In addition to their conventional role as a versatile transport system, blood vessels provide signals controlling organ development, regeneration, and stem cell behavior. In the skeletal system, certain capillaries support perivascular osteoprogenitor cells and thereby control bone formation. Blood vessels are also a critical component of niche microenvironments for hematopoietic stem cells. Here we discuss key pathways and factors controlling endothelial cell behavior in bone, the role of vessels in osteogenesis, and the nature of vascular stem cell niches in bone marrow.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Abkowitz JL, Robinson AE, Kale S, Long MW, Chen J. 2003. Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 102:1249–53 [Google Scholar]
  2. Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H. et al. 2015. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature 526:126–30 [Google Scholar]
  3. Adams RH, Alitalo K. 2007. Molecular regulation of angiogenesis and lymphangiogenesis. Nat. Rev. Mol. Cell Biol. 8:464–78 [Google Scholar]
  4. Akeno N, Robins J, Zhang M, Czyzyk-Krzeska MF, Clemens TL. 2002. Induction of vascular endothelial growth factor by IGF-I in osteoblast-like cells is mediated by the PI3K signaling pathway through the hypoxia-inducible factor-2α. Endocrinology 143:420–25 [Google Scholar]
  5. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S. et al. 2004. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–61 [Google Scholar]
  6. Artavanis-Tsakonas S, Rand MD, Lake RJ. 1999. Notch signaling: cell fate control and signal integration in development. Science 284:770–76 [Google Scholar]
  7. Balazs AB, Fabian AJ, Esmon CT, Mulligan RC. 2006. Endothelial protein C receptor (CD201) explicitly identifies hematopoietic stem cells in murine bone marrow. Blood 107:2317–21 [Google Scholar]
  8. Barnes GL, Kostenuik PJ, Gerstenfeld LC, Einhorn TA. 1999. Growth factor regulation of fracture repair. J. Bone Miner. Res. 14:1805–15 [Google Scholar]
  9. Bear MD, Liu T, Abualkhair S, Ghamloush MA, Hill NS. et al. 2016. Alpha-catulin co-localizes with vimentin intermediate filaments and functions in pulmonary vascular endothelial cell migration via ROCK. J. Cell. Physiol. 231:934–43 [Google Scholar]
  10. Beets K, Huylebroeck D, Moya IM, Umans L, Zwijsen A. 2013. Robustness in angiogenesis: Notch and BMP shaping waves. Trends Genet 29:140–49 [Google Scholar]
  11. Benedito R, Roca C, Sorensen I, Adams S, Gossler A. et al. 2009. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–35 [Google Scholar]
  12. Brookes M. 1958. The vascular architecture of tubular bone in the rat. Anat. Rec. 132:25–47 [Google Scholar]
  13. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S. et al. 2005. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med 201:1307–18 [Google Scholar]
  14. Brunet LJ, McMahon JA, McMahon AP, Harland RM. 1998. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280:1455–57 [Google Scholar]
  15. Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP. et al. 2014. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat. Med. 20:1315–20 [Google Scholar]
  16. Butler JM, Kobayashi H, Rafii S. 2010. Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat. Rev. Cancer 10:138–46 [Google Scholar]
  17. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP. et al. 2003. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–46 [Google Scholar]
  18. Canalis E, Giustina A, Bilezikian JP. 2007. Mechanisms of anabolic therapies for osteoporosis. N. Engl. J. Med. 357:905–16 [Google Scholar]
  19. Cao Y. 2013. Angiogenesis and vascular functions in modulation of obesity, adipose metabolism, and insulin sensitivity. Cell Metab 18:478–89 [Google Scholar]
  20. Carano RA, Filvaroff EH. 2003. Angiogenesis and bone repair. Drug Discov. Today 8:980–89 [Google Scholar]
  21. Carmeliet P. 2003. Blood vessels and nerves: common signals, pathways and diseases. Nat. Rev. Genet. 4:710–20 [Google Scholar]
  22. Chang C-H, Hale SJ, Cox CV, Blair A, Kronsteiner B. et al. 2016. Junctional adhesion molecule-A is highly expressed on human hematopoietic repopulating cells and associates with the key hematopoietic chemokine receptor CXCR4. Stem Cells 341664–78 [Google Scholar]
  23. Chen JY, Miyanishi M, Wang SK, Yamazaki S, Sinha R. et al. 2016. Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche. Nature 530:223–27 [Google Scholar]
  24. Christov C, Chretien F, Abou-Khalil R, Bassez G, Vallet G. et al. 2007. Muscle satellite cells and endothelial cells: close neighbors and privileged partners. Mol. Biol. Cell 18:1397–409 [Google Scholar]
  25. Clarkin C, Olsen BR. 2010. On bone-forming cells and blood vessels in bone development. Cell Metab 12:314–16 [Google Scholar]
  26. Collin-Osdoby P, Rothe L, Bekker S, Anderson F, Huang Y, Osdoby P. 2002. Basic fibroblast growth factor stimulates osteoclast recruitment, development, and bone pit resorption in association with angiogenesis in vivo on the chick chorioallantoic membrane and activates isolated avian osteoclast resorption in vitro. J. Bone Miner. Res. 17:1859–71 [Google Scholar]
  27. Colnot C, Lu C, Hu D, Helms JA. 2004. Distinguishing the contributions of the perichondrium, cartilage, and vascular endothelium to skeletal development. Dev. Biol. 269:55–69 [Google Scholar]
  28. Conway EM, Van de Wouwer M, Pollefeyt S, Jurk K, Van Aken H. et al. 2002. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor κB and mitogen-activated protein kinase pathways. J. Exp. Med. 196:565–77 [Google Scholar]
  29. Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T. et al. 2011. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells. Leukemia 25:1286–96 [Google Scholar]
  30. De Bock K, Georgiadou M, Schoors S, Kuchnio A, Wong BW. et al. 2013. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154:651–63 [Google Scholar]
  31. De Smet F, Tembuyser B, Lenard A, Claes F, Zhang J. et al. 2014. Fibroblast growth factor signaling affects vascular outgrowth and is required for the maintenance of blood vessel integrity. Chem. Biol. 21:1310–17 [Google Scholar]
  32. Deckers MM, Karperien M, van der Bent C, Yamashita T, Papapoulos SE, Lowik CW. 2000. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 141:1667–74 [Google Scholar]
  33. Deckers MM, van Bezooijen RL, van der Horst G, Hoogendam J, van Der Bent C. et al. 2002. Bone morphogenetic proteins stimulate angiogenesis through osteoblast-derived vascular endothelial growth factor A. Endocrinology 143:1545–53 [Google Scholar]
  34. Dequeker J. 1975. Bone and ageing. Ann. Rheum. Dis. 34:100–15 [Google Scholar]
  35. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P. et al. 2014. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505:97–102 [Google Scholar]
  36. Engin F, Yao Z, Yang T, Zhou G, Bertin T. et al. 2008. Dimorphic effects of Notch signaling in bone homeostasis. Nat. Med. 14:299–305 [Google Scholar]
  37. Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R. 1995. Toward a molecular understanding of skeletal development. Cell 80:371–78 [Google Scholar]
  38. Esmon CT. 1995. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB Jl 9:946–55 [Google Scholar]
  39. Esmon CT. 2003. The protein C pathway. Chest 124:S26–32 [Google Scholar]
  40. Ewalt MD, Gratzinger D. 2016. Selective quantitation of microvessel density reveals sinusoidal expansion in myelodysplastic syndromes. Leuk. Lymphoma 221–4 [Google Scholar]
  41. Fukudome K, Esmon CT. 1994. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J. Biol. Chem. 269:26486–91 [Google Scholar]
  42. Gahmberg CG, Jokinen M, Andersson LC. 1978. Expression of the major sialoglycoprotein (glycophorin) on erythroid cells in human bone marrow. Blood 52:379–87 [Google Scholar]
  43. Garrison KR, Shemilt I, Donell S, Ryder JJ, Mugford M. et al. 2010. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst. Rev. 2010:CD006950 [Google Scholar]
  44. Geiger H, Pawar SA, Kerschen EJ, Nattamai KJ, Hernandez I. et al. 2012. Pharmacological targeting of the thrombomodulin-activated protein C pathway mitigates radiation toxicity. Nat. Med. 18:1123–29 [Google Scholar]
  45. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. 1999. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat. Med. 5:623–28 [Google Scholar]
  46. Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. 2003. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J. Cell. Biochem. 88:873–84 [Google Scholar]
  47. Gleeson EM, O'Donnell JS, Preston RJ. 2012. The endothelial cell protein C receptor: cell surface conductor of cytoprotective coagulation factor signaling. Cell. Mol. Life Sci. 69:717–26 [Google Scholar]
  48. Globus RK, Patterson-Buckendahl P, Gospodarowicz D. 1988. Regulation of bovine bone cell proliferation by fibroblast growth factor and transforming growth factor beta. Endocrinology 123:98–105 [Google Scholar]
  49. Glomski K, Monette S, Manova K, De Strooper B, Saftig P, Blobel CP. 2011. Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures. Blood 118:1163–74 [Google Scholar]
  50. Glowacki J. 1998. Angiogenesis in fracture repair. Clin. Orthop. Relat. Res. 1998:S82–89 [Google Scholar]
  51. Golan K, Vagima Y, Ludin A, Itkin T, Cohen-Gur S. et al. 2012. S1P promotes murine progenitor cell egress and mobilization via S1P1-mediated ROS signaling and SDF-1 release. Blood 119:2478–88 [Google Scholar]
  52. Grassinger J, Haylock DN, Williams B, Olsen GH, Nilsson SK. 2010. Phenotypically identical hemopoietic stem cells isolated from different regions of bone marrow have different biologic potential. Blood 116:3185–96 [Google Scholar]
  53. Guezguez B, Campbell CJ, Boyd AL, Karanu F, Casado FL. et al. 2013. Regional localization within the bone marrow influences the functional capacity of human HSCs. Cell Stem Cell 13:175–89 [Google Scholar]
  54. Gur-Cohen S, Itkin T, Chakrabarty S, Graf C, Kollet O. et al. 2015. PAR1 signaling regulates the retention and recruitment of EPCR-expressing bone marrow hematopoietic stem cells. Nat. Med. 21:1307–17 [Google Scholar]
  55. Harada S, Nagy JA, Sullivan KA, Thomas KA, Endo N. et al. 1994. Induction of vascular endothelial growth factor expression by prostaglandin E2 and E1 in osteoblasts. J. Clin. Investig. 93:2490–96 [Google Scholar]
  56. Harper J, Klagsbrun M. 1999. Cartilage to bone—angiogenesis leads the way. Nat. Med. 5:617–18 [Google Scholar]
  57. Hausman MR, Schaffler MB, Majeska RJ. 2001. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone 29:560–64 [Google Scholar]
  58. Haylock DN, Williams B, Johnston HM, Liu MC, Rutherford KE. et al. 2007. Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. Stem Cells 25:1062–69 [Google Scholar]
  59. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L. et al. 2007. Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776–80 [Google Scholar]
  60. Hilton MJ, Tu X, Wu X, Bai S, Zhao H. et al. 2008. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat. Med. 14:306–14 [Google Scholar]
  61. Hooper AT, Butler JM, Nolan DJ, Kranz A, Iida K. 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]
  62. Hu J, Srivastava K, Wieland M, Runge A, Mogler C. et al. 2014. Endothelial cell–derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343:416–19 [Google Scholar]
  63. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF. 1996. Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat. Med. 2:1132–36 [Google Scholar]
  64. Inui K, Maeda M, Sano A, Fujioka K, Yutani Y. et al. 1998. Local application of basic fibroblast growth factor minipellet induces the healing of segmental bony defects in rabbits. Calcif. Tissue Int. 63:490–95 [Google Scholar]
  65. Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK. et al. 2016. Distinct bone marrow blood vessels differentially regulate hematopoiesis. Nature 532:323–28 [Google Scholar]
  66. Itkin T, Kaufmann KB, Gur-Cohen S, Ludin A, Lapidot T. 2013. Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self-renewal. Curr. Opin. Hematol. 20:237–44 [Google Scholar]
  67. Itkin T, Ludin A, Gradus B, Gur-Cohen S, Kalinkovich A. et al. 2012. FGF-2 expands murine hematopoietic stem and progenitor cells via proliferation of stromal cells, c-Kit activation, and CXCL12 down-regulation. Blood 120:1843–55 [Google Scholar]
  68. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K. et al. 2004. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431:997–1002 [Google Scholar]
  69. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S. et al. 2006. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat. Med. 12:446–51 [Google Scholar]
  70. Iwasaki H, Arai F, Kubota Y, Dahl M, Suda T. 2010. Endothelial protein C receptor–expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood 116:544–53 [Google Scholar]
  71. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J. et al. 2001. Targeting of HIF-alpha to the von Hippel–Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–72 [Google Scholar]
  72. Jilka RL, Hangoc G, Girasole G, Passeri G, Williams DC. et al. 1992. Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91 [Google Scholar]
  73. Junt T, Schulze H, Chen Z, Massberg S, Goerge T. et al. 2007. Dynamic visualization of thrombopoiesis within bone marrow. Science 317:1767–70 [Google Scholar]
  74. Kanno T, Takahashi T, Tsujisawa T, Ariyoshi W, Nishihara T. 2007. Mechanical stress–mediated Runx2 activation is dependent on Ras/ERK1/2 MAPK signaling in osteoblasts. J. Cell. Biochem. 101:1266–77 [Google Scholar]
  75. Kato T, Kawaguchi H, Hanada K, Aoyama I, Hiyama Y. et al. 1998. Single local injection of recombinant fibroblast growth factor-2 stimulates healing of segmental bone defects in rabbits. J. Orthop. Res. 16:654–59 [Google Scholar]
  76. Kent DG, Copley MR, Benz C, Wohrer S, Dykstra BJ. et al. 2009. Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood 113:6342–50 [Google Scholar]
  77. Kobayashi K, Sato K, Kida T, Omori K, Hori M. et al. 2014. Stromal cell–derived factor-1α/C-X-C chemokine receptor type 4 axis promotes endothelial cell barrier integrity via phosphoinositide 3-kinase and Rac1 activation. Arterioscler. Thromb. Vasc. Biol. 34:1716–22 [Google Scholar]
  78. Kozawa O, Matsuno H, Uematsu T. 2001. Involvement of p70 S6 kinase in bone morphogenetic protein signaling: vascular endothelial growth factor synthesis by bone morphogenetic protein-4 in osteoblasts. J. Cell. Biochem. 81:430–36 [Google Scholar]
  79. Krasnov P, Michurina T, Packer MA, Stasiv Y, Nakaya N. et al. 2008. Neuronal nitric oxide synthase contributes to the regulation of hematopoiesis. Mol. Med. 14:141–49 [Google Scholar]
  80. Kronenberg HM. 2003. Developmental regulation of the growth plate. Nature 423:332–36 [Google Scholar]
  81. Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S. et al. 2013. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502:637–43 [Google Scholar]
  82. Kusumbe AP, Ramasamy SK, Adams RH. 2014. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507:323–28 [Google Scholar]
  83. Kusumbe AP, Ramasamy SK, Langen U, Itkin T, Andaloussi M. et al. 2016. Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature 532:380–84 [Google Scholar]
  84. Kwan Tat S, Padrines M, Theoleyre S, Heymann D, Fortun Y. 2004. IL-6, RANKL, TNF-α/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 15:49–60 [Google Scholar]
  85. Kwon TG, Zhao X, Yang Q, Li Y, Ge C. et al. 2011. Physical and functional interactions between Runx2 and HIF-1α induce vascular endothelial growth factor gene expression. J. Cell. Biochem. 112:3582–93 [Google Scholar]
  86. Lammert E, Cleaver O, Melton D. 2001. Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–67 [Google Scholar]
  87. Laurencin C, Khan Y, El-Amin SF. 2006. Bone graft substitutes. Expert Rev. Med. Devices 3:49–57 [Google Scholar]
  88. Lichtman MA. 1981. The ultrastructure of the hemopoietic environment of the marrow: a review. Exp. Hematol. 9:391–410 [Google Scholar]
  89. Lieberman JR, Daluiski A, Einhorn TA. 2002. The role of growth factors in the repair of bone. Biology and clinical applications. J. Bone Joint Surg. Am. 84:1032–44 [Google Scholar]
  90. Lin GL, Hankenson KD. 2011. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J. Cell. Biochem. 112:3491–501 [Google Scholar]
  91. Liu Y, Berendsen AD, Jia S, Lotinun S, Baron R. et al. 2012. Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation. J. Clin. Investig. 122:3101–13 [Google Scholar]
  92. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S. et al. 2009. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457:92–96 [Google Scholar]
  93. Long F, Ornitz DM. 2013. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5:a008334 [Google Scholar]
  94. Lopez-Lopez C, LeRoith D, Torres-Aleman I. 2004. Insulin-like growth factor I is required for vessel remodeling in the adult brain. PNAS 101:9833–38 [Google Scholar]
  95. Ludin A, Gur-Cohen S, Golan K, Kaufmann KB, Itkin T. et al. 2014. Reactive oxygen species regulate hematopoietic stem cell self-renewal, migration and development, as well as their bone marrow microenvironment. Antioxid. Redox Signal. 21:1605–19 [Google Scholar]
  96. Ludin A, Itkin T, Gur-Cohen S, Mildner A, Shezen E. et al. 2012. Monocytes-macrophages that express alpha-smooth muscle actin preserve primitive hematopoietic cells in the bone marrow. Nat. Immunol. 13:1072–82 [Google Scholar]
  97. Maes C, Carmeliet P, Moermans K, Stockmans I, Smets N. et al. 2002. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech. Dev. 111:61–73 [Google Scholar]
  98. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI. et al. 2010. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev. Cell 19:329–44 [Google Scholar]
  99. Maes C, Stockmans I, Moermans K, Van Looveren R, Smets N. et al. 2004. Soluble VEGF isoforms are essential for establishing epiphyseal vascularization and regulating chondrocyte development and survival. J. Clin. Investig. 113:188–99 [Google Scholar]
  100. Matsumoto K, Yoshitomi H, Rossant J, Zaret KS. 2001. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294:559–63 [Google Scholar]
  101. Mayer H, Bertram H, Lindenmaier W, Korff T, Weber H, Weich H. 2005. Vascular endothelial growth factor (VEGF-A) expression in human mesenchymal stem cells: autocrine and paracrine role on osteoblastic and endothelial differentiation. J. Cell Biochem. 95:827–39 [Google Scholar]
  102. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. 2008. Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452:442–47 [Google Scholar]
  103. Mercier FE, Scadden DT. 2015. Not all created equal: lineage hard-wiring in the production of blood. Cell 163:1568–70 [Google Scholar]
  104. Michurina T, Krasnov P, Balazs A, Nakaya N, Vasilieva T. et al. 2004. Nitric oxide is a regulator of hematopoietic stem cell activity. Mol. Ther. 10:241–48 [Google Scholar]
  105. Midy V, Plouet J. 1994. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem. Biophys. Res. Commun. 199:380–86 [Google Scholar]
  106. Miyamoto K, Araki KY, Naka K, Arai F, Takubo K. et al. 2007. Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1:101–12 [Google Scholar]
  107. Morrison SJ, Scadden DT. 2014. The bone marrow niche for haematopoietic stem cells. Nature 505:327–34 [Google Scholar]
  108. Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. 1996. The aging of hematopoietic stem cells. Nat. Med. 2:1011–16 [Google Scholar]
  109. Murakami M, Nguyen LT, Zhuang ZW, Moodie KL, Carmeliet P. et al. 2008. The FGF system has a key role in regulating vascular integrity. J. Clin. Investig. 118:3355–66 [Google Scholar]
  110. Nakamura-Ishizu A, Takubo K, Fujioka M, Suda T. 2014. Megakaryocytes are essential for HSC quiescence through the production of thrombopoietin. Biochem. Biophys. Res. Commun. 454:353–57 [Google Scholar]
  111. Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. 2009. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460:259–63 [Google Scholar]
  112. Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K. et al. 2006. The vascular basement membrane: a niche for insulin gene expression and β cell proliferation. Dev. Cell 10:397–405 [Google Scholar]
  113. Nilsson SK, Johnston HM, Whitty GA, Williams B, Webb RJ. 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]
  114. Noireaud J, Andriantsitohaina R. 2014. Recent insights in the paracrine modulation of cardiomyocyte contractility by cardiac endothelial cells. Biomed. Res. Int. 2014:923805 [Google Scholar]
  115. Nolan DJ, Ginsberg M, Israely E, Palikuqi B, Poulos MG. et al. 2013. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev. Cell 26:204–19 [Google Scholar]
  116. North TE, Goessling W, Peeters M, Li P, Ceol C. et al. 2009. Hematopoietic stem cell development is dependent on blood flow. Cell 137:736–48 [Google Scholar]
  117. Ono N, Ono W, Nagasawa T, Kronenberg HM. 2014. A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat. Cell Biol. 16:1157–67 [Google Scholar]
  118. Ota K, Nakamura J, Li W, Kozakae M, Watarai A. et al. 2007. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells. Biochem. Biophys. Res. Commun. 357:270–5 [Google Scholar]
  119. Park JH, Park BH, Kim HK, Park TS, Baek HS. 2002. Hypoxia decreases Runx2/Cbfa1 expression in human osteoblast-like cells. Mol. Cell. Endocrinol. 192:197–203 [Google Scholar]
  120. Paul F, Arkin Y, Giladi A, Jaitin DA, Kenigsberg E. et al. 2015. Transcriptional heterogeneity and lineage commitment in myeloid progenitors. Cell 163:1663–77 [Google Scholar]
  121. Peiris-Pages M, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. 2015. Metastasis and oxidative stress: Are antioxidants a metabolic driver of progression?. Cell Metab 22:956–58 [Google Scholar]
  122. Peng H, Wright V, Usas A, Gearhart B, Shen HC. et al. 2002. Synergistic enhancement of bone formation and healing by stem cell–expressed VEGF and bone morphogenetic protein-4. J. Clin. Investig. 110:751–59 [Google Scholar]
  123. Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE. et al. 2015. Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527:186–91 [Google Scholar]
  124. Potente M, Gerhardt H, Carmeliet P. 2011. Basic and therapeutic aspects of angiogenesis. Cell 146:873–87 [Google Scholar]
  125. Prisby R, Guignandon A, Vanden-Bossche A, Mac-Way F, Linossier MT. et al. 2011. Intermittent PTH(1–84) is osteoanabolic but not osteoangiogenic and relocates bone marrow blood vessels closer to bone-forming sites. J. Bone Miner. Res. 26:2583–96 [Google Scholar]
  126. Rafii S, Butler JM, Ding BS. 2016. Angiocrine functions of organ-specific endothelial cells. Nature 529:316–25 [Google Scholar]
  127. Rajpurohit R, Koch CJ, Tao Z, Teixeira CM, Shapiro IM. 1996. Adaptation of chondrocytes to low oxygen tension: relationship between hypoxia and cellular metabolism. J. Cell. Physiol. 168:424–32 [Google Scholar]
  128. Ramasamy SK, Kusumbe AP, Adams RH. 2015. Regulation of tissue morphogenesis by endothelial cell–derived signals. Trends Cell Biol 25:148–57 [Google Scholar]
  129. Ramasamy SK, Kusumbe AP, Wang L, Adams RH. 2014. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature 507:376–80 [Google Scholar]
  130. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC. et al. 2006. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083–87 [Google Scholar]
  131. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R. et al. 2005. Cell intrinsic alterations underlie hematopoietic stem cell aging. PNAS 102:9194–99 [Google Scholar]
  132. Schindeler A, McDonald MM, Bokko P, Little DG. 2008. Bone remodeling during fracture repair: the cellular picture. Semin. Cell Dev. Biol. 19:459–66 [Google Scholar]
  133. Schipani E, Ryan HE, Didrickson S, Kobayashi T, Knight M, Johnson RS. 2001. Hypoxia in cartilage: HIF-1α is essential for chondrocyte growth arrest and survival. Genes Dev 15:2865–76 [Google Scholar]
  134. Semenza GL. 2003. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3:721–32 [Google Scholar]
  135. Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM. 2010. Aging of the innate immune system. Curr. Opin. Immunol. 22:507–13 [Google Scholar]
  136. Shen Q, Goderie SK, Jin L, Karanth N, Sun Y. et al. 2004. Endothelial cells stimulate self-renewal and expand neurogenesis of neural stem cells. Science 304:1338–40 [Google Scholar]
  137. Shen Q, Wang Y, Kokovay E, Lin G, Chuang SM. et al. 2008. Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions. Cell Stem Cell 3:289–300 [Google Scholar]
  138. Shigematsu S, Yamauchi K, Nakajima K, Iijima S, Aizawa T, Hashizume K. 1999. IGF-1 regulates migration and angiogenesis of human endothelial cells. Endocr. J. 46:Suppl.59–62 [Google Scholar]
  139. Siekmann AF, Lawson ND. 2007. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781–84 [Google Scholar]
  140. Slungaard A, Fernandez JA, Griffin JH, Key NS, Long JR. et al. 2003. Platelet factor 4 enhances generation of activated protein C in vitro and in vivo. Blood 102:146–51 [Google Scholar]
  141. Smith-Berdan S, Nguyen A, Hassanein D, Zimmer M, Ugarte F. et al. 2011. Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell Stem Cell 8:72–83 [Google Scholar]
  142. Smith-Berdan S, Nguyen A, Hong MA, Forsberg EC. 2015. ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking. Stem Cell Rep 4:255–68 [Google Scholar]
  143. Sonntag WE, Lynch CD, Cefalu WT, Ingram RL, Bennett SA. et al. 1999. Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals. J. Gerontol. A 54:B521–38 [Google Scholar]
  144. Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J. et al. 2014. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–73 [Google Scholar]
  145. Steinbrech DS, Mehrara BJ, Saadeh PB, Chin G, Dudziak ME. et al. 1999. Hypoxia regulates VEGF expression and cellular proliferation by osteoblasts in vitro. Plast. Reconstr. Surg. 104:738–47 [Google Scholar]
  146. Steinbrech DS, Mehrara BJ, Saadeh PB, Greenwald JA, Spector JA. et al. 2000. VEGF expression in an osteoblast-like cell line is regulated by a hypoxia response mechanism. Am. J. Physiol. Cell Physiol. 278:C853–60 [Google Scholar]
  147. Storan MJ, Heazlewood SY, Heazlewood CK, Haylock DN, Alexander WS. 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]
  148. Street J, Bao M, deGuzman L, Bunting S, Peale FV Jr. 2002. Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. PNAS 99:9656–61 [Google Scholar]
  149. Street J, Winter D, Wang JH, Wakai A, McGuinness A, Redmond HP. 2000. Is human fracture hematoma inherently angiogenic?. Clin. Orthop. Relat. Res.224–37
  150. Sugimura R, He XC, Venkatraman A, Arai F, Box A. et al. 2012. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell 150:351–65 [Google Scholar]
  151. Takeda N, Maemura K, Horie S, Oishi K, Imai Y. et al. 2007. Thrombomodulin is a clock-controlled gene in vascular endothelial cells. J. Biol. Chem. 282:32561–67 [Google Scholar]
  152. Takubo K, Nagamatsu G, Kobayashi CI, Nakamura-Ishizu A, Kobayashi H. et al. 2013. Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells. Cell Stem Cell 12:49–61 [Google Scholar]
  153. Tatsuyama K, Maezawa Y, Baba H, Imamura Y, Fukuda M. 2000. Expression of various growth factors for cell proliferation and cytodifferentiation during fracture repair of bone. Eur. J. Histochem. 44:269–78 [Google Scholar]
  154. Tavassoli M. 1979. The marrow-blood barrier. Br. J. Haematol. 41:297–302 [Google Scholar]
  155. Tavassoli M. 1986. Modulation of megakaryocyte emperipolesis by phlebotomy: megakaryocytes as a component of marrow-blood barrier. Blood Cells 12:205–16 [Google Scholar]
  156. Tavazoie M, Van der Veken L, Silva-Vargas V, Louissaint M, Colonna L. et al. 2008. A specialized vascular niche for adult neural stem cells. Cell Stem Cell 3:279–88 [Google Scholar]
  157. Tesio M, Golan K, Corso S, Giordano S, Schajnovitz A. et al. 2011. Enhanced c-Met activity promotes G-CSF-induced mobilization of hematopoietic progenitor cells via ROS signaling. Blood 117:419–28 [Google Scholar]
  158. Tokuda H, Hirade K, Wang X, Oiso Y, Kozawa O. 2003. Involvement of SAPK/JNK in basic fibroblast growth factor–induced vascular endothelial growth factor release in osteoblasts. J. Endocrinol. 177:101–7 [Google Scholar]
  159. Ugarte F, Ryser M, Thieme S, Fierro FA, Navratiel K. et al. 2009. Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp. Hematol. 37:867–75.e1 [Google Scholar]
  160. Utting JC, Robins SP, Brandao-Burch A, Orriss IR, Behar J, Arnett TR. 2006. Hypoxia inhibits the growth, differentiation and bone-forming capacity of rat osteoblasts. Exp. Cell Res. 312:1693–702 [Google Scholar]
  161. Vagima Y, Lapid K, Kollet O, Goichberg P, Alon R, Lapidot T. 2011. Pathways implicated in stem cell migration: the SDF-1/CXCR4 axis. Methods Mol. Biol. 750:277–89 [Google Scholar]
  162. Vandekeere S, Dewerchin M, Carmeliet P. 2015. Angiogenesis revisited: an overlooked role of endothelial cell metabolism in vessel sprouting. Microcirculation 22:509–17 [Google Scholar]
  163. Wang B, Zhao L, Fish M, Logan CY, Nusse R. 2015. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524:180–85 [Google Scholar]
  164. Wang DS, Yamazaki K, Nohtomi K, Shizume K, Ohsumi K. et al. 1996. Increase of vascular endothelial growth factor mRNA expression by 1,25-dihydroxyvitamin D3 in human osteoblast-like cells. J. Bone Miner. Res. 11:472–79 [Google Scholar]
  165. Wang FS, Wang CJ, Chen YJ, Chang PR, Huang YT. et al. 2004. Ras induction of superoxide activates ERK-dependent angiogenic transcription factor HIF-1α and VEGF-A expression in shock wave-stimulated osteoblasts. J. Biol. Chem. 279:10331–37 [Google Scholar]
  166. Wang Y, Wan C, Deng L, Liu X, Cao X. et al. 2007. The hypoxia-inducible factor α pathway couples angiogenesis to osteogenesis during skeletal development. J. Clin. Investig. 117:1616–26 [Google Scholar]
  167. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. 2009. The aging of the immune system. Transpl. Int. 22:1041–50 [Google Scholar]
  168. Wilson NK, Kent DG, Buettner F, Shehata M, Macaulay IC. et al. 2015. Combined single-cell functional and gene expression analysis resolves heterogeneity within stem cell populations. Cell Stem Cell 16:712–24 [Google Scholar]
  169. Worthley DL, Churchill M, Compton JT, Tailor Y, Rao M. et al. 2015. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269–84 [Google Scholar]
  170. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. 2001. Physiological migration of hematopoietic stem and progenitor cells. Science 294:1933–36 [Google Scholar]
  171. Xie H, Cui Z, Wang L, Xia Z, Hu Y. et al. 2014. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat. Med. 20:1270–78 [Google Scholar]
  172. Xie Y, Yin T, Wiegraebe W, He XC, Miller D. et al. 2009. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457:97–101 [Google Scholar]
  173. Yakar S, Rosen CJ, Beamer WG, Ackert-Bicknell CL, Wu Y. et al. 2002. Circulating levels of IGF-1 directly regulate bone growth and density. J. Clin. Investig. 110:771–81 [Google Scholar]
  174. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H. et al. 2011. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147:1146–58 [Google Scholar]
  175. Yamazaki S, Iwama A, Takayanagi S, Eto K, Ema H, Nakauchi H. 2009. TGF-β as a candidate bone marrow niche signal to induce hematopoietic stem cell hibernation. Blood 113:1250–56 [Google Scholar]
  176. Yang B, Cai B, Deng P, Wu X, Guan Y. et al. 2015. Nitric oxide increases arterial endotheial permeability through mediating VE-cadherin expression during arteriogenesis. PLOS ONE 10:e0127931 [Google Scholar]
  177. Yoshida S, Sukeno M, Nabeshima Y. 2007. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 317:1722–26 [Google Scholar]
  178. Zamurovic N, Cappellen D, Rohner D, Susa M. 2004. Coordinated activation of notch, Wnt, and transforming growth factor-β signaling pathways in bone morphogenic protein 2–induced osteogenesis: Notch target gene Hey1 inhibits mineralization and Runx2 transcriptional activity. J. Biol. Chem. 279:37704–15 [Google Scholar]
  179. Zelzer E, Glotzer DJ, Hartmann C, Thomas D, Fukai N. et al. 2001. Tissue specific regulation of VEGF expression during bone development requires Cbfa1/Runx2. Mech. Dev. 106:97–106 [Google Scholar]
  180. Zelzer E, Olsen BR. 2003. The genetic basis for skeletal diseases. Nature 423:343–48 [Google Scholar]
  181. Zhang J, Niu C, Ye L, Huang H, He X. et al. 2003. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425:836–41 [Google Scholar]
  182. Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P. et al. 2014. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat. Med. 20:1321–26 [Google Scholar]
  183. Zhao M, Ross JT, Itkin T, Perry JM, Venkatraman A. et al. 2012. FGF signaling facilitates postinjury recovery of mouse hematopoietic system. Blood 120:1831–42 [Google Scholar]
  184. Zhou BO, Ding L, Morrison SJ. 2015. Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. eLife 4:e05521 [Google Scholar]
  185. Zlokovic BV. 2008. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57:178–201 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error