Fujiwara, M. Gendron-Maguire, T. Gridley, H. Wolburg, W. Risau, and Y. Qin. 1995. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature 376(6535): 70–74.CrossRefPubMedGoogle Scholar
  32. 32.
    Sato, A., A. Iwama, N. Takakura, H. Nishio, G.D. Yancopoulos, and T. Suda. 1998. Characterization of TEK receptor tyrosine kinase and its ligands, angiopoietins, in human hematopoietic progenitor cells. Int Immunol 10(8): 1217–1227.CrossRefPubMedGoogle Scholar
  33. 33.
    Schofield, R. 1978. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4(1–2): 7–25.PubMedGoogle Scholar
  34. 34.
    Spangrude, G.J., S. Heimfeld, and I.L. Weissman. 1988. Purification and characterization of mouse hematopoietic stem cells. Science 241(4861): 58–62.CrossRefPubMedGoogle Scholar
  35. 35.
    Suda, T., F. Arai, and A. Hirao. 2005. Hematopoietic stem cells and their niche. Trends Immunol 26(8): 426–433.CrossRefPubMedGoogle Scholar
  36. 36.
    Suri, C., P.F. Jones, S. Patan, S. Bartunkova, P.C. Maisonpierre, S. Davis, T.N. Sato, and G.D. Yancopoulos. 1996. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87(7): 1171–1180.CrossRefPubMedGoogle Scholar
  37. 37.
    Takakura, N., X.L. Huang, T. Naruse, I. Hamaguchi, D.J. Dumont, G.D. Yancopoulos, and T. Suda. 1998. Critical role of the TIE2 endothelial cell receptor in the development of definitive hematopoiesis. Immunity 9(5): 677–686.CrossRefPubMedGoogle Scholar
  38. 38.
    Taichman, R.S., and S.G. Emerson. 1998. The role of osteoblasts in the hematopoietic microenvironment. Stem Cells 16(1): 7–15.CrossRefPubMedGoogle Scholar
  39. 39.
    Tumbar, T., G. Guasch, V. Greco, C. Blanpain, W.E. Lowry, M. Rendl, and E. Fuchs. 2004. Defining the epithelial stem cell niche in skin. Science 303(5656): 359–363.CrossRefPubMedGoogle Scholar
  40. 40.
    Vikkula, M., L.M. Boon, K.L. Carraway, 3rd, J.T. Calvert, A.J. Diamonti, B. Goumnerov, K.A. Pasyk, D.A. Marchuk, M.L. Warman, L.C. Cantley, J.B. Mulliken, and B.R. Olsen. 1996. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87(7): 1181–1190.CrossRefPubMedGoogle Scholar
  41. 41.
    Visnjic, D., Z. Kalajzic, D.W. Rowe, V. Katavic, J. Lorenzo, and H.L. Aguila. 2004. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103(9): 3258–3264.CrossRefPubMedGoogle Scholar
  42. 42.
    Wilson, A., and A. Trumpp. 2006. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 6(2): 93–106.CrossRefPubMedGoogle Scholar
  43. 43.
    Wilson, A., M.J. Murphy, T. Oskarsson, K. Kaloulis, M.D. Bettess, G.M. Oser, A.C. Pasche, C. Knabenhans, H.R. Macdonald, and A. Trumpp. 2004. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev 18(22): 2747–2763.CrossRefPubMedGoogle Scholar
  44. 44.
    Wu, S., C. Cetinkaya, M.J. Munoz-Alonso, N. von der Lehr, F. Bahram, V. Beuger, M. Eilers, J. Leon, and L.G. Larsson. 2003. Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 22(3): 351–360.CrossRefPubMedGoogle Scholar
  45. 45.
    Yamashita, Y.M., D.L. Jones, and M.T. Fuller. 2003. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 301(5639): 1547–1550.CrossRefPubMedGoogle Scholar
  46. 46.
    Zhang, J., C. Niu, L. Ye, H. Huang, X. He, W.G. Tong, J. Ross, J. Haug, T. Johnson, J.Q. Feng, S. Harris, L.M. Wiedemann, Y. Mishina, and L. Li. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425(6960): 836–841.CrossRefPubMedGoogle Scholar
  47. 47.
    Zhou, S., J.D. Schuetz, K.D. Bunting, A.M. Colapietro, J. Sampath, J.J. Morris, I. Lagutina, G.C. Grosveld, M. Osawa, H. Nakauchi, and B.P. Sorrentino. 2001. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med 7(9): 1028–1034.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Fumio Aria
    • 1
  • Toshio Suda
    • 1
  1. 1.Department of Cell DifferentiationKeio UniversityShinjuku-kuJapan

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