Skip to main content

Vascular Niche in HSC Development, Maintenance and Regulation

  • Chapter
  • First Online:
Tissue-Specific Stem Cell Niche

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Hematopoietic stem cells (HSC) are multi-potent cells that have ability to self-renew and differentiate to all blood cell lineages. To function properly, HSC are regulated within unique microenvironments, or so called HSC niches , which are composed of specialized supporting cells and extracellular matrix. During mammalian embryogenesis, sites of hematopoiesis change over the course of gestation, as does the HSC niche composition: from extraembryonic yolk sac and placenta, to embryonic aorta-gonad-mesonephros region, fetal liver, and finally fetal bone marrow where HSC predominantly reside postnatally. From their first emergence to their final destination in bone marrow, HSC reside in close proximity to, and interact with vascular cells. There are three main vascular niche types; sinusoidal, arteriolar and perivascular. The interactions between HSC and vascular niche cells have been of great research interest; however, our understanding of the cellular phenotypes within vascular niches, and the molecular basis of vascular niche-HSC interactions, is still rudimentary. In this chapter, we will discuss the developmental relationships between HSC and vascular endothelial cells during HSC ontogeny, and the role of postnatal vascular niches in the regulation of HSC maintenance and function.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Schofield R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells. 1978;4(1–2):7–25.

    CAS  PubMed  Google Scholar 

  2. Becker AJ, McCulloch EA, Till JE. Cytological demonstration of the clonal nature of spleen colonies derived from transplanted mouse marrow cells. Nature. 1963;197:452–4.

    Article  CAS  PubMed  Google Scholar 

  3. Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–22.

    Article  CAS  PubMed  Google Scholar 

  4. Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity. 1994;1(8):661–73.

    Article  CAS  PubMed  Google Scholar 

  5. Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc Natl Acad Sci USA. 2001;98(25):14541–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kondo M, Weissman IL, Akashi K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell. 1997;91(5):661–72.

    Article  CAS  PubMed  Google Scholar 

  7. Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121(7):1109–21.

    Article  CAS  PubMed  Google Scholar 

  8. Chen CZ, Li M, de Graaf D, Monti S, Gottgens B, Sanchez MJ, et al. Identification of endoglin as a functional marker that defines long-term repopulating hematopoietic stem cells. Proc Natl Acad Sci USA. 2002;99(24):15468–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Osawa M, Hanada K, Hamada H, Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science. 1996;273(5272):242–5.

    Article  CAS  PubMed  Google Scholar 

  10. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med. 1996;183(4):1797–806.

    Article  CAS  PubMed  Google Scholar 

  11. Challen GA, Boles N, Lin KK, Goodell MA. Mouse hematopoietic stem cell identification and analysis. Cytometry A. 2009;75(1):14–24.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Akashi K, Reya T, Dalma-Weiszhausz D, Weissman IL. Lymphoid precursors. Curr Opin Immunol. 2000;12(2):144–50.

    Article  CAS  PubMed  Google Scholar 

  13. Oguro H, Ding L, Morrison SJ. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors. Cell Stem Cell. 2013;13(1):102–16 Epub 2013/07/06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Dykstra B, Kent D, Bowie M, McCaffrey L, Hamilton M, Lyons K, et al. Long-term propagation of distinct hematopoietic differentiation programs in vivo. Cell Stem Cell. 2007;1(2):218–29.

    Article  CAS  PubMed  Google Scholar 

  15. Sieburg HB, Cho RH, Dykstra B, Uchida N, Eaves CJ, Muller-Sieburg CE. The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood. 2006;107(6):2311–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Yilmaz OH, Kiel MJ, Morrison SJ. SLAM family markers are conserved among hematopoietic stem cells from old and reconstituted mice and markedly increase their purity. Blood. 2006;107(3):924–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mikkola HK, Fujiwara Y, Schlaeger TM, Traver D, Orkin SH. Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo. Blood. 2003;101(2):508–16.

    Article  CAS  PubMed  Google Scholar 

  18. Goldie LC, Lucitti JL, Dickinson ME, Hirschi KK. Cell signaling directing the formation and function of hemogenic endothelium during murine embryogenesis. Blood. 2008;112(8):3194–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. North TE, de Bruijn MF, Stacy T, Talebian L, Lind E, Robin C, et al. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 2002;16(5):661–72.

    Article  CAS  PubMed  Google Scholar 

  20. Kim I, Yilmaz OH, Morrison SJ. CD144 (VE-cadherin) is transiently expressed by fetal liver hematopoietic stem cells. Blood. 2005;106(3):903–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morrison SJ, Hemmati HD, Wandycz AM, Weissman IL. The purification and characterization of fetal liver hematopoietic stem cells. Proc Natl Acad Sci USA. 1995;92(22):10302–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Petrenko O, Beavis A, Klaine M, Kittappa R, Godin I, Lemischka IR. The molecular characterization of the fetal stem cell marker AA4. Immunity. 1999;10(6):691–700.

    Article  CAS  PubMed  Google Scholar 

  23. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR. A stem cell molecular signature. Science. 2002;298(5593):601–4 Epub 2002/09/14.

    Article  CAS  PubMed  Google Scholar 

  24. Kiel MJ, Iwashita T, Yilmaz OH, Morrison SJ. Spatial differences in hematopoiesis but not in stem cells indicate a lack of regional patterning in definitive hematopoietic stem cells. Dev Biol. 2005;283(1):29–39.

    Article  CAS  PubMed  Google Scholar 

  25. Phillips RL, Ernst RE, Brunk B, Ivanova N, Mahan MA, Deanehan JK, et al. The genetic program of hematopoietic stem cells. Science. 2000;288(5471):1635–40 Epub 2000/06/02.

    Article  CAS  PubMed  Google Scholar 

  26. Harrison DE, Zhong RK, Jordan CT, Lemischka IR, Astle CM. Relative to adult marrow, fetal liver repopulates nearly five times more effectively long-term than short-term. Exp Hematol. 1997;25(4):293–7.

    CAS  PubMed  Google Scholar 

  27. Rebel VI, Miller CL, Thornbury GR, Dragowska WH, Eaves CJ, Lansdorp PM. A comparison of long-term repopulating hematopoietic stem cells in fetal liver and adult bone marrow from the mouse. Exp Hematol. 1996;24(5):638–48.

    CAS  PubMed  Google Scholar 

  28. Tajima F, Deguchi T, Laver JH, Zeng H, Ogawa M. Reciprocal expression of CD38 and CD34 by adult murine hematopoietic stem cells. Blood. 2001;97(9):2618–24.

    Article  CAS  PubMed  Google Scholar 

  29. Bowie MB, McKnight KD, Kent DG, McCaffrey L, Hoodless PA, Eaves CJ. Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. J Clin Invest. 2006;116(10):2808–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ogawa M, Tajima F, Ito T, Sato T, Laver JH, Deguchi T. CD34 expression by murine hematopoietic stem cells. Developmental changes and kinetic alterations. Ann NY Acad Sci. 2001;938:139–45.

    Article  CAS  PubMed  Google Scholar 

  31. McKinney-Freeman SL, Naveiras O, Yates F, Loewer S, Philitas M, Curran M, et al. Surface antigen phenotypes of hematopoietic stem cells from embryos and murine embryonic stem cells. Blood. 2009;114(2):268–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kajiume T, Ninomiya Y, Ishihara H, Kanno R, Kanno M. Polycomb group gene mel-18 modulates the self-renewal activity and cell cycle status of hematopoietic stem cells. Exp Hematol. 2004;32(6):571–8.

    Article  CAS  PubMed  Google Scholar 

  33. Ohta H, Sawada A, Kim JY, Tokimasa S, Nishiguchi S, Humphries RK, et al. Polycomb group gene rae28 is required for sustaining activity of hematopoietic stem cells. J Exp Med. 2002;195(6):759–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, et al. Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature. 2003;423(6937):302–5.

    Article  CAS  PubMed  Google Scholar 

  35. Palis J, Yoder MC. Yolk-sac hematopoiesis: the first blood cells of mouse and man. Exp Hematol. 2001;29(8):927–36 Epub 2001/08/10.

    Article  CAS  PubMed  Google Scholar 

  36. Coskun S, Hirschi KK. Establishment and regulation of the HSC niche: Roles of osteoblastic and vascular compartments. Birth Defects Res C Embryo Today. 2010;90(4):229–42.

    Article  CAS  PubMed  Google Scholar 

  37. Ivanovs A, Rybtsov S, Welch L, Anderson RA, Turner ML, Medvinsky A. Highly potent human hematopoietic stem cells first emerge in the intraembryonic aorta-gonad-mesonephros region. J Exp Med. 2011;208(12):2417–27 Epub 2011/11/02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Palis J, McGrath KE, Kingsley PD. Initiation of hematopoiesis and vasculogenesis in murine yolk sac explants. Blood. 1995;86(1):156–63.

    CAS  PubMed  Google Scholar 

  39. Liu CP, Auerbach R. In vitro development of murine T cells from prethymic and preliver embryonic yolk sac hematopoietic stem cells. Development. 1991;113(4):1315–23 Epub 1991/12/01.

    CAS  PubMed  Google Scholar 

  40. Moore MA, Metcalf D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Br J Haematol. 1970;18(3):279–96.

    Article  CAS  PubMed  Google Scholar 

  41. Dieterlen-Lievre F. On the origin of haemopoietic stem cells in the avian embryo: an experimental approach. J Embryol Exp Morphol. 1975;33(3):607–19 Epub 1975/06/01.

    CAS  PubMed  Google Scholar 

  42. Chen XD, Turpen JB. Intraembryonic origin of hepatic hematopoiesis in Xenopus laevis. J Immunol. 1995;154(6):2557–67 Epub 1995/03/15.

    CAS  PubMed  Google Scholar 

  43. Cumano A, Garcia-Porrero J, Dieterlen-Lievre F, Godin I. Intra-embryonic hematopoiesis in mice. C R Seances Soc Biol Fil. 1995;189(4):617–27.

    CAS  PubMed  Google Scholar 

  44. Medvinsky A, Dzierzak E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell. 1996;86(6):897–906.

    Article  CAS  PubMed  Google Scholar 

  45. Yoder MC, Hiatt K, Dutt P, Mukherjee P, Bodine DM, Orlic D. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity. 1997;7(3):335–44.

    Article  CAS  PubMed  Google Scholar 

  46. Yoder MC, Hiatt K. Engraftment of embryonic hematopoietic cells in conditioned newborn recipients. Blood. 1997;89(6):2176–83.

    CAS  PubMed  Google Scholar 

  47. Matsuoka S, Tsuji K, Hisakawa H, Xu M, Ebihara Y, Ishii T, et al. Generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleures by aorta-gonad-mesonephros region-derived stromal cells. Blood. 2001;98(1):6–12.

    Article  CAS  PubMed  Google Scholar 

  48. Rossant J, Cross JC. Placental development: lessons from mouse mutants. Nat Rev Genet. 2001;2(7):538–48.

    Article  CAS  PubMed  Google Scholar 

  49. Gekas C, Dieterlen-Lievre F, Orkin SH, Mikkola HK. The placenta is a niche for hematopoietic stem cells. Dev Cell. 2005;8(3):365–75.

    Article  CAS  PubMed  Google Scholar 

  50. Ottersbach K, Dzierzak E. The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Dev Cell. 2005;8(3):377–87.

    Article  CAS  PubMed  Google Scholar 

  51. Corbel C, Salaun J, Belo-Diabangouaya P, Dieterlen-Lievre F. Hematopoietic potential of the pre-fusion allantois. Dev Biol. 2007;301(2):478–88.

    Article  CAS  PubMed  Google Scholar 

  52. Zeigler BM, Sugiyama D, Chen M, Guo Y, Downs KM, Speck NA. The allantois and chorion, when isolated before circulation or chorio-allantoic fusion, have hematopoietic potential. Development. 2006;133(21):4183–92.

    Article  CAS  PubMed  Google Scholar 

  53. Rhodes KE, Gekas C, Wang Y, Lux CT, Francis CS, Chan DN, et al. The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell. 2008;2(3):252–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tam PP, Behringer RR. Mouse gastrulation: the formation of a mammalian body plan. Mech Dev. 1997;68(1–2):3–25.

    Article  CAS  PubMed  Google Scholar 

  55. Kumaravelu P, Hook L, Morrison AM, Ure J, Zhao S, Zuyev S, et al. Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver. Development. 2002;129(21):4891–9.

    CAS  PubMed  Google Scholar 

  56. Charbord P, Oostendorp R, Pang W, Herault O, Noel F, Tsuji T, et al. Comparative study of stromal cell lines derived from embryonic, fetal, and postnatal mouse blood-forming tissues. Exp Hematol. 2002;30(10):1202–10.

    Article  CAS  PubMed  Google Scholar 

  57. Durand C, Robin C, Dzierzak E. Mesenchymal lineage potentials of aorta-gonad-mesonephros stromal clones. Haematologica. 2006;91(9):1172–9.

    PubMed  Google Scholar 

  58. Cumano A, Godin I. Ontogeny of the hematopoietic system. Annu Rev Immunol. 2007;25:745–85.

    Article  CAS  PubMed  Google Scholar 

  59. Ema H, Nakauchi H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood. 2000;95(7):2284–8.

    CAS  PubMed  Google Scholar 

  60. Mikkola HK, Orkin SH. The journey of developing hematopoietic stem cells. Development. 2006;133(19):3733–44.

    Article  CAS  PubMed  Google Scholar 

  61. Takeuchi M, Sekiguchi T, Hara T, Kinoshita T, Miyajima A. Cultivation of aorta-gonad-mesonephros-derived hematopoietic stem cells in the fetal liver microenvironment amplifies long-term repopulating activity and enhances engraftment to the bone marrow. Blood. 2002;99(4):1190–6.

    Article  CAS  PubMed  Google Scholar 

  62. Klassen LW, Birks J, Allen E, Gurney CW. Experimental medullary aplasia. J Lab Clin Med. 1972;80(1):8–17.

    CAS  PubMed  Google Scholar 

  63. Visnjic D, Kalajzic Z, Rowe DW, Katavic V, Lorenzo J, Aguila HL. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004;103(9):3258–64.

    Article  CAS  PubMed  Google Scholar 

  64. Ohno H, Ogawa M, Nishikawa S, Hayashi S, Kunisada T. Conditions required for myelopoiesis in murine spleen. Immunol Lett. 1993;35(2):197–204 Epub 1993/02/01.

    Article  CAS  PubMed  Google Scholar 

  65. Sasaki K, Matsumura G. Hemopoietic cells in the liver and spleen of the embryonic and early postnatal mouse: a karyometrical observation. Anat Rec. 1987;219(4):378–83 Epub 1987/12/01.

    Article  CAS  PubMed  Google Scholar 

  66. Yanai N, Satoh T, Obinata M. Endothelial cells create a hematopoietic inductive microenvironment preferential to erythropoiesis in the mouse spleen. Cell Struct Funct. 1991;16(1):87–93 Epub 1991/02/01.

    Article  CAS  PubMed  Google Scholar 

  67. Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol. 2008;40(1):46–62.

    Article  CAS  PubMed  Google Scholar 

  68. Coskun S, Chao H, Vasavada H, Heydari K, Gonzales N, Zhou X, et al. Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Rep. 2014;9(2):581–90 Epub 2014/10/15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457(7225):92–6.

    Google Scholar 

  70. Shalaby F, Ho J, Stanford WL, Fischer KD, Schuh AC, Schwartz L, et al. A requirement for Flk1 in primitive and definitive hematopoiesis and vasculogenesis. Cell. 1997;89(6):981–90 Epub 1997/06/13.

    Article  CAS  PubMed  Google Scholar 

  71. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature. 1995;376(6535):62–6.

    Article  CAS  PubMed  Google Scholar 

  72. Sabin FR. Studies on the origin of blood-vessels and of red blood corpuscles as seen in the living blastoderm of chicks during the second day of incubation. Carnegie Contrib Embryol. 1920;27:214–62.

    Google Scholar 

  73. Hirschi KK. Hemogenic endothelium during development and beyond. Blood. 2012;119(21):4823–7 Epub 2012/03/15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Jaffredo T, Gautier R, Eichmann A, Dieterlen-Lievre F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development. 1998;125(22):4575–83.

    CAS  PubMed  Google Scholar 

  75. Sugiyama D, Arai K, Tsuji K. Definitive hematopoiesis from acetyl LDL incorporating endothelial cells in the mouse embryo. Stem Cells Dev. 2005;14(6):687–96.

    Article  CAS  PubMed  Google Scholar 

  76. Zovein AC, Hofmann JJ, Lynch M, French WJ, Turlo KA, Yang Y, et al. Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell. 2008;3(6):625–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bertrand JY, Chi NC, Santoso B, Teng S, Stainier DY, Traver D. Haematopoietic stem cells derive directly from aortic endothelium during development. Nature. 2010;464(7285):108–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Boisset JC, van Cappellen W, Andrieu-Soler C, Galjart N, Dzierzak E, Robin C. In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature. 2010;464(7285):116–20.

    Article  CAS  PubMed  Google Scholar 

  79. Kissa K, Herbomel P. Blood stem cells emerge from aortic endothelium by a novel type of cell transition. Nature. 2010;464(7285):112–5.

    Article  CAS  PubMed  Google Scholar 

  80. Taoudi S, Medvinsky A. Functional identification of the hematopoietic stem cell niche in the ventral domain of the embryonic dorsal aorta. Proc Natl Acad Sci USA. 2007;104(22):9399–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Boisset JC, Clapes T, Klaus A, Papazian N, Onderwater J, Mommaas-Kienhuis M, et al. Progressive maturation towards hematopoietic stem cells in the mouse embryo aorta. Blood. 2014. Epub 2014/10/11.

    Google Scholar 

  82. Swiers G, Baumann C, O’Rourke J, Giannoulatou E, Taylor S, Joshi A, et al. Early dynamic fate changes in haemogenic endothelium characterized at the single-cell level. Nat Commun. 2013;4:2924 Epub 2013/12/12.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Chen MJ, Li Y, De Obaldia ME, Yang Q, Yzaguirre AD, Yamada-Inagawa T, et al. Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell Stem Cell. 2011;9(6):541–52 Epub 2011/12/06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development. 1998;125(9):1747–57 Epub 1998/06/12.

    CAS  PubMed  Google Scholar 

  85. Marcelo KL, Sills TM, Coskun S, Vasavada H, Sanglikar S, Goldie LC, et al. Hemogenic endothelial cell specification requires c-Kit, Notch signaling, and p27-mediated cell-cycle control. Dev Cell. 2013;27(5):504–15 Epub 2013/12/18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Nadin BM, Goodell MA, Hirschi KK. Phenotype and hematopoietic potential of side population cells throughout embryonic development. Blood. 2003;102(7):2436–43.

    Article  CAS  PubMed  Google Scholar 

  87. Hierlihy AM, Seale P, Lobe CG, Rudnicki MA, Megeney LA. The post-natal heart contains a myocardial stem cell population. FEBS Lett. 2002;530(1–3):239–43 Epub 2002/10/22.

    Article  CAS  PubMed  Google Scholar 

  88. Kubota H, Avarbock MR, Brinster RL. Spermatogonial stem cells share some, but not all, phenotypic and functional characteristics with other stem cells. Proc Natl Acad Sci USA. 2003;100(11):6487–92 Epub 2003/05/10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Welm B, Behbod F, Goodell MA, Rosen JM. Isolation and characterization of functional mammary gland stem cells. Cell Prolif. 2003;36(Suppl 1):17–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wulf GG, Luo KL, Jackson KA, Brenner MK, Goodell MA. Cells of the hepatic side population contribute to liver regeneration and can be replenished with bone marrow stem cells. Haematologica. 2003;88(4):368–78 Epub 2003/04/12.

    PubMed  Google Scholar 

  91. Mizuochi C, Fraser ST, Biasch K, Horio Y, Kikushige Y, Tani K, et al. Intra-aortic clusters undergo endothelial to hematopoietic phenotypic transition during early embryogenesis. PLoS ONE. 2012;7(4):e35763. Epub 2012/05/05.

    Google Scholar 

  92. Murray PDF. The development in vitro of the blood of the Early Chick Embryo1932 1932-10-01 00:00:00. p. 497–521.

    Google Scholar 

  93. Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development. 1998;125(4):725–32.

    CAS  PubMed  Google Scholar 

  94. Kennedy M, Firpo M, Choi K, Wall C, Robertson S, Kabrun N, et al. A common precursor for primitive erythropoiesis and definitive haematopoiesis. Nature. 1997;386(6624):488–93.

    Article  CAS  PubMed  Google Scholar 

  95. Fehling HJ, Lacaud G, Kubo A, Kennedy M, Robertson S, Keller G, et al. Tracking mesoderm induction and its specification to the hemangioblast during embryonic stem cell differentiation. Development. 2003;130(17):4217–27 Epub 2003/07/23.

    Article  CAS  PubMed  Google Scholar 

  96. Huber TL, Kouskoff V, Fehling HJ, Palis J, Keller G. Haemangioblast commitment is initiated in the primitive streak of the mouse embryo. Nature. 2004;432(7017):625–30.

    Article  CAS  PubMed  Google Scholar 

  97. Nishikawa S. Hemangioblast: an in vitro phantom. Wiley interdisciplinary reviews. Dev Biol. 2012;1(4):603–8 Epub 2013/06/27.

    CAS  Google Scholar 

  98. Lancrin C, Sroczynska P, Stephenson C, Allen T, Kouskoff V, Lacaud G. The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature. 2009;457(7231):892–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Padron-Barthe L, Temino S, Villa del Campo C, Carramolino L, Isern J, Torres M. Clonal analysis identifies hemogenic endothelium as the source of the blood-endothelial common lineage in the mouse embryo. Blood. 2014;124(16):2523–32. Epub 2014/08/21.

    Google Scholar 

  100. Pereira CF, Chang B, Qiu J, Niu X, Papatsenko D, Hendry CE, et al. Induction of a hemogenic program in mouse fibroblasts. Cell Stem Cell. 2013;13(2):205–18 Epub 2013/06/19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Doulatov S, Vo LT, Chou SS, Kim PG, Arora N, Li H, et al. Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Cell Stem Cell. 2013;13(4):459–70 Epub 2013/10/08.

    Article  CAS  PubMed  Google Scholar 

  102. Myers CT, Krieg PA. BMP-mediated specification of the erythroid lineage suppresses endothelial development in blood island precursors. Blood. 2013;122(24):3929–39 Epub 2013/10/09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wright DE, Wagers AJ, Gulati AP, Johnson FL, Weissman IL. Physiological migration of hematopoietic stem and progenitor cells. Science. 2001;294(5548):1933–6.

    Article  CAS  PubMed  Google Scholar 

  104. Rafii S, Shapiro F, Pettengell R, Ferris B, Nachman RL, Moore MA, et al. Human bone marrow microvascular endothelial cells support long-term proliferation and differentiation of myeloid and megakaryocytic progenitors. Blood. 1995;86(9):3353–63 Epub 1995/11/01.

    CAS  PubMed  Google Scholar 

  105. Avecilla ST, Hattori K, Heissig B, Tejada R, Liao F, Shido K, et al. Chemokine-mediated interaction of hematopoietic progenitors with the bone marrow vascular niche is required for thrombopoiesis. Nat Med. 2004;10(1):64–71.

    Article  CAS  PubMed  Google Scholar 

  106. Kiel MJ, Radice GL, Morrison SJ. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell. 2007;1(2):204–17.

    Article  CAS  PubMed  Google Scholar 

  107. Hooper AT, Butler JM, Nolan DJ, Kranz A, Iida K, Kobayashi M, et al. Engraftment and reconstitution of hematopoiesis is dependent on VEGFR2-mediated regeneration of sinusoidal endothelial cells. Cell Stem Cell. 2009;4(3):263–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kopp HG, Hooper AT, Avecilla ST, Rafii S. Functional heterogeneity of the bone marrow vascular niche. Ann NY Acad Sci. 2009;1176:47–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yao Y, Song X, Cheng H, Tang G, Hu X, Zhou H, et al. Dysfunction of bone marrow vascular niche in acute graft-versus-host disease after MHC-haploidentical bone marrow transplantation. PLoS ONE. 2014;9(8):e104607. Epub 2014/08/15.

    Google Scholar 

  110. Himburg HA, Harris JR, Ito T, Daher P, Russell JL, Quarmyne M, et al. Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. Cell reports. 2012;2(4):964–75 Epub 2012/10/23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43 Epub 2013/04/30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Takaku T, Malide D, Chen J, Calado RT, Kajigaya S, Young NS. Hematopoiesis in 3 dimensions: human and murine bone marrow architecture visualized by confocal microscopy. Blood. 2010;116(15):e41–55 Epub 2010/07/22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Godin I, Garcia-Porrero JA, Dieterlen-Lievre F, Cumano A. Stem cell emergence and hemopoietic activity are incompatible in mouse intraembryonic sites. J Exp Med. 1999;190(1):43–52 Epub 1999/08/03.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Muller AM, Medvinsky A, Strouboulis J, Grosveld F, Dzierzak E. Development of hematopoietic stem cell activity in the mouse embryo. Immunity. 1994;1(4):291–301.

    Article  CAS  PubMed  Google Scholar 

  115. de Bruijn MF, Ma X, Robin C, Ottersbach K, Sanchez MJ, Dzierzak E. Hematopoietic stem cells localize to the endothelial cell layer in the midgestation mouse aorta. Immunity. 2002;16(5):673–83.

    Article  PubMed  Google Scholar 

  116. Cumano A, Dieterlen-Lievre F, Godin I. Lymphoid potential, probed before circulation in mouse, is restricted to caudal intraembryonic splanchnopleura. Cell. 1996;86(6):907–16.

    Article  CAS  PubMed  Google Scholar 

  117. Li Z, Lan Y, He W, Chen D, Wang J, Zhou F, et al. Mouse embryonic head as a site for hematopoietic stem cell development. Cell Stem Cell. 2012;11(5):663–75 Epub 2012/11/06.

    Article  CAS  PubMed  Google Scholar 

  118. Kunisaki Y, Frenette PS. Influences of vascular niches on hematopoietic stem cell fate. Int J Hematol. 2014;99(6):699–705 Epub 2014/04/24.

    Article  PubMed  Google Scholar 

  119. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat Med. 2012;18(11):1651–7 Epub 2012/10/23.

    Article  CAS  PubMed  Google Scholar 

  120. Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637–43 Epub 2013/10/11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sugiyama T, Kohara H, Noda M, Nagasawa T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity. 2006;25(6):977–88.

    Article  CAS  PubMed  Google Scholar 

  122. Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell. 2007;131(2):324–36.

    Article  CAS  PubMed  Google Scholar 

  123. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010;466(7308):829–34 Epub 2010/08/13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227–30 Epub 2013/02/26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Ding L, Morrison SJ. Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature. 2013;495(7440):231–5 Epub 2013/02/26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481(7382):457–62 Epub 2012/01/28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124(2):407–21.

    Article  CAS  PubMed  Google Scholar 

  128. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452(7186):442–7.

    Article  CAS  PubMed  Google Scholar 

  129. Hanoun M, Zhang D, Mizoguchi T, Pinho S, Pierce H, Kunisaki Y, et al. Acute myelogenous leukemia-induced sympathetic neuropathy promotes malignancy in an altered hematopoietic stem cell niche. Cell Stem Cell. 2014;15(3):365–75 Epub 2014/07/16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Arranz L, Sanchez-Aguilera A, Martin-Perez D, Isern J, Langa X, Tzankov A, et al. Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms. Nature. 2014;512(7512):78–81 Epub 2014/07/22.

    CAS  PubMed  Google Scholar 

  131. Vannucchi AM, Bianchi L, Cellai C, Paoletti F, Rana RA, Lorenzini R, et al. Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice). Blood. 2002;100(4):1123–32 Epub 2002/08/01.

    Article  CAS  PubMed  Google Scholar 

  132. Shivdasani RA, Orkin SH. Erythropoiesis and globin gene expression in mice lacking the transcription factor NF-E2. Proc Natl Acad Sci USA. 1995;92(19):8690–4 Epub 1995/09/12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Heazlewood SY, Neaves RJ, Williams B, Haylock DN, Adams TE, Nilsson SK. Megakaryocytes co-localise with hemopoietic stem cells and release cytokines that up-regulate stem cell proliferation. Stem Cell Res. 2013;11(2):782–92 Epub 2013/06/25.

    Article  CAS  PubMed  Google Scholar 

  134. Olson TS, Caselli A, Otsuru S, Hofmann TJ, Williams R, Paolucci P, et al. Megakaryocytes promote murine osteoblastic HSC niche expansion and stem cell engraftment after radioablative conditioning. Blood. 2013;121(26):5238–49 Epub 2013/05/15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bruns I, Lucas D, Pinho S, Ahmed J, Lambert MP, Kunisaki Y, et al. Megakaryocytes regulate hematopoietic stem cell quiescence through CXCL4 secretion. Nat Med. 2014;20(11):1315–20 Epub 2014/10/20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Storan MJ, Heazlewood SY, Heazlewood CK, Haylock DN, Alexander WS, Neaves RJ, et al. Factors released by megakaryocytes thrombin cleave osteopontin to negatively regulate hemopoietic stem cells. Stem Cells. 2015. Epub 2015/04/14.

    Google Scholar 

  137. Joseph C, Quach JM, Walkley CR, Lane SW, Lo Celso C, Purton LE. Deciphering hematopoietic stem cells in their niches: a critical appraisal of genetic models, lineage tracing, and imaging strategies. Cell Stem Cell. 2013;13(5):520–33. Epub 2013/11/12.

    Google Scholar 

  138. Wang L, Benedito R, Bixel MG, Zeuschner D, Stehling M, Savendahl L, et al. Identification of a clonally expanding haematopoietic compartment in bone marrow. EMBO J. 2013;32(2):219–30 Epub 2012/11/29.

    Article  PubMed  CAS  Google Scholar 

  139. Brandt JE, Galy AH, Luens KM, Travis M, Young J, Tong J, et al. Bone marrow repopulation by human marrow stem cells after long-term expansion culture on a porcine endothelial cell line. Exp Hematol. 1998;26(10):950–61.

    CAS  PubMed  Google Scholar 

  140. Chute JP, Saini AA, Chute DJ, Wells MR, Clark WB, Harlan DM, et al. Ex vivo culture with human brain endothelial cells increases the SCID-repopulating capacity of adult human bone marrow. Blood. 2002;100(13):4433–9.

    Article  CAS  PubMed  Google Scholar 

  141. Li W, Johnson SA, Shelley WC, Ferkowicz M, Morrison P, Li Y, et al. Primary endothelial cells isolated from the yolk sac and para-aortic splanchnopleura support the expansion of adult marrow stem cells in vitro. Blood. 2003;102(13):4345–53.

    Article  CAS  PubMed  Google Scholar 

  142. Li W, Johnson SA, Shelley WC, Yoder MC. Hematopoietic stem cell repopulating ability can be maintained in vitro by some primary endothelial cells. Exp Hematol. 2004;32(12):1226–37.

    Article  CAS  PubMed  Google Scholar 

  143. Duncan AW, Rattis FM, DiMascio LN, Congdon KL, Pazianos G, Zhao C, et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol. 2005;6(3):314–22.

    Article  CAS  PubMed  Google Scholar 

  144. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423(6938):409–14.

    Article  CAS  PubMed  Google Scholar 

  145. Robert-Moreno A, Guiu J, Ruiz-Herguido C, Lopez ME, Ingles-Esteve J, Riera L, et al. Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J. 2008;27(13):1886–95 Epub 2008/06/06.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Robert-Moreno A, Espinosa L, de la Pompa JL, Bigas A. RBPjkappa-dependent Notch function regulates Gata2 and is essential for the formation of intra-embryonic hematopoietic cells. Development. 2005;132(5):1117–26.

    Article  CAS  PubMed  Google Scholar 

  147. Kim AD, Melick CH, Clements WK, Stachura DL, Distel M, Panakova D, et al. Discrete Notch signaling requirements in the specification of hematopoietic stem cells. EMBO J. 2014;33(20):2363–73 Epub 2014/09/19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Hadland BK, Huppert SS, Kanungo J, Xue Y, Jiang R, Gridley T, et al. A requirement for Notch1 distinguishes 2 phases of definitive hematopoiesis during development. Blood. 2004;104(10):3097–105 Epub 2004/07/15.

    Article  CAS  PubMed  Google Scholar 

  149. Kumano K, Chiba S, Kunisato A, Sata M, Saito T, Nakagami-Yamaguchi E, et al. Notch1 but not Notch2 is essential for generating hematopoietic stem cells from endothelial cells. Immunity. 2003;18(5):699–711.

    Article  CAS  PubMed  Google Scholar 

  150. Maillard I, Koch U, Dumortier A, Shestova O, Xu L, Sai H, et al. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2008;2(4):356–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Mancini SJ, Mantei N, Dumortier A, Suter U, MacDonald HR, Radtke F. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood. 2005;105(6):2340–2.

    Article  CAS  PubMed  Google Scholar 

  152. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID. Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med. 2010;16(2):232–6 Epub 2010/01/19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, et al. Endothelial cells are essential for the self-renewal and repopulation of Notch-dependent hematopoietic stem cells. Cell Stem Cell. 2010;6(3):251–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hadland BK, Varnum-Finney B, Poulos MG, Moon RT, Butler JM, Rafii S, et al. Endothelium and NOTCH specify and amplify aorta-gonad-mesonephros-derived hematopoietic stem cells. J Clin Invest. 2015;125(5):2032–45 Epub 2015/04/14.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Poulos MG, Guo P, Kofler NM, Pinho S, Gutkin MC, Tikhonova A, et al. Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep. 2013;4(5):1022–34 Epub 2013/09/10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Gerhardt DM, Pajcini KV, D’Altri T, Tu L, Jain R, Xu L, et al. The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev. 2014;28(6):576–93 Epub 2014/03/19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Chiang MY, Shestova O, Xu L, Aster JC, Pear WS. Divergent effects of supraphysiologic Notch signals on leukemia stem cells and hematopoietic stem cells. Blood. 2013;121(6):905–17 Epub 2012/11/02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Varnum-Finney B, Halasz LM, Sun M, Gridley T, Radtke F, Bernstein ID. Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J Clin Invest. 2011;121(3):1207–16 Epub 2011/02/03.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Rattis FM, Voermans C, Reya T. Wnt signaling in the stem cell niche. Curr Opin Hematol. 2004;11(2):88–94.

    Article  CAS  PubMed  Google Scholar 

  160. Scheller M, Huelsken J, Rosenbauer F, Taketo MM, Birchmeier W, Tenen DG, et al. Hematopoietic stem cell and multilineage defects generated by constitutive beta-catenin activation. Nat Immunol. 2006;7(10):1037–47.

    Article  CAS  PubMed  Google Scholar 

  161. Kirstetter P, Anderson K, Porse BT, Jacobsen SE, Nerlov C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat Immunol. 2006;7(10):1048–56.

    Article  CAS  PubMed  Google Scholar 

  162. Mazo IB, Gutierrez-Ramos JC, Frenette PS, Hynes RO, Wagner DD, von Andrian UH. Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1. J Exp Med. 1998;188(3):465–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Wilson A, Trumpp A. Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol. 2006;6(2):93–106.

    Article  CAS  PubMed  Google Scholar 

  164. Whetton AD, Graham GJ. Homing and mobilization in the stem cell niche. Trends Cell Biol. 1999;9(6):233–8.

    Article  CAS  PubMed  Google Scholar 

  165. Dao MA, Nolta JA. Cytokine and integrin stimulation synergize to promote higher levels of GATA-2, c-myb, and CD34 protein in primary human hematopoietic progenitors from bone marrow. Blood. 2007;109(6):2373–9 Epub 2006/11/11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Schweitzer KM, Drager AM, van der Valk P, Thijsen SF, Zevenbergen A, Theijsmeijer AP, et al. Constitutive expression of E-selectin and vascular cell adhesion molecule-1 on endothelial cells of hematopoietic tissues. Am J Pathol. 1996;148(1):165–75 Epub 1996/01/01.

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Kansas GS. Selectins and their ligands: current concepts and controversies. Blood. 1996;88(9):3259–87 Epub 1996/11/01.

    CAS  PubMed  Google Scholar 

  168. Sipkins DA, Wei X, Wu JW, Runnels JM, Cote D, Means TK, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature. 2005;435(7044):969–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10(8):858–64.

    Article  CAS  PubMed  Google Scholar 

  170. Ara T, Tokoyoda K, Sugiyama T, Egawa T, Kawabata K, Nagasawa T. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity. 2003;19(2):257–67.

    Article  CAS  PubMed  Google Scholar 

  171. Nie Y, Han YC, Zou YR. CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med. 2008;205(4):777–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N, Kohno K, et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity. 2010;33(3):387–99 Epub 2010/09/21.

    Article  CAS  PubMed  Google Scholar 

  173. Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell. 2011;147(5):1146–58 Epub 2011/11/29.

    Article  CAS  PubMed  Google Scholar 

  174. Ogawa M, Matsuzaki Y, Nishikawa S, Hayashi S, Kunisada T, Sudo T, et al. Expression and function of c-kit in hemopoietic progenitor cells. J Exp Med. 1991;174(1):63–71 Epub 1991/07/01.

    Article  CAS  PubMed  Google Scholar 

  175. Russell ES. Hereditary anemias of the mouse: a review for geneticists. Adv Genet. 1979;20:357–459 Epub 1979/01/01.

    Article  CAS  PubMed  Google Scholar 

  176. McCulloch EA, Siminovitch L, Till JE, Russell ES, Bernstein SE. The cellular basis of the genetically determined hemopoietic defect in anemic mice of genotype Sl-Sld. Blood. 1965;26(4):399–410.

    CAS  PubMed  Google Scholar 

  177. Barker JE. Sl/Sld hematopoietic progenitors are deficient in situ. Exp Hematol. 1994;22(2):174–7 Epub 1994/02/01.

    CAS  PubMed  Google Scholar 

  178. Kimura Y, Ding B, Imai N, Nolan DJ, Butler JM, Rafii S. c-Kit-mediated functional positioning of stem cells to their niches is essential for maintenance and regeneration of adult hematopoiesis. PLoS ONE. 2011;6(10):e26918. Epub 2011/11/03.

    Google Scholar 

  179. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425(6960):841–6.

    Article  CAS  PubMed  Google Scholar 

  180. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611 Epub 2004/08/06.

    Article  CAS  PubMed  Google Scholar 

  181. Kabrun N, Buhring HJ, Choi K, Ullrich A, Risau W, Keller G. Flk-1 expression defines a population of early embryonic hematopoietic precursors. Development. 1997;124(10):2039–48.

    CAS  PubMed  Google Scholar 

  182. Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, et al. Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. Nat Med. 2002;8(8):841–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  183. Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR. VEGFA is necessary for chondrocyte survival during bone development. Development. 2004;131(9):2161–71 Epub 2004/04/10.

    Article  CAS  PubMed  Google Scholar 

  184. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010;19(2):329–44 Epub 2010/08/17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Gerber HP, Malik AK, Solar GP, Sherman D, Liang XH, Meng G, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417(6892):954–8.

    Article  CAS  PubMed  Google Scholar 

  186. Sitnicka E, Ruscetti FW, Priestley GV, Wolf NS, Bartelmez SH. Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells. Blood. 1996;88(1):82–8.

    CAS  PubMed  Google Scholar 

  187. Garbe A, Spyridonidis A, Mobest D, Schmoor C, Mertelsmann R, Henschler R. Transforming growth factor-beta 1 delays formation of granulocyte-macrophage colony-forming cells, but spares more primitive progenitors during ex vivo expansion of CD34+ haemopoietic progenitor cells. Br J Haematol. 1997;99(4):951–8.

    Article  CAS  PubMed  Google Scholar 

  188. Batard P, Monier MN, Fortunel N, Ducos K, Sansilvestri-Morel P, Phan T, et al. TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation. J Cell Sci. 2000;113(Pt 3):383–90.

    CAS  PubMed  Google Scholar 

  189. Soma T, Yu JM, Dunbar CE. Maintenance of murine long-term repopulating stem cells in ex vivo culture is affected by modulation of transforming growth factor-beta but not macrophage inflammatory protein-1 alpha activities. Blood. 1996;87(11):4561–7.

    CAS  PubMed  Google Scholar 

  190. Hatzfeld J, Li ML, Brown EL, Sookdeo H, Levesque JP, O’Toole T, et al. Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides. J Exp Med. 1991;174(4):925–9.

    Article  CAS  PubMed  Google Scholar 

  191. Fortunel N, Batard P, Hatzfeld A, Monier MN, Panterne B, Lebkowski J, et al. High proliferative potential-quiescent cells: a working model to study primitive quiescent hematopoietic cells. J Cell Sci. 1998;111(Pt 13):1867–75.

    CAS  PubMed  Google Scholar 

  192. Goey H, Keller JR, Back T, Longo DL, Ruscetti FW, Wiltrout RH. Inhibition of early murine hemopoietic progenitor cell proliferation after in vivo locoregional administration of transforming growth factor-beta 1. J Immunol. 1989;143(3):877–80.

    CAS  PubMed  Google Scholar 

  193. Fan X, Valdimarsdottir G, Larsson J, Brun A, Magnusson M, Jacobsen SE, et al. Transient disruption of autocrine TGF-beta signaling leads to enhanced survival and proliferation potential in single primitive human hemopoietic progenitor cells. J Immunol. 2002;168(2):755–62.

    Article  CAS  PubMed  Google Scholar 

  194. Kim SJ, Letterio J. Transforming growth factor-beta signaling in normal and malignant hematopoiesis. Leukemia. 2003;17(9):1731–7.

    Article  CAS  PubMed  Google Scholar 

  195. Wierenga AT, Vellenga E, Schuringa JJ. Convergence of hypoxia and TGFbeta pathways on cell cycle regulation in human hematopoietic stem/progenitor cells. PLoS ONE. 2014;9(3):e93494. Epub 2014/04/02.

    Google Scholar 

  196. Chute JP, Muramoto GG, Dressman HK, Wolfe G, Chao NJ, Lin S. Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis. Stem Cells. 2006;24(5):1315–27.

    Article  CAS  PubMed  Google Scholar 

  197. Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF. Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood. 2008;111(7):3415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121(9):3375–83 Epub 2011/09/02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Yoshida K, Taga T, Saito M, Suematsu S, Kumanogoh A, Tanaka T, et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc Natl Acad Sci USA. 1996;93(1):407–11 Epub 1996/01/09.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Yao L, Yokota T, Xia L, Kincade PW, McEver RP. Bone marrow dysfunction in mice lacking the cytokine receptor gp130 in endothelial cells. Blood. 2005;106(13):4093–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A. Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell. 2010;7(2):150–61 Epub 2010/08/05.

    Article  CAS  PubMed  Google Scholar 

  202. Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298–310 Epub 2011/10/11.

    Article  CAS  PubMed  Google Scholar 

  203. Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD. Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA. 2007;104(13):5431–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Takubo K, Goda N, Yamada W, Iriuchishima H, Ikeda E, Kubota Y, et al. Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell. 2010;7(3):391–402 Epub 2010/09/02.

    Article  CAS  PubMed  Google Scholar 

  205. Eliasson P, Jonsson JI. The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol. 2010;222(1):17–22 Epub 2009/09/03.

    Article  CAS  PubMed  Google Scholar 

  206. Levesque JP, Winkler IG, Hendy J, Williams B, Helwani F, Barbier V, et al. Hematopoietic progenitor cell mobilization results in hypoxia with increased hypoxia-inducible transcription factor-1 alpha and vascular endothelial growth factor A in bone marrow. Stem Cells. 2007;25(8):1954–65 Epub 2007/05/05.

    Article  CAS  PubMed  Google Scholar 

  207. Kubota Y, Takubo K, Suda T. Bone marrow long label-retaining cells reside in the sinusoidal hypoxic niche. Biochem Biophys Res Commun. 2008;366(2):335–9.

    Article  CAS  PubMed  Google Scholar 

  208. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408 Epub 2012/02/07.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Kocabas F, Zheng J, Thet S, Copeland NG, Jenkins NA, DeBerardinis RJ, et al. Meis1 regulates the metabolic phenotype and oxidant defense of hematopoietic stem cells. Blood. 2012;120(25):4963–72 Epub 2012/09/22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Simsek T, Kocabas F, Zheng J, Deberardinis RJ, Mahmoud AI, Olson EN, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7(3):380–90 Epub 2010/09/02.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Miharada K, Karlsson G, Rehn M, Rorby E, Siva K, Cammenga J, et al. Cripto regulates hematopoietic stem cells as a hypoxic-niche-related factor through cell surface receptor GRP78. Cell Stem Cell. 2011;9(4):330–44 Epub 2011/10/11.

    Article  CAS  PubMed  Google Scholar 

  212. Rehn M, Olsson A, Reckzeh K, Diffner E, Carmeliet P, Landberg G, et al. Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche. Blood. 2011;118(6):1534–43 Epub 2011/06/15.

    Article  CAS  PubMed  Google Scholar 

  213. Rouault-Pierre K, Lopez-Onieva L, Foster K, Anjos-Afonso F, Lamrissi-Garcia I, Serrano-Sanchez M, et al. HIF-2alpha protects human hematopoietic stem/progenitors and acute myeloid leukemic cells from apoptosis induced by endoplasmic reticulum stress. Cell Stem Cell. 2013;13(5):549–63 Epub 2013/10/08.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

KKH has been supported by NIH grants HL077675, HL096360, HL128064, EB005173, EB017103 and EB016629.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Süleyman Coşkun .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Coşkun, S., Hirschi, K.K. (2015). Vascular Niche in HSC Development, Maintenance and Regulation. In: Turksen, K. (eds) Tissue-Specific Stem Cell Niche. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-21705-5_9

Download citation

Publish with us

Policies and ethics