Regulation of stem cells in adult tissues is a key determinant of how well an organism can respond to the stresses of physiological challenge and disease. This is particularly true of the hematopoietic system, where demands on host defenses can call for an acute increase in cell production. Hematopoietic stem cells receive the regulatory signals for cell production in adult mammals in the bone marrow, a tissue with higher-order architectural and functional organization than previously appreciated. Here, we review the data defining particular structural components and heterologous cells in the bone marrow that participate in hematopoietic stem cell function. Further, we explore the case for stromal-hematopoietic cell interactions contributing to neoplastic myeloid disease. As the hematopoietic regulatory networks in the bone marrow are revealed, it is anticipated that strategies will emerge for how to enhance or inhibit production of specific blood cells. In that way, the control of hematopoiesis will enter the domain of therapies to modulate broad aspects of hematopoiesis, both normal and malignant.


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Literature Cited

  1. Abkowitz JL, Catlin SN, McCallie MT, Guttorp P. 1.  2002. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 100:2665–67 [Google Scholar]
  2. Jacobson LO, Simmons EL, Marks EK, Robson MJ, Bethard WF, Gaston EO. 2.  1950. The role of the spleen in radiation injury and recovery. J. Lab. Clin. Med. 35:746–70 [Google Scholar]
  3. Jacobson LO, Simmons EL, Marks EK, Eldredge JH. 3.  1951. Recovery from radiation injury. Science 113:510–11 [Google Scholar]
  4. Lorenz E, Uphoff D, Reid TR, Shelton E. 4.  1951. Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J. Natl. Cancer Inst. 12:197–201 [Google Scholar]
  5. Main JM, Prehn RT. 5.  1955. Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J. Natl. Cancer Inst. 15:1023–29 [Google Scholar]
  6. Ford CE, Hamerton JL, Barnes DW, Loutit JF. 6.  1956. Cytological identification of radiation-chimaeras. Nature 177:452–54 [Google Scholar]
  7. Nowell PC, Cole LJ, Habermeyer JG, Roan PL. 7.  1956. Growth and continued function of rat marrow cells in x-radiated mice. Cancer Res. 16:258–61 [Google Scholar]
  8. Trentin JJ. 8.  1956. Mortality and skin transplantability in x-irradiated mice receiving isologous, homologous or heterologous bone marrow. Proc. Soc. Exp. Biol. Med. 92:688–93 [Google Scholar]
  9. Till JE, McCulloch EA. 9.  1961. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat. Res. 14:213–22 [Google Scholar]
  10. Becker AJ, McCulloch EA, Till JE. 10.  1963. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature 197:452–54 [Google Scholar]
  11. Siminovitch L, McCulloch EA, Till JE. 11.  1963. The distribution of colony-forming cells among spleen colonies. J. Cell Physiol. 62:327–36 [Google Scholar]
  12. Wu AM, Till JE, Siminovitch L, McCulloch EA. 12.  1967. A cytological study of the capacity for differentiation of normal hemopoietic colony-forming cells. J. Cell Physiol. 69:177–84 [Google Scholar]
  13. Wu AM, Till JE, Siminovitch L, McCulloch EA. 13.  1968. Cytological evidence for a relationship between normal hematopoietic colony-forming cells and cells of the lymphoid system. J. Exp. Med. 127:455–64 [Google Scholar]
  14. Commoner B. 14.  1971. The Closing Circle: Nature, Man, and Technology New York: Knopf [Google Scholar]
  15. Maloney MA, Patt HM. 15.  1968. Origin in repopulating cells after localized bone marrow depletion. Science 165:71–73 [Google Scholar]
  16. Maloney MA, Patt HM. 16.  1972. Migration of cells from shielded to irradiated marrow. Blood 39:804–8 [Google Scholar]
  17. Dexter TM, Allen TD, Lajtha LG. 17.  1977. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell Physiol. 91:335–44 [Google Scholar]
  18. Lord BI, Hendry JH. 18.  1972. The distribution of haemopoietic colony-forming units in the mouse femur, and its modification by x rays. Br. J. Radiol. 45:110–15 [Google Scholar]
  19. Lord BI, Testa NG, Hendry JH. 19.  1975. The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46:65–72 [Google Scholar]
  20. Schofield R. 20.  1978. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7–25 [Google Scholar]
  21. Tavassoli M, Crosby WH. 21.  1968. Transplantation of marrow to extramedullary sites. Science 161:54–56 [Google Scholar]
  22. Gong JK. 22.  1978. Endosteal marrow: a rich source of hematopoietic stem cells. Science 199:1443–45 [Google Scholar]
  23. Kohler A, Schmithorst V, Filippi MD, Ryan MA, Daria D. 23.  et al. 2009. Altered cellular dynamics and endosteal location of aged early hematopoietic progenitor cells revealed by time-lapse intravital imaging in long bones. Blood 114:290–98 [Google Scholar]
  24. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S. 24.  et al. 2009. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457:92–96 [Google Scholar]
  25. Nilsson SK, Johnston HM, Coverdale JA. 25.  2001. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood 97:2293–99 [Google Scholar]
  26. Xie Y, Yin T, Wiegraebe W, He XC, Miller D. 26.  et al. 2009. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457:97–101 [Google Scholar]
  27. Haylock DN, Williams B, Johnston HM, Liu MC, Rutherford KE. 27.  et al. 2007. Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. Stem Cells 25:1062–69 [Google Scholar]
  28. Taichman RS, Emerson SG. 28.  1994. Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J. Exp. Med. 179:1677–82 [Google Scholar]
  29. Taichman RS, Reilly MJ, Emerson SG. 29.  1996. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood 87:518–24 [Google Scholar]
  30. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S. 30.  et al. 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–61 [Google Scholar]
  31. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP. 31.  et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–46 [Google Scholar]
  32. Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. 32.  2004. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood 103:3258–64 [Google Scholar]
  33. Zhang J, Niu C, Ye L, Huang H, He X. 33.  et al. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425:836–41 [Google Scholar]
  34. Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M. 34.  et al. 2000. The Notch ligand Jagged-1 represents a novel growth factor of human hematopoietic stem cells. J. Exp. Med. 192:1365–72 [Google Scholar]
  35. Stier S, Cheng T, Dombkowski D, Carlesso N, Scadden DT. 35.  2002. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood 99:2369–78 [Google Scholar]
  36. Varnum-Finney B, Brashem-Stein C, Bernstein ID. 36.  2003. Combined effects of Notch signaling and cytokines induce a multiple log increase in precursors with lymphoid and myeloid reconstituting ability. Blood 101:1784–89 [Google Scholar]
  37. Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J. 37.  et al. 2012. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 10:259–72 [Google Scholar]
  38. Maillard I, Koch U, Dumortier A, Shestova O, Xu L. 38.  et al. 2008. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell 2:356–66 [Google Scholar]
  39. Kiel MJ, Acar M, Radice GL, Morrison SJ. 39.  2009. Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell 4:170–79 [Google Scholar]
  40. Kiel MJ, Radice GL, Morrison SJ. 40.  2007. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1:204–17 [Google Scholar]
  41. Levesque JP, Leavesley DI, Niutta S, Vadas M, Simmons PJ. 41.  1995. Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins. J. Exp. Med. 181:1805–15 [Google Scholar]
  42. Levesque JP, Takamatsu Y, Nilsson SK, Haylock DN, Simmons PJ. 42.  2001. Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood 98:1289–97 [Google Scholar]
  43. Papayannopoulou T, Priestley GV, Nakamoto B, Zafiropoulos V, Scott LM. 43.  2001. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins. Blood 98:2403–11 [Google Scholar]
  44. Peled A, Kollet O, Ponomaryov T, Petit I, Franitza S. 44.  et al. 2000. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood 95:3289–96 [Google Scholar]
  45. Vermeulen M, Le Pesteur F, Gagnerault MC, Mary JY, Sainteny F, Lepault F. 45.  1998. Role of adhesion molecules in the homing and mobilization of murine hematopoietic stem and progenitor cells. Blood 92:894–900 [Google Scholar]
  46. Zanjani ED, Flake AW, Almeida-Porada G, Tran N, Papayannopoulou T. 46.  1999. Homing of human cells in the fetal sheep model: modulation by antibodies activating or inhibiting very late activation antigen-4-dependent function. Blood 94:2515–22 [Google Scholar]
  47. van der Loo JC, Xiao X, McMillin D, Hashino K, Kato I, Williams DA. 47.  1998. VLA-5 is expressed by mouse and human long-term repopulating hematopoietic cells and mediates adhesion to extracellular matrix protein fibronectin. J. Clin. Investig. 102:1051–61 [Google Scholar]
  48. Katayama Y, Hidalgo A, Peired A, Frenette PS. 48.  2004. Integrin α4β7 and its counterreceptor MAdCAM-1 contribute to hematopoietic progenitor recruitment into bone marrow following transplantation. Blood 104:2020–26 [Google Scholar]
  49. Qian H, Georges-Labouesse E, Nystrom A, Domogatskaya A, Tryggvason K. 49.  et al. 2007. Distinct roles of integrins α6 and α4 in homing of fetal liver hematopoietic stem and progenitor cells. Blood 110:2399–407 [Google Scholar]
  50. Qian H, Tryggvason K, Jacobsen SE, Ekblom M. 50.  2006. Contribution of α6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with α4 integrins. Blood 107:3503–10 [Google Scholar]
  51. Schmits R, Filmus J, Gerwin N, Senaldi G, Kiefer F. 51.  et al. 1997. CD44 regulates hematopoietic progenitor distribution, granuloma formation, and tumorigenicity. Blood 90:2217–33 [Google Scholar]
  52. Frenette PS, Subbarao S, Mazo IB, von Andrian UH, Wagner DD. 52.  1998. Endothelial selectins and vascular cell adhesion molecule-1 promote hematopoietic progenitor homing to bone marrow. PNAS 95:14423–28 [Google Scholar]
  53. Katayama Y, Hidalgo A, Furie BC, Vestweber D, Furie B, Frenette PS. 53.  2003. PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: evidence for cooperation between E-selectin ligands and α4 integrin. Blood 102:2060–67 [Google Scholar]
  54. Sackstein R. 54.  2004. The bone marrow is akin to skin: HCELL and the biology of hematopoietic stem cell homing. J. Investig. Dermatol. 122:1061–69 [Google Scholar]
  55. Forde S, Tye BJ, Newey SE, Roubelakis M, Smythe J. 55.  et al. 2007. Endolyn (CD164) modulates the CXCL12-mediated migration of umbilical cord blood CD133+ cells. Blood 109:1825–33 [Google Scholar]
  56. Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM. 56.  et al. 2006. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439:599–603 [Google Scholar]
  57. Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L. 57.  et al. 2000. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J. Clin. Investig. 106:1331–39 [Google Scholar]
  58. Grassinger J, Haylock DN, Storan MJ, Haines GO, Williams B. 58.  et al. 2009. Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with α9β1 and α4β1 integrins. Blood 114:49–59 [Google Scholar]
  59. Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ. 59.  et al. 2005. Osteopontin, a key component of the hematopoietic stem cell niche and regulator of primitive hematopoietic progenitor cells. Blood 106:1232–39 [Google Scholar]
  60. Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T. 60.  et al. 2005. Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J. Exp. Med. 201:1781–91 [Google Scholar]
  61. Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR. 61.  et al. 2013. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature 495:365–69 [Google Scholar]
  62. Mazzon C, Anselmo A, Cibella J, Soldani C, Destro A. 62.  et al. 2011. The critical role of agrin in the hematopoietic stem cell niche. Blood 118:2733–42 [Google Scholar]
  63. Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B. 63.  et al. 2013. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat. Cell Biol. 15:533–43 [Google Scholar]
  64. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D. 64.  et al. 2005. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435:969–73 [Google Scholar]
  65. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. 65.  2005. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121:1109–21 [Google Scholar]
  66. Ding L, Morrison SJ. 66.  2013. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495:231–35 [Google Scholar]
  67. Ding L, Saunders TL, Enikolopov G, Morrison SJ. 67.  2012. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481:457–62 [Google Scholar]
  68. Himburg HA, Harris JR, Ito T, Daher P, Russell JL. 68.  et al. 2012. Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell Rep. 2:964–75 [Google Scholar]
  69. Hooper AT, Butler JM, Nolan DJ, Kranz A, Iida K. 69.  et al. 2009. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell 4:263–74 [Google Scholar]
  70. Li W, Johnson SA, Shelley WC, Yoder MC. 70.  2004. Hematopoietic stem cell repopulating ability can be maintained in vitro by some primary endothelial cells. Exp. Hematol. 32:1226–37 [Google Scholar]
  71. Ohneda O, Fennie C, Zheng Z, Donahue C, La H. 71.  et al. 1998. Hematopoietic stem cell maintenance and differentiation are supported by embryonic aorta-gonad-mesonephros region-derived endothelium. Blood 92:908–19 [Google Scholar]
  72. Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC. 72.  et al. 2013. Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep. 4:1022–34 [Google Scholar]
  73. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE. 73.  et al. 2012. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat. Med. 18:1651–57 [Google Scholar]
  74. Yao L, Yokota T, Xia L, Kincade PW, McEver RP. 74.  2005. Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells. Blood 106:4093–101 [Google Scholar]
  75. Kobayashi H, Butler JM, O'Donnell R, Kobayashi M, Ding BS. 75.  et al. 2010. Angiocrine factors from Akt-activated endothelial cells balance self-renewal and differentiation of haematopoietic stem cells. Nat. Cell Biol. 12:1046–56 [Google Scholar]
  76. Slayton WB, Li XM, Butler J, Guthrie SM, Jorgensen ML. 76.  et al. 2007. The role of the donor in the repair of the marrow vascular niche following hematopoietic stem cell transplant. Stem Cells 25:2945–55 [Google Scholar]
  77. Ellis SL, Grassinger J, Jones A, Borg J, Camenisch T. 77.  et al. 2011. The relationship between bone, hemopoietic stem cells, and vasculature. Blood 118:1516–24 [Google Scholar]
  78. Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S. 78.  et al. 2013. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502:637–43 [Google Scholar]
  79. Mendelson A, Frenette PS. 79.  2014. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat. Med. 20:833–46 [Google Scholar]
  80. Chow DC, Wenning LA, Miller WM, Papoutsakis ET. 80.  2001. Modeling pO2 distributions in the bone marrow hematopoietic compartment. II. Modified Kroghian models. Biophys. J. 81:685–96 [Google Scholar]
  81. Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N. 81.  et al. 2010. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33:387–99 [Google Scholar]
  82. Sugiyama T, Kohara H, Noda M, Nagasawa T. 82.  2006. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25:977–88 [Google Scholar]
  83. Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ. 83.  et al. 2013. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495:227–30 [Google Scholar]
  84. Isern J, Garcia-Garcia A, Martin AM, Arranz L, Martin-Perez D. 84.  et al. 2014. The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function. eLife 3:e03696 [Google Scholar]
  85. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD. 85.  et al. 2010. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–34 [Google Scholar]
  86. Coskun S, Chao H, Vasavada H, Heydari K, Gonzales N. 86.  et al. 2014. Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep. 9:581–90 [Google Scholar]
  87. Wu JY, Purton LE, Rodda SJ, Chen M, Weinstein LS. 87.  et al. 2008. Osteoblastic regulation of B lymphopoiesis is mediated by Gsα-dependent signaling pathways. PNAS 105:16976–81 [Google Scholar]
  88. Jung Y, Wang J, Havens A, Sun Y, Wang J. 88.  et al. 2005. Cell-to-cell contact is critical for the survival of hematopoietic progenitor cells on osteoblasts. Cytokine 32:155–62 [Google Scholar]
  89. Gillette JM, Larochelle A, Dunbar CE, Lippincott-Schwartz J. 89.  2009. Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche. Nat. Cell Biol. 11:303–11 [Google Scholar]
  90. Zhou BO, Ding L, Morrison SJ. 90.  2015. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. eLife 4:e05521 [Google Scholar]
  91. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG. 91.  et al. 2011. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469:415–18 [Google Scholar]
  92. Hsu YC, Pasolli HA, Fuchs E. 92.  2011. Dynamics between stem cells, niche, and progeny in the hair follicle. Cell 144:92–105 [Google Scholar]
  93. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ. 93.  et al. 2006. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124:407–21 [Google Scholar]
  94. Semerad CL, Christopher MJ, Liu F, Short B, Simmons PJ. 94.  et al. 2005. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood 106:3020–27 [Google Scholar]
  95. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B. 95.  et al. 2010. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116:4815–28 [Google Scholar]
  96. Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL. 96.  et al. 2008. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J. Immunol. 181:1232–44 [Google Scholar]
  97. Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D. 97.  et al. 2011. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208:261–71 [Google Scholar]
  98. Christopher MJ, Rao M, Liu F, Woloszynek JR, Link DC. 98.  2011. Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice. J. Exp. Med. 208:251–60 [Google Scholar]
  99. Perez-Amodio S, Beertsen W, Everts V. 99.  2004. (Pre-)osteoclasts induce retraction of osteoblasts before their fusion to osteoclasts. J. Bone Miner. Res. 19:1722–31 [Google Scholar]
  100. Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SE, Wakkach A, Blin-Wakkach C. 100.  2012. Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J. Exp. Med. 209:537–49 [Google Scholar]
  101. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K. 101.  et al. 2006. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12:657–64 [Google Scholar]
  102. Cho KA, Joo SY, Han HS, Ryu KH, Woo SY. 102.  2010. Osteoclast activation by receptor activator of NF-κB ligand enhances the mobilization of hematopoietic progenitor cells from the bone marrow in acute injury. Int. J. Mol. Med. 26:557–63 [Google Scholar]
  103. Shivtiel S, Kollet O, Lapid K, Schajnovitz A, Goichberg P. 103.  et al. 2008. CD45 regulates retention, motility, and numbers of hematopoietic progenitors, and affects osteoclast remodeling of metaphyseal trabecules. J. Exp. Med. 205:2381–95 [Google Scholar]
  104. Takamatsu Y, Simmons PJ, Moore RJ, Morris HA, To LB, Levesque JP. 104.  1998. Osteoclast-mediated bone resorption is stimulated during short-term administration of granulocyte colony-stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. Blood 92:3465–73 [Google Scholar]
  105. Christopher MJ, Link DC. 105.  2008. Granulocyte colony-stimulating factor induces osteoblast apoptosis and inhibits osteoblast differentiation. J. Bone Miner. Res. 23:1765–74 [Google Scholar]
  106. Hirbe AC, Uluckan O, Morgan EA, Eagleton MC, Prior JL. 106.  et al. 2007. Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner. Blood 109:3424–31 [Google Scholar]
  107. Miyamoto K, Yoshida S, Kawasumi M, Hashimoto K, Kimura T. 107.  et al. 2011. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J. Exp. Med. 208:2175–81 [Google Scholar]
  108. Rao M, Supakorndej T, Schmidt AP, Link DC. 108.  2015. Osteoclasts are dispensable for hematopoietic progenitor mobilization by granulocyte colony-stimulating factor in mice. Exp. Hematol. 43:110–14 e1–2 [Google Scholar]
  109. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P. 109.  et al. 2011. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474:216–19 [Google Scholar]
  110. Dominici M, Rasini V, Bussolari R, Chen X, Hofmann TJ. 110.  et al. 2009. Restoration and reversible expansion of the osteoblastic hematopoietic stem cell niche after marrow radioablation. Blood 114:2333–43 [Google Scholar]
  111. Olson TS, Caselli A, Otsuru S, Hofmann TJ, Williams R. 111.  et al. 2013. Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood 121:5238–49 [Google Scholar]
  112. Kacena MA, Shivdasani RA, Wilson K, Xi Y, Troiano N. 112.  et al. 2004. Megakaryocyte-osteoblast interaction revealed in mice deficient in transcription factors GATA-1 and NF-E2. J. Bone Miner. Res. 19:652–60 [Google Scholar]
  113. Ciovacco WA, Cheng YH, Horowitz MC, Kacena MA. 113.  2010. Immature and mature megakaryocytes enhance osteoblast proliferation and inhibit osteoclast formation. J. Cell Biochem. 109:774–81 [Google Scholar]
  114. Ciovacco WA, Goldberg CG, Taylor AF, Lemieux JM, Horowitz MC. 114.  et al. 2009. The role of gap junctions in megakaryocyte-mediated osteoblast proliferation and differentiation. Bone 44:80–86 [Google Scholar]
  115. Storan MJ, Heazlewood SY, Heazlewood CK, Haylock DN, Alexander WS. 115.  et al. 2015. Brief report: Factors released by megakaryocytes thrombin cleave osteopontin to negatively regulate hematopoietic stem cells. Stem Cells 33:2351–57 [Google Scholar]
  116. Heazlewood SY, Neaves RJ, Williams B, Haylock DN, Adams TE, Nilsson SK. 116.  2013. Megakaryocytes co-localise with hemopoietic stem cells and release cytokines that up-regulate stem cell proliferation. Stem Cell Res. 11:782–92 [Google Scholar]
  117. Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP. 117.  et al. 2014. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20:1315–20 [Google Scholar]
  118. Nakamura-Ishizu A, Takubo K, Fujioka M, Suda T. 118.  2014. Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin. Biochem. Biophys. Res. Commun. 454:353–57 [Google Scholar]
  119. Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P. 119.  et al. 2014. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20:1321–26 [Google Scholar]
  120. Semenza GL. 120.  2014. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. 9:47–71 [Google Scholar]
  121. Semenza GL, Nejfelt MK, Chi SM, Antonarakis SE. 121.  1991. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. PNAS 88:5680–84 [Google Scholar]
  122. Cormier-Regard S, Nguyen SV, Claycomb WC. 122.  1998. Adrenomedullin gene expression is developmentally regulated and induced by hypoxia in rat ventricular cardiac myocytes. J. Biol. Chem. 273:17787–92 [Google Scholar]
  123. Feldser D, Agani F, Iyer NV, Pak B, Ferreira G, Semenza GL. 123.  1999. Reciprocal positive regulation of hypoxia-inducible factor 1α and insulin-like growth factor 2. Cancer Res. 59:3915–18 [Google Scholar]
  124. Krishnamachary B, Berg-Dixon S, Kelly B, Agani F, Feldser D. 124.  et al. 2003. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63:1138–43 [Google Scholar]
  125. Levy AP, Levy NS, Wegner S, Goldberg MA. 125.  1995. Transcriptional regulation of the rat vascular endothelial growth factor gene by hypoxia. J. Biol. Chem. 270:13333–40 [Google Scholar]
  126. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N. 126.  et al. 2004. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med. 10:858–64 [Google Scholar]
  127. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. 127.  2003. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature 425:307–11 [Google Scholar]
  128. Kirito K, Hu Y, Komatsu N. 128.  2009. HIF-1 prevents the overproduction of mitochondrial ROS after cytokine stimulation through induction of PDK-1. Cell Cycle 8:2844–49 [Google Scholar]
  129. Lin Q, Lee YJ, Yun Z. 129.  2006. Differentiation arrest by hypoxia. J. Biol. Chem. 281:30678–83 [Google Scholar]
  130. Danet GH, Pan Y, Luongo JL, Bonnet DA, Simon MC. 130.  2003. Expansion of human SCID-repopulating cells under hypoxic conditions. J. Clin. Investig. 112:126–35 [Google Scholar]
  131. Roy S, Tripathy M, Mathur N, Jain A, Mukhopadhyay A. 131.  2012. Hypoxia improves expansion potential of human cord blood-derived hematopoietic stem cells and marrow repopulation efficiency. Eur. J. Haematol. 88:396–405 [Google Scholar]
  132. Broxmeyer HE, Cooper S, Gabig T. 132.  1989. The effects of oxidizing species derived from molecular oxygen on the proliferation in vitro of human granulocyte-macrophage progenitor cells. Ann. N. Y. Acad. Sci. 554:177–84 [Google Scholar]
  133. Broxmeyer HE, Cooper S, Lu L, Miller ME, Langefeld CD, Ralph P. 133.  1990. Enhanced stimulation of human bone marrow macrophage colony formation in vitro by recombinant human macrophage colony-stimulating factor in agarose medium and at low oxygen tension. Blood 76:323–29 [Google Scholar]
  134. Smith S, Broxmeyer HE. 134.  1986. The influence of oxygen tension on the long-term growth in vitro of haematopoietic progenitor cells from human cord blood. Br. J. Haematol. 63:29–34 [Google Scholar]
  135. Rehn M, Olsson A, Reckzeh K, Diffner E, Carmeliet P. 135.  et al. 2011. Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. Blood 118:1534–43 [Google Scholar]
  136. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E. 136.  et al. 2010. Regulation of the HIF-1α level is essential for hematopoietic stem cells. Cell Stem Cell 7:391–402 [Google Scholar]
  137. Miharada K, Karlsson G, Rehn M, Rorby E, Siva K. 137.  et al. 2011. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell 9:330–44 [Google Scholar]
  138. Krock BL, Eisinger-Mathason TS, Giannoukos DN, Shay JE, Gohil M. 138.  et al. 2015. The aryl hydrocarbon receptor nuclear translocator is an essential regulator of murine hematopoietic stem cell viability. Blood 125:3263–72 [Google Scholar]
  139. Kubota Y, Takubo K, Suda T. 139.  2008. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche. Biochem. Biophys. Res. Commun. 366:335–39 [Google Scholar]
  140. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. 140.  2007. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. PNAS 104:5431–36 [Google Scholar]
  141. Winkler IG, Barbier V, Wadley R, Zannettino AC, Williams S, Levesque JP. 141.  2010. Positioning of bone marrow hematopoietic and stromal cells relative to blood flow in vivo: Serially reconstituting hematopoietic stem cells reside in distinct nonperfused niches. Blood 116:375–85 [Google Scholar]
  142. Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J. 142.  et al. 2014. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–73 [Google Scholar]
  143. Finikova OS, Lebedev AY, Aprelev A, Troxler T, Gao F. 143.  et al. 2008. Oxygen microscopy by two-photon-excited phosphorescence. ChemPhysChem 9:1673–79 [Google Scholar]
  144. Lebedev AY, Troxler T, Vinogradov SA. 144.  2008. Design of metalloporphyrin-based dendritic nanoprobes for two-photon microscopy of oxygen. J. Porphyr. Phthalocyanines 12:1261–69 [Google Scholar]
  145. Mantel CR, O'Leary HA,, Chitteti BR, Huang X, Cooper S. 145.  et al. 2015. Enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell 161:1553–65 [Google Scholar]
  146. Asada N, Katayama Y, Sato M, Minagawa K, Wakahashi K. 146.  et al. 2013. Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. Cell Stem Cell 12:737–47 [Google Scholar]
  147. Lucas D, Battista M, Shi PA, Isola L, Frenette PS. 147.  2008. Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3:364–66 [Google Scholar]
  148. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. 148.  2008. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452:442–47 [Google Scholar]
  149. Spiegel A, Shivtiel S, Kalinkovich A, Ludin A, Netzer N. 149.  et al. 2007. Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling. Nat. Immunol. 8:1123–31 [Google Scholar]
  150. Kawamori Y, Katayama Y, Asada N, Minagawa K, Sato M. 150.  et al. 2010. Role for vitamin D receptor in the neuronal control of the hematopoietic stem cell niche. Blood 116:5528–35 [Google Scholar]
  151. Cho Y, Noshiro M, Choi M, Morita K, Kawamoto T. 151.  et al. 2009. The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. Mol. Pharmacol. 76:1360–69 [Google Scholar]
  152. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H. 152.  et al. 2011. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147:1146–58 [Google Scholar]
  153. Blank U, Karlsson S. 153.  2011. The role of Smad signaling in hematopoiesis and translational hematology. Leukemia 25:1379–88 [Google Scholar]
  154. Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H. 154.  2009. TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113:1250–56 [Google Scholar]
  155. Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I. 155.  et al. 2013. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat. Med. 19:695–703 [Google Scholar]
  156. Walkley CR, Olsen GH, Dworkin S, Fabb SA, Swann J. 156.  et al. 2007. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell 129:1097–110 [Google Scholar]
  157. Walkley CR, Shea JM, Sims NA, Purton LE, Orkin SH. 157.  2007. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell 129:1081–95 [Google Scholar]
  158. Kim YW, Koo BK, Jeong HW, Yoon MJ, Song R. 158.  et al. 2008. Defective Notch activation in microenvironment leads to myeloproliferative disease. Blood 112:4628–38 [Google Scholar]
  159. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T. 159.  et al. 2010. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464:852–57 [Google Scholar]
  160. Santamaria C, Muntion S, Roson B, Blanco B, Lopez-Villar O. 160.  et al. 2012. Impaired expression of DICER, DROSHA, SBDS and some microRNAs in mesenchymal stromal cells from myelodysplastic syndrome patients. Haematologica 97:1218–24 [Google Scholar]
  161. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV. 161.  et al. 2014. Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts. Nature 506:240–44 [Google Scholar]
  162. Wiseman DH. 162.  2011. Donor cell leukemia: a review. Biol. Blood Marrow Transplant. 17:771–89 [Google Scholar]
  163. Boyd AL, Campbell CJ, Hopkins CI, Fiebig-Comyn A, Russell J. 163.  et al. 2014. Niche displacement of human leukemic stem cells uniquely allows their competitive replacement with healthy HSPCs. J. Exp. Med. 211:1925–35 [Google Scholar]
  164. Zhang B, Ho YW, Huang Q, Maeda T, Lin A. 164.  et al. 2012. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell 21:577–92 [Google Scholar]
  165. Schmidt T, Kharabi Masouleh B, Loges S, Cauwenberghs S, Fraisl P. 165.  et al. 2011. Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1+ leukemia. Cancer Cell 19:740–53 [Google Scholar]
  166. Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M. 166.  et al. 2013. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell 13:285–99 [Google Scholar]
  167. Krevvata M, Silva BC, Manavalan JS, Galan-Diez M, Kode A. 167.  et al. 2014. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood 124:2834–46 [Google Scholar]
  168. Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X. 168.  et al. 2010. Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis. Nat. Med. 16:308–12 [Google Scholar]
  169. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N. 169.  et al. 2005. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–61 [Google Scholar]
  170. Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R. 170.  et al. 2005. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352:1779–90 [Google Scholar]
  171. Arranz L, Sanchez-Aguilera A, Martin-Perez D, Isern J, Langa X. 171.  et al. 2014. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature 512:78–81 [Google Scholar]
  172. Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H. 172.  et al. 2014. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell 15:365–75 [Google Scholar]
  173. Zhu J, Garrett R, Jung Y, Zhang Y, Kim N. 173.  et al. 2007. Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells. Blood 109:3706–12 [Google Scholar]
  174. Bowers M, Zhang B, Ho Y, Agarwal P, Chen CC, Bhatia R. 174.  2015. Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. Blood 125:2678–88 [Google Scholar]
  175. Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K. 175.  et al. 2007. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1:685–97 [Google Scholar]
  176. Qian H, Buza-Vidas N, Hyland CD, Jensen CT, Antonchuk J. 176.  et al. 2007. Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells. Cell Stem Cell 1:671–84 [Google Scholar]
  177. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. 177.  2009. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460:259–63 [Google Scholar]

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