Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Microenvironmental niches in the bone marrow required for B-cell development

Nature Reviews Immunology volume 6, pages 107–116 (2006)Cite this article

Key Points

  • The bone marrow occupies the medullary cavities of bones throughout the skeleton, and B-cell development occurs within a complex microenvironment in the bone marrow.

  • B-cell precursors are divided into four populations termed fraction A (pre-pro-B cells), fraction B (pro-B cells), fraction C (pro-B cells) and fraction D (pre-B cells), and the differentiation pathway is thought to proceed from fractions A to B to C to D.

  • Cells in the pre-pro-B-cell fraction have the potential to give rise to the T-cell, natural killer-cell and dendritic-cell lineages as well as the B-cell lineage. Intermediate precursor cells, between haematopoietic stem cells (HSCs) and the earliest B-cell precursors, including lymphoid-primed multipotential progenitors, which lack erythro-megakaryocytic differentiation potential but retain myeloid-cell, B-cell and T-cell differentiation potential, and common lymphoid progenitors (CLPs), which can generate B cells and T cells but not myeloid-lineage cells, have been identified.

  • The development of B-cell precursors requires environmental factors that are probably secreted in bone-marrow niches. CXC-chemokine ligand 12 (CXCL12) is essential for the generation of pre-pro-B and pro-B cells, and for the homing of plasma cells to the bone marrow. FLT3 (fms-related tyrosine kinase 3) ligand is essential for the generation of CLPs and pre-pro-B cells. Interleukin-7 (IL-7) is essential for generation of pro-B and pre-B cells but not CLPs or pre-pro-B cells. However, it is required for B-cell differentiation potential of CLPs and pre-pro-B cells. Stem-cell factor plays an essential role in B-cell development from pro-B cells in adults. RANK (receptor activator of nuclear factor-κB) ligand is involved in the generation of pre-B cells and immature B cells.

  • All known requisite factors for B-cell development are thought to be produced by the cells that are located in the bone marrow. Primary osteoblasts produce factors that support early B-cell lymphopoiesis in in vitro culture. In addition, there is a small population of reticular cells that express high levels of CXCL12 (CXCL12hi reticular cells), and a distinct subset of fibroblast-like cells that bind IL-7-specific antibody and are located away from the osteoblasts and CXCL12hi reticular cells. CXCL12hi reticular cells and IL-7-expressing cells might be cellular niches for B-cell development.

  • Multipotential haematopoietic cells are located near the osteoblasts, endothelial cells or CXCL12hi reticular cells. Pre-pro-B cells are in contact with CXCL12hi reticular cells, whereas pro-B cells move away and instead adjoin the IL-7-expressing cells. Subsequently, pre-B cells leave IL-7-expressing cells. End-stage B cells (plasma cells) again associate with CXCL12hi reticular cells.

  • It will be important to know what cell populations are the main intermediates between HSCs and early B-cell precursors and to identify their cellular niches. Studies of cellular niches would provide insight into the nature of spatiotemporal regulation of B-cell development in vivo.

Abstract

B-cell development is known to occur in a complex bone-marrow microenvironment but its functional organization remains unclear. It is thought that bone-marrow stromal cells create distinct microenvironments, known as niches, that provide support for haematopoiesis and B-cell development. Although it has been more than 20 years since the development of a culture system that allows the growth of B-cell progenitors on bone-marrow-derived stromal cells in vitro, it is only recently that studies have provided a novel basis for understanding the nature of the niches for B-cell development in vivo. This article summarizes the recent advances in research on the earliest B-cell precursors, their requisite environmental factors and the cellular niches that supply these factors and maintain B cells during their development.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Morphological construction of bone marrow.
Figure 2: A pathway for early B-cell differentiation and environmental factor requirement in the bone marrow.
Figure 3: Candidates for cellular niches for B-cell development and a model of the movement of B cells and their precursors in the bone marrow.

Similar content being viewed by others

References

  1. Lichtman, M. A. The ultrastructure of the hemopoietic environment of the marrow: a review. Exp. Hematol. 9, 391–410 (1981).

    CAS  PubMed  Google Scholar 

  2. Lord., B. I., Testa, N. G. & Hendry, J. H. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46, 65–72 (1975).

    CAS  PubMed  Google Scholar 

  3. Hermans, M. H., Hartsuiker, H. & Opstelten, D. An in situ study of B-lymphocytopoiesis in rat bone marrow. Topographical arrangement of terminal deoxynucleotidyl transferase-positive cells and pre-B cells. J. Immunol. 142, 67–73 (1989).

    CAS  PubMed  Google Scholar 

  4. Jacobsen, K. & Osmond, D. G. Microenvironmental organization and stromal cell associations of B lymphocyte precursor cells in mouse bone marrow. Eur. J. Immunol. 20, 2395–2404 (1990).

    CAS  PubMed  Google Scholar 

  5. Gong, J, K. Endosteal marrow: a rich source of hematopoietic stem cells. Science 199, 1443–1445 (1978).

    CAS  PubMed  Google Scholar 

  6. Nilsson, S. K., Johnston H. M. & Coverdale, J. A. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97, 2293–2299 (2001).

    CAS  PubMed  Google Scholar 

  7. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

    CAS  PubMed  Google Scholar 

  8. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).

    CAS  PubMed  Google Scholar 

  9. Hirose, J. et al. A developing picture of lymphopoiesis in bone marrow. Immunol. Rev. 189, 28–40 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B. I. & Nagasawa, T. Cellular niches controlling B lymphocyte behaviour within bone marrow during development. Immunity 20, 707–718 (2004). The first identification of specific cellular niches for B-cell development: a small population of reticular cells that express a requisite factor (CXCL12) for the earliest and end stages in B-cell development.

    CAS  PubMed  Google Scholar 

  11. Manz, R. A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    CAS  PubMed  Google Scholar 

  12. Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).

    CAS  PubMed  Google Scholar 

  13. Li, Y. S., Wasserman, R., Hayakawa, K. & Hardy, R. R. Identification of the earliest B lineage stage in mouse bone marrow. Immunity 5, 527–535 (1996).

    CAS  PubMed  Google Scholar 

  14. Allman, D., Li, J. & Hardy, R. R. Commitment to the B lymphoid lineage occurs before DH–JH recombination. J. Exp. Med. 189, 735–740 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Loffert, D. et al. Early B-cell development in the mouse: insights from mutations introduced by gene targeting. Immunol. Rev. 137, 135–153 (1994).

    CAS  PubMed  Google Scholar 

  16. Martin, C. H. et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nature Immunol. 4, 866–873 (2003).

    CAS  Google Scholar 

  17. Rolink, A. et al. A subpopulation of B220+ cells in murine bone marrow does not express CD19 and contains natural killer cell progenitors. J. Exp. Med. 183, 187–194 (1996).

    CAS  PubMed  Google Scholar 

  18. Diao, J., Winter, E., Chen, W., Cantin, C. & Cattral, M. S. Characterization of distinct conventional and plasmacytoid dendritic cell-committed precursors in murine bone marrow. J. Immunol. 173, 1826–1833 (2004).

    CAS  PubMed  Google Scholar 

  19. Pelayo, R. et al. Derivation of 2 categories of plasmacytoid dendritic cells in murine bone marrow. Blood 105, 4407–4415 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Nutt, S. L., Heavey, B., Rolink, A. G. & Busslinger, M. Commitment to the B-lymphoid lineage depends on the transcription factor Pax5. Nature 401, 556–562 (1999).

    CAS  PubMed  Google Scholar 

  21. Rolink, A. G., Nutt, S. L., Melchers, F. & Busslinger, M. Long-term in vivo reconstitution of T-cell development by Pax5-deficient B-cell. Nature 401, 603–606 (1999).

    CAS  PubMed  Google Scholar 

  22. Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).

    CAS  PubMed  Google Scholar 

  23. Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    CAS  PubMed  Google Scholar 

  24. Izon, D. et al. A common pathway for dendritic cell and early B cell development. J. Immunol. 167, 1387–1392 (2001).

    CAS  PubMed  Google Scholar 

  25. Montecino-Rodriguez, E., Leathers, H. & Dorshkind, K. Bipotential B-macrophage progenitors are present in adult bone marrow. Nature Immunol. 2, 83–88 (2001).

    CAS  Google Scholar 

  26. Tudor, K. S., Payne, K. J., Yamashita, Y. & Kincade, P. W. Functional assessment of precursors from murine bone marrow suggests a sequence of early B lineage differentiation events. Immunity 12, 335–345 (2000).

    CAS  PubMed  Google Scholar 

  27. Mojica, M. P. et al. Phenotypic distinction and functional characterization of pro-B cells in adult mouse bone marrow. J. Immunol. 166, 3042–3051 (2001).

    CAS  PubMed  Google Scholar 

  28. Allman, D. et al. Thymopoiesis independent of common lymphoid progenitors. Nature Immunol. 4, 168–174 (2003).

    CAS  Google Scholar 

  29. Whitlock, C. A. & Witte, O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc. Natl Acad. Sci. USA 79, 3608–3612 (1982). This paper describes the first development of a culture system that allows the growth of B-cell progenitors on bone-marrow-derived stromal cells in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hunt, P. et al. A single bone marrow-derived stromal cell type supports the in vitro growth of early lymphoid and myeloid cells. Cell 48, 997–1007 (1987).

    CAS  PubMed  Google Scholar 

  31. Whitlock, C. A., Tidmarsh, G. F., Muller-Sieburg, C. & Weissman, I. L. Bone marrow stromal cell lines with lymphopoietic activity express high levels of a pre-B neoplasia-associated molecule. Cell 48, 1009–1021 (1987).

    CAS  PubMed  Google Scholar 

  32. Collins, L. S. & Dorshkind, K. A stromal cell line from myeloid long-term bone marrow cultures can support myelopoiesis and B lymphopoiesis. J. Immunol. 138, 1082–1087 (1987).

    CAS  PubMed  Google Scholar 

  33. Egawa, T. et al. The earliest stages of B cell development require a chemokine stromal cell-derived factor/pre-B cell growth-stimulating factor. Immunity 15, 323–334 (2001). The first paper to describe a cytokine that is essential for the earliest identifiable B-cell precursors.

    CAS  PubMed  Google Scholar 

  34. Baggiolini, M., Dewald, B. & Moser, B. Human chemokines: an update. Annu. Rev. Immunol. 15, 675–705 (1997).

    CAS  PubMed  Google Scholar 

  35. Tashiro, K. et al. Signal sequence trap: a cloning strategy for secreted proteins and type I membrane proteins. Science 261, 600–603 (1993).

    CAS  PubMed  Google Scholar 

  36. Nagasawa, T., Kikutani, H. & Kishimoto, T. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc. Natl Acad. Sci. USA 91, 2305–2309 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996). This paper shows for the first time that a chemokine (CXCL12) is essential for haematopoiesis including B-cell lymphopoiesis and colonization of bone marrow by haematopoietic cells during ontogeny.

    CAS  PubMed  Google Scholar 

  38. Bleul, C. C. et al. The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382, 829–833 (1996).

    CAS  PubMed  Google Scholar 

  39. Oberlin, E. et al. The CXC chemokine SDF-1 is the ligand for LESTR/fusin and prevents infection by T-cell-line-adapted HIV-1. Nature 382, 833–835 (1996).

    CAS  PubMed  Google Scholar 

  40. Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998).

    CAS  PubMed  Google Scholar 

  41. Zou, Y. R., Kottmann, A. H., Kuroda, M., Taniuchi, I. & Littman, D. R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998).

    CAS  PubMed  Google Scholar 

  42. Ma, Q. et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc. Natl Acad. Sci. USA 95, 9448–9453 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Feng, Y., Broder, C. C., Kennedy, P. E. & Berger, E. A. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872–877 (1996).

    CAS  PubMed  Google Scholar 

  44. Ara, T. et al. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 19, 257–267 (2003).

    CAS  PubMed  Google Scholar 

  45. Ma, Q., Jones, D. & Springer, T. A. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10, 463–471 (1999).

    CAS  PubMed  Google Scholar 

  46. D'Apuzzo, M. et al. The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4. Eur. J. Immunol. 27, 1788–1793 (1997).

    CAS  PubMed  Google Scholar 

  47. Nie, Y. et al. The role of CXCR4 in maintaining peripheral B cell compartments and humoral immunity. J. Exp. Med. 200, 1145–1156 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Kawabata, K. et al. A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. Proc. Natl Acad. Sci. USA 96, 5663–5667 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ara, T. et al. A role of CXC chemokine ligand 12/stromal cell-derived factor-1/pre-B cell growth stimulating factor and its receptor CXCR4 in fetal and adult T cell development in vivo. J. Immunol. 170, 4649–4655 (2003).

    CAS  PubMed  Google Scholar 

  51. Lyman, S. D. et al. Molecular cloning of a ligand for the flt3/flk-2 tyrosine kinase receptor: a proliferative factor for primitive hematopoietic cells. Cell 75, 1157–1167 (1993).

    CAS  PubMed  Google Scholar 

  52. Hannum, C. et al. Ligand for FLT3/FLK2 receptor tyrosine kinase regulates growth of haematopoietic stem cells and is encoded by variant RNAs. Nature 368, 643–648 (1994).

    CAS  PubMed  Google Scholar 

  53. Matthews, W., Jordan, C. T., Wiegand, G. W., Pardoll, D. & Lemischka, I. R. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell 65, 1143–1152 (1991).

    CAS  PubMed  Google Scholar 

  54. Rosnet O., Marchetto, S., deLapeyriere, O. & Birnbaum, D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene 6, 1641–1650 (1991).

    CAS  PubMed  Google Scholar 

  55. Mackarehtschian, K. et al. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity 3, 147–161 (1995).

    CAS  PubMed  Google Scholar 

  56. Sitnicka, E. et al. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 17, 463–472 (2002).

    CAS  PubMed  Google Scholar 

  57. Sitnicka, E. et al. Complementary signalling through flt3 and interleukin-7 receptor α is indispensable for fetal and adult B cell genesis. J. Exp. Med. 198, 1495–1506 (2003). This paper shows that FLT3L is essential for development of pre-pro-B cells and that complementary signalling through the cytokine receptors FLT3 and IL-7Rα is essential for fetal and adult B-cell development.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Hunte B. E., Hudak, S., Campbell, D., Xu, Y. M. & Rennick, D. flk2/flt3 ligand is a potent cofactor for the growth of primitive B cell progenitors. J. Immunol. 156, 489–496 (1995).

    Google Scholar 

  59. Ikuta, K. & Weissman, I. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc. Natl Acad. Sci. USA 89, 1502–1506 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Sambandam, A. et al. Notch signalling controls the generation and differentiation of early T lineage progenitors. Nature Immunol. 6, 663–670 (2005).

    CAS  Google Scholar 

  61. McKenna, H. et al. Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. Blood 95, 3489–3497 (2000).

    CAS  PubMed  Google Scholar 

  62. Brawand, P. et al. Murine plasmacytoid pre-dendritic cells generated from Flt3 ligand-supplemented bone marrow cultures are immature APCs. J. Immunol. 169, 6711–6719 (2002).

    CAS  PubMed  Google Scholar 

  63. Namen, A. E. et al. Stimulation of B-cell progenitors by cloned murine interleukin-7. Nature 333, 571–573 (1988). The first identification of an environmental factor that shows marked activity in inducing proliferation of B-cell precursors.

    CAS  PubMed  Google Scholar 

  64. Peschon, J. J. et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    CAS  PubMed  Google Scholar 

  65. von Freeden-Jeffry, U. et al. Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine. J. Exp. Med. 181, 1519–1526 (1995).

    CAS  PubMed  Google Scholar 

  66. DiSanto, J. P., Muller, W., Guy-Grand, D., Fischer, A. & Rajewsky, K. Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor γ chain. Proc. Natl Acad. Sci. USA 92, 377–381 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Cao, X. et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor γ-chain. Immunity 2, 223–238 (1995).

    CAS  PubMed  Google Scholar 

  68. Thomis, D. C., Gurniak, C. B., Tivol, E., Sharpe, A. H. & Berg, L. J. Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270, 794–800 (1995).

    CAS  PubMed  Google Scholar 

  69. Nosaka, T. et al. Defective lymphoid development in mice lacking Jak3. Science 270, 800–802 (1995)

    CAS  PubMed  Google Scholar 

  70. Park, S. Y. et al. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3, 771–782 (1995).

    CAS  PubMed  Google Scholar 

  71. Moore, T. A., von Freeden-Jeffry, U., Murray, R. & Zlotnik, A. Inhibition of δ T cell development and early thymocyte maturation in IL-7−/− mice. J. Immunol. 157, 2366–2373 (1996).

    CAS  PubMed  Google Scholar 

  72. Rodewald, H. R., Brocker, T. & Haller, C. Developmental dissociation of thymic dendritic cell and thymocyte lineages revealed in growth factor receptor mutant mice. Proc. Natl Acad. Sci. USA 96, 15068–15073 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Dias, S., Silva, H. Jr, Cumano, A. & Vieira, P. Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors. J. Exp. Med. 201, 971–979 (2005). This paper describes the analysis of IL-7-deficient mice and indicates that, in contrast to previous findings, IL-7 has an important role as early as the CLP stage during B-cell development.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Opferman, J. T. et al. Development and maintenance of B and T lymphocytes requires antiapoptotic MCL-1. Nature 426, 671–676 (2003).

    CAS  PubMed  Google Scholar 

  75. Corcoran, A. E., Riddell, A., Krooshoop, D. & Venkitaraman, A. R. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391, 904–907 (1998).

    CAS  PubMed  Google Scholar 

  76. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–267 (1995).

    CAS  PubMed  Google Scholar 

  77. Kikuchi, K., Lai, A. Y., Hsu, C. L. & Kondo, M. IL-7 receptor signalling is necessary for stage transition in adult B cell development through upregulation of EBF. J. Exp. Med. 201, 1197–1203 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Vosshenrich, C. A., Cumano, A., Muller, W., Di Santo, J. P. & Vieira, P. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nature Immunol. 4, 773–739 (2003).

    CAS  Google Scholar 

  79. Al-Shami, A. et al. A role for thymic stromal lymphopoietin in CD4+ T cell development. J. Exp. Med. 200, 159–168 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Carpino, N. et al. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol. Cell. Biol. 24, 2584–2592 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Martin, F. H. et al. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell 63, 203–211 (1990).

    CAS  PubMed  Google Scholar 

  82. Huang, E. et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 63, 225–233 (1990).

    CAS  PubMed  Google Scholar 

  83. Anderson, D. M. et al. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 63, 235–243 (1990).

    CAS  PubMed  Google Scholar 

  84. Russell, E. S. Hereditary anemias of the mouse: a review for geneticists. Adv. Genet. 20, 357–459 (1979).

    CAS  PubMed  Google Scholar 

  85. Takeda, S., Shimizu, T. & Rodewald, H. R. Interactions between c-kit and stem cell factor are not required for B-cell development in vivo. Blood 89, 518–525 (1997).

    CAS  PubMed  Google Scholar 

  86. McNiece, I. K., Langley, K. E. & Zsebo, K. M. The role of recombinant stem cell factor in early B cell development. Synergistic interaction with IL-7. J. Immunol. 146, 3785–3790 (1991).

    CAS  PubMed  Google Scholar 

  87. Waskow, C., Paul, S., Haller, C., Gassmann, M. & Rodewald, H. R. Viable c-KitW/W mutants reveal pivotal role for c-kit in the maintenance of lymphopoiesis. Immunity 17, 277–288 (2002). Using viable KIT-mutant mice (Vickid and Wepo mice), this paper shows the physiological roles of the SCF–KIT axis in adult haematopoiesis, including B-cell development.

    CAS  PubMed  Google Scholar 

  88. McCulloch, E. A., Siminovitch, L., Till, J. E., Russell, E. S. & Bernstein, S. E. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood 26, 399–410 (1965).

    CAS  PubMed  Google Scholar 

  89. Driessen, R. L., Johnston, H. M. & Nilsson, S. K. Membrane-bound stem cell factor is a key regulator in the initial lodgment of stem cells within the endosteal marrow region. Exp. Hematol. 31, 1284–1291 (2003).

    CAS  PubMed  Google Scholar 

  90. Yasuda, H. et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl Acad. Sci. USA 95, 3597–3602 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    CAS  PubMed  Google Scholar 

  92. Kong, Y. T. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).

    CAS  PubMed  Google Scholar 

  93. Anderson, D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390, 175–179 (1997).

    CAS  PubMed  Google Scholar 

  94. Dougall, W. C. et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Weiss, L. The hematopoietic microenvironment of the bone marrow: an ultrastructural study of the stroma in rats. Anat. Rec. 186, 161–184 (1976).

    CAS  PubMed  Google Scholar 

  96. Zipori, D. et al. Cultured mouse marrow stromal cell lines. II. Distinct subtypes differing in morphology, collagen types, myelopoietic factors, and leukemic cell growth modulating activities. J. Cell. Physiol. 122, 81–90 (1985).

    CAS  PubMed  Google Scholar 

  97. Sudo, T. et al. Interleukin 7 production and function in stromal cell-dependent B cell development. J. Exp. Med. 170, 333–338 (1989).

    CAS  PubMed  Google Scholar 

  98. Taichman, R. S., Reilly, M. J. & Emerson, S. G. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow Blood 87, 518–524 (1996). This report shows for the first time that primary osteoblasts could support haematopoietic progenitors in vitro.

    CAS  PubMed  Google Scholar 

  99. Taichman, R. S. Blood and bone: two tissues whose fates are intertwined to create the hematopoietic stem-cell niche. Blood 105, 2631–2639 (2005).

    CAS  PubMed  Google Scholar 

  100. Visnjic, D. et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103, 3258–3264 (2004). This report shows that differentiated osteoblasts are essential for haematopoiesis, including B-cell development in vivo using transgenic mice expressing herpesvirus thymidine kinase (TK) gene under the control of a 2.3-kilobase fragment of the rat collagen α1 type 1 osteoblast-specific promoter.

    CAS  PubMed  Google Scholar 

  101. Zhu, J. et al. Osteoblasts support early B lymphopoiesis as well as stem cell proliferation and myelopoiesis: Identification of the mammalian cellular analogue of the bursa of fabricius. Blood 104, 508 (2004).

    Google Scholar 

  102. Ponomaryov, T. et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J. Clin Invest. 106, 1331–1339 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Jacobsen, K., Kravitz, J., Kincade, P. W. & Osmond, D. G. Adhesion receptors on bone marrow stromal cells: in vivo expression of vascular cell adhesion molecule-1 by reticular cells and sinusoidal endothelium in normal and γ-irradiated mice. Blood 87, 73–82 (1996).

    CAS  PubMed  Google Scholar 

  104. Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and upregulating CXCR4. Nature Immunol. 3, 687–694 (2002).

    CAS  Google Scholar 

  105. Semerad, C. L. et al. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106, 3020–3027 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Funk, P. E., Stephan, R. P. & Witte, P. L. Vascular cell adhesion molecule 1-positive reticular cells express interleukin-7 and stem cell factor in the bone marrow. Blood 86, 2661–2671 (1995).

    CAS  PubMed  Google Scholar 

  107. Sudo, T. et al. Interleukin 7 production and function in stromal cell-dependent B cell development. J. Exp. Med. 170, 333–338 (1989).

    CAS  PubMed  Google Scholar 

  108. de Bruijn, M. et al. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity 16, 673–683 (2002).

    CAS  PubMed  Google Scholar 

  109. Sanderson, R. D., Lalor, P. & Bernfield, M. B lymphocytes express and lose syndecan at specific stages of differentiation. Cell Regul. 1, 27–35 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lalor, P. A., Nossal, G. J., Sanderson, R. D. & McHeyzer-Williams, M. G. Functional and molecular characterization of single, (4-hydroxy-3-nitrophenyl) acetyl (NP)-specific, IgG1+ B cells from antibody-secreting and memory B cell pathways in the C57BL/6 immune response to NP. Eur. J. Immunol. 22, 3001–3011 (1992).

    CAS  PubMed  Google Scholar 

  111. Fleming, H. E. & Paige, C. J. Pre-B cell receptor signalling mediates selective response to IL-7 at the pro-B to pre-B cell transition via an ERK/MAP kinase-dependent pathway. Immunity 15, 521–531 (2001).

    CAS  PubMed  Google Scholar 

  112. Rolink, A. G., Winkler, T., Melchers, F. & Andersson, J. Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J. Exp. Med. 191, 23–31 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kiel, M. J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    CAS  PubMed  Google Scholar 

  114. Avecilla, S. T. et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nature Med. 10, 64–71 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank K. Tokoyoda and T. Egawa for their contribution to the work cited, and M. Sato, H. Yoshida and S. Sakaguchi for their help in preparation of this paper and discussions. Our studies were funded by grants from the Ministry of Education, Science, Sports and Culture of Japan, and the Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Department of Medical Systems Control, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, 606-8507, Kyoto, Japan

    Takashi Nagasawa

Authors
  1. Takashi Nagasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The author declares no competing financial interests.

Related links

Related links

DATABASES

FURTHER INFORMATION

Takashi Nagasawa's laboratory

Glossary

Medullary cavities

In typical long bones, such as the femur or the humerus, the shaft consists of a thick-walled, hollow cylinder of compact bone with a large central-marrow cavity. This cavity is occupied by bone marrow and is called the medullary cavity.

Medullary vascular sinuses

Thin-walled vessels, the endothelium of which allows the passage of large numbers of blood cells. The arterioles in bone marrow continue into the endosteum as typical capillaries that are confluent with medullary vascular sinuses.

Stromal cell

A general term for a large adherent cell. Stromal cells in the bone marrow include reticular cells, endothelial cells and macrophages.

Endosteum

A thin layer of cells that have osteogenic properties and line the medullary cavity.

Ikaros

A haematopoietic-cell-specific member of a family of zinc-finger transcription factors. It is an integral component of a complex containing chromatin remodelling and modifying activities. Ikaros-deficient mice lack all B cells, natural killer cells and fetal T cells, and they have severely reduced numbers of T cells and dendritic cells after birth, indicating that Ikaros is essential for development of lymphoid-lineage cells.

Transfilter migration assay

An assay that allows the in vitro quantification of activities of soluble factors in inducing cell transmigration. It involves a chamber separated by a microporous polycarbonate or nitrocellulose membrane, with the lower compartment for the soluble factor and the upper compartment for the cells. After several hours, the cells harvested from the lower chamber are counted.

SI/SI mice

Mice homozygous for a spontaneous null mutation at the steel (SI) locus located on chromosome 10 die around the first week of life, with many defects including severe anaemia, lack of hair pigmentation, sterility and defective intestinal-pacemaker function. They have deficiencies in melanoblasts, primordial germ cells and haematopoietic cells, including multipotential progenitors, erythrocytes and mast cells.

W/W mice

Mice homozygous for a spontaneous null mutation at the dominant white spotting (W) locus located on chromosome 5 die around the first week of life, with the same symptoms as SI/SI mice.

Vickid mice

(Viable c-KIT-deficient mice). Vickid mice are white, black-eyed, apparently healthy KIT-deficient mice that arose from a cross between W/+ and W/+ heterozygous mice. The molecular basis for the survival of these mice is unknown.

Wepo mice

(W mutant mice rescued by erythropoietin). Wepo mice were generated by crosses between erythropoietin-transgenic W/+ mice and W/+ mice. Transgenic expression of erythropoietin is thought to boost erythropoiesis even in the absence of KIT, and rescue the W/W mice.

Osteoclasts

Multinucleated cells that resorb bone. They are specialized monocyte/macrophage family members that arise from haematopoietic stem cells. Morphogenesis and remodelling of bone is controlled by processes that include the synthesis of bone by osteoblasts and the coordinate resorption of bone by osteoclasts.

Reticular cells

The main stromal cells in the bone marrow, with dendritic-cell (DC)-like morphology. Unlike DCs, they have broad, sheet-like cytoplasmic processes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagasawa, T. Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 6, 107–116 (2006). https://doi.org/10.1038/nri1780

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1780

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing