Skip to main content
SpringerLink
Log in

Translating HSC Niche Biology for Clinical Applications

  • Cellular Therapies: Preclinical and Clinical (EM Horwitz, Section Editor)
  • Published:
Current Stem Cell Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Over the final 3 decades of the twentieth century, the advent and evolution of hematopoietic stem cell transplantation (HSCT) to cure refractory malignancies and severe non-malignant diseases created a need to better understand basic scientific mechanisms underlying the maintenance and migration of hematopoietic stem cells (HSC). Over the past 20 years, researchers have discovered complex overlapping bone marrow (BM) HSC niches that utilize a number of signaling pathways to tightly regulate HSC physiology. Here, we review recent efforts to define critical mediators of HSC niche function in health and disease, and how these discoveries are now enabling the development of the next generation of cellular therapies for cancer and severe non-malignant diseases.

Recent Findings

A number of cellular interactions and molecular pathways critical for HSC mobilization, donor HSC engraftment after HSCT, and HSC/progenitor cell recovery following chemotherapy have recently been identified. Additional studies have defined mechanisms by which cancer and bone marrow failure states disrupt the normal function of these pathways. Translational investigators are now leveraging these discoveries to develop preclinical and clinical strategies to target the niche for regenerative and cancer therapy.

Summary

Ongoing research to define fundamental aspects of HSC niche biology will lead to further refinements and precision approaches to improve the safety and efficacy of clinical cell therapy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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

    PubMed  CAS  Google Scholar 

  2. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425(6960):836–41.

    Article  PubMed  CAS  Google Scholar 

  3. 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  PubMed  CAS  Google Scholar 

  4. Kiel MJ, Yilmaz OH, Iwashita T, 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  PubMed  CAS  Google Scholar 

  5. Garrett RW, Emerson SG. Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches. Cell Stem Cell. 2009;4(6):503–6.

    Article  PubMed  CAS  Google Scholar 

  6. Mendelson A, Frenette PS. Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med. 2014;20(8):833–46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Yu VW, Scadden DT. Hematopoietic stem cell and its bone marrow niche. Curr Top Dev Biol. 2016;118:21–44.

    Article  PubMed  CAS  Google Scholar 

  8. Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505(7483):327–34.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. 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.

    Article  PubMed  CAS  Google Scholar 

  11. Banfi A, Podesta M, Fazzuoli L, Sertoli MR, Venturini M, Santini G, et al. High-dose chemotherapy shows a dose-dependent toxicity to bone marrow osteoprogenitors: a mechanism for post-bone marrow transplantation osteopenia. Cancer. 2001;92(9):2419–28.

    Article  PubMed  CAS  Google Scholar 

  12. Krevvata M, Silva BC, Manavalan JS, Galan-Diez M, Kode A, Matthews BG, et al. Inhibition of leukemia cell engraftment and disease progression in mice by osteoblasts. Blood. 2014;124(18):2834–46.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Frisch BJ, Ashton JM, Xing L, Becker MW, Jordan CT, Calvi LM. Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia. Blood. 2012;119(2):540–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  14. Korn C, Mendez-Ferrer S. Myeloid malignancies and the microenvironment. Blood. 2017;129(7):811–22.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. 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  PubMed  CAS  Google Scholar 

  16. Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL, et al. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell. 2012;10(3):259–72.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E, et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med. 2009;206(11):2483–96.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  18. Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, et al. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell. 2018;22(1):64–77 e6.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Taichman RS, Reilly MJ, Emerson SG. Human osteoblasts support human hematopoietic progenitor cells in vitro bone marrow cultures. Blood. 1996;87(2):518–24.

    PubMed  CAS  Google Scholar 

  20. Nakamura Y, Arai F, Iwasaki H, Hosokawa K, Kobayashi I, Gomei Y, et al. Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood. 2010;116(9):1422–32.

    Article  PubMed  CAS  Google Scholar 

  21. Calvi LM, Link DC. The hematopoietic stem cell niche in homeostasis and disease. Blood. 2015;126(22):2443–51.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Yu VW, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med. 2015;212(5):759–74.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  23. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  25. Ferraro F, Lymperi S, Mendez-Ferrer S, Saez B, Spencer JA, Yeap BY, et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function. Sci Transl Med. 2011;3(104):104ra1.

    Article  CAS  Google Scholar 

  26. Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, et al. Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood. 2013;121(6):930–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  27. Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, et al. Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature. 2010;464(7290):852–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. 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  PubMed  CAS  Google Scholar 

  29. 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.

    Article  PubMed  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Chang MK, Raggatt LJ, Alexander KA, Kuliwaba JS, Fazzalari NL, Schroder K, et al. Osteal tissue macrophages are intercalated throughout human and mouse bone lining tissues and regulate osteoblast function in vitro and in vivo. J Immunol. 2008;181(2):1232–44.

    Article  PubMed  CAS  Google Scholar 

  32. Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, et al. Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood. 2010;116(23):4815–28.

    Article  PubMed  CAS  Google Scholar 

  33. Chow A, Lucas D, Hidalgo A, Mendez-Ferrer S, Hashimoto D, Scheiermann C, et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J Exp Med. 2011;208(2):261–71.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  34. Kaur S, Raggatt LJ, Millard SM, Wu AC, Batoon L, Jacobsen RN, et al. Self-repopulating recipient bone marrow resident macrophages promote long-term hematopoietic stem cell engraftment. Blood 2018;132:735–49.

  35. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC, et al. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014;20(11):1321–6.

    Article  PubMed  CAS  Google Scholar 

  37. Niswander LM, Fegan KH, Kingsley PD, McGrath KE, Palis J. SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood. 2014;124(2):277–86.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  38. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Tay J, Levesque JP, Winkler IG. Cellular players of hematopoietic stem cell mobilization in the bone marrow niche. Int J Hematol. 2017;105(2):129–40.

    Article  PubMed  CAS  Google Scholar 

  40. Levesque JP, Liu F, Simmons PJ, Betsuyaku T, Senior RM, Pham C, et al. Characterization of hematopoietic progenitor mobilization in protease-deficient mice. Blood. 2004;104(1):65–72.

    Article  PubMed  CAS  Google Scholar 

  41. Singh P, Hu P, Hoggatt J, Moh A, Pelus LM. Expansion of bone marrow neutrophils following G-CSF administration in mice results in osteolineage cell apoptosis and mobilization of hematopoietic stem and progenitor cells. Leukemia. 2012;26(11):2375–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Bendall L. Extracellular molecules in hematopoietic stem cell mobilisation. Int J Hematol. 2017;105(2):118–28.

    Article  PubMed  CAS  Google Scholar 

  43. Bendall LJ, Basnett J. Role of sphingosine 1-phosphate in trafficking and mobilization of hematopoietic stem cells. Curr Opin Hematol. 2013;20(4):281–8.

    Article  PubMed  CAS  Google Scholar 

  44. Imai K, Kobayashi M, Wang J, Shinobu N, Yoshida H, Hamada J, et al. Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenitor cells to bone marrow. Br J Haematol. 1999;106(4):905–11.

    Article  PubMed  CAS  Google Scholar 

  45. Ratajczak MZ, Suszynska M. Emerging strategies to enhance homing and engraftment of hematopoietic stem cells. Stem Cell Rev. 2016;12(1):121–8.

    Article  PubMed  CAS  Google Scholar 

  46. Hoggatt J, Singh P, Sampath J, Pelus LM. Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood. 2009;113(22):5444–55.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Ratajczak MZ, Kim CH, Abdel-Latif A, Schneider G, Kucia M, Morris AJ, et al. A novel perspective on stem cell homing and mobilization: review on bioactive lipids as potent chemoattractants and cationic peptides as underappreciated modulators of responsiveness to SDF-1 gradients. Leukemia. 2012;26(1):63–72.

    Article  PubMed  CAS  Google Scholar 

  48. Petit I, Szyper-Kravitz M, Nagler A, Lahav M, Peled A, Habler L, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687–94.

    Article  PubMed  CAS  Google Scholar 

  49. Ratajczak MZ, Lee H, Wysoczynski M, Wan W, Marlicz W, Laughlin MJ, et al. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia. 2010;24(5):976–85.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Juarez JG, Harun N, Thien M, Welschinger R, Baraz R, Pena AD, et al. Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice. Blood. 2012;119(3):707–16.

    Article  PubMed  CAS  Google Scholar 

  51. Mazo IB, Massberg S, von Andrian UH. Hematopoietic stem and progenitor cell trafficking. Trends Immunol. 2011;32(10):493–503.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  52. 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  PubMed  CAS  PubMed Central  Google Scholar 

  53. Murakami JL, Xu B, Franco CB, Hu X, Galli SJ, Weissman IL, et al. Evidence that beta7 integrin regulates hematopoietic stem cell homing and engraftment through interaction with MAdCAM-1. Stem Cells Dev. 2016;25(1):18–26.

    Article  PubMed  CAS  Google Scholar 

  54. Avigdor A, Goichberg P, Shivtiel S, Dar A, Peled A, Samira S, et al. CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow. Blood. 2004;103(8):2981–9.

    Article  PubMed  CAS  Google Scholar 

  55. 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.

    Article  PubMed  CAS  Google Scholar 

  56. Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood. 2008;111(7):3893–5.

    Article  PubMed  CAS  Google Scholar 

  57. Choi JS, Harley BA. Marrow-inspired matrix cues rapidly affect early fate decisions of hematopoietic stem and progenitor cells. Sci Adv. 2017;3(1):e1600455.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Grassinger J, Haylock DN, Storan MJ, Haines GO, Williams B, Whitty GA, et al. Thrombin-cleaved osteopontin regulates hemopoietic stem and progenitor cell functions through interactions with alpha9beta1 and alpha4beta1 integrins. Blood. 2009;114(1):49–59.

    Article  PubMed  CAS  Google Scholar 

  59. Rak J, Foster K, Potrzebowska K, Talkhoncheh MS, Miharada N, Komorowska K, et al. Cytohesin 1 regulates homing and engraftment of human hematopoietic stem and progenitor cells. Blood. 2017;129(8):950–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. 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  PubMed  CAS  PubMed Central  Google Scholar 

  61. Zhao M, Ross JT, Itkin T, Perry JM, Venkatraman A, Haug JS, et al. FGF signaling facilitates postinjury recovery of mouse hematopoietic system. Blood. 2012;120(9):1831–42.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  62. Huynh H, Zheng J, Umikawa M, Zhang C, Silvany R, Iizuka S, et al. IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. Blood. 2011;118(12):3236–43.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  63. 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.

    Article  PubMed  CAS  Google Scholar 

  64. Caselli A, Olson TS, Otsuru S, Chen X, Hofmann TJ, Nah HD, et al. IGF-1-mediated osteoblastic niche expansion enhances long-term hematopoietic stem cell engraftment after murine bone marrow transplantation. Stem Cells. 2013;31:2193–204.

    Article  PubMed  CAS  Google Scholar 

  65. Himburg HA, Termini CM, Schlussel L, Kan J, Li M, Zhao L, et al. Distinct bone marrow sources of pleiotrophin control hematopoietic stem cell maintenance and regeneration. Cell Stem Cell. 2018;23:370–81 e5.

  66. Baldridge MT, King KY, Boles NC, Weksberg DC, Goodell MA. Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection. Nature. 2010;465(7299):793–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  67. Smith JN, Kanwar VS, MacNamara KC. Hematopoietic stem cell regulation by type I and II interferons in the pathogenesis of acquired aplastic anemia. Front Immunol. 2016;7:330.

    PubMed  PubMed Central  Google Scholar 

  68. Schepers K, Pietras EM, Reynaud D, Flach J, Binnewies M, Garg T, et al. Myeloproliferative neoplasia remodels the endosteal bone marrow niche into a self-reinforcing leukemic niche. Cell Stem Cell. 2013;13(3):285–99.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Welner RS, Amabile G, Bararia D, Czibere A, Yang H, Zhang H, et al. Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells. Cancer Cell. 2015;27(5):671–81.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  70. Lampreia FP, Carmelo JG, Anjos-Afonso F. Notch signaling in the regulation of hematopoietic stem cell. Curr Stem Cell Rep. 2017;3(3):202–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  71. Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, et al. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. J Clin Invest. 2017;127(12):4242–56.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kabiri Z, Numata A, Kawasaki A, Edison, Tenen DG, Virshup DM. Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells. Blood. 2015;126(9):1086–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS. Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med. 2012;18(12):1778–85.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  74. 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  PubMed  CAS  Google Scholar 

  75. Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, et al. Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell Stem Cell. 2008;2(3):274–83.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Sugimura R, He XC, Venkatraman A, Arai F, Box A, Semerad C, et al. Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell. 2012;150(2):351–65.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  77. • Itkin T, Gur-Cohen S, Spencer JA, Schajnovitz A, Ramasamy SK, Kusumbe AP, et al. Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature. 2016;532(7599):323–8. Critical study defining the that the differential permeability of endosteal arterioles and and venous sinusoids in BM leads to distinct levels of hypoxia, that in turn regulate HSC cell fate decisions.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, et al. Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature. 2014;508(7495):269–73.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  79. Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.

    Article  PubMed  CAS  Google Scholar 

  80. 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.

    Article  PubMed  CAS  Google Scholar 

  81. 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  PubMed  CAS  Google Scholar 

  82. Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, et al. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med. 2013;19(6):695–703.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  83. Park MH, Jin HK, Min WK, Lee WW, Lee JE, Akiyama H, et al. Neuropeptide Y regulates the hematopoietic stem cell microenvironment and prevents nerve injury in the bone marrow. EMBO J. 2015;34(12):1648–60.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  84. Vagima Y, Avigdor A, Goichberg P, Shivtiel S, Tesio M, Kalinkovich A, et al. MT1-MMP and RECK are involved in human CD34+ progenitor cell retention, egress, and mobilization. J Clin Invest. 2009;119(3):492–503.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Saez B, Ferraro F, Yusuf RZ, Cook CM, Yu VW, Pardo-Saganta A et al. Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood 2014;124:2937–47.

  86. Korbling M, Przepiorka D, Gajewski J, Champlin RE, Chan KW. With first successful allogeneic transplantations of apheresis-derived hematopoietic progenitor cells reported, can the recruitment of volunteer matched, unrelated stem cell donors be expanded substantially? Blood. 1995;86(3):1235.

    PubMed  CAS  Google Scholar 

  87. •• Pierce H, Zhang D, Magnon C, Lucas D, Christin JR, Huggins M, et al. Cholinergic signals from the CNS regulate G-CSF-mediated HSC mobilization from bone marrow via a glucocorticoid signaling relay. Cell Stem Cell. 2017;20(5):648–58 e4. Critical study demonstrating the mechanism by which G-CSF treatment induces changes in autonomic nervous system function, including increases in both cholinergic and adrenergic signals, that lead to stem cell mobilization.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  88. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 2011;118(17):4530–40.

    Article  PubMed  CAS  Google Scholar 

  89. Adler BK, Salzman DE, Carabasi MH, Vaughan WP, Reddy VV, Prchal JT. Fatal sickle cell crisis after granulocyte colony-stimulating factor administration. Blood. 2001;97(10):3313–4.

    Article  PubMed  CAS  Google Scholar 

  90. Liles WC, Broxmeyer HE, Rodger E, Wood B, Hubel K, Cooper S, et al. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102(8):2728–30.

    Article  PubMed  CAS  Google Scholar 

  91. Flomenberg N, Devine SM, Dipersio JF, Liesveld JL, McCarty JM, Rowley SD, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood. 2005;106(5):1867–74.

    Article  PubMed  CAS  Google Scholar 

  92. Lagresle-Peyrou C, Lefrere F, Magrin E, Ribeil JA, Romano O, Weber L, et al. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion. Haematologica. 2018;103(5):778–86.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  93. Boulad F, Shore T, van Besien K, Minniti C, Barbu-Stevanovic M, Fedus SW, et al. Safety and efficacy of plerixafor dose escalation for the mobilization of CD34(+) hematopoietic progenitor cells in patients with sickle cell disease: interim results. Haematologica. 2018;103(5):770–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  94. Domingues MJ, Nilsson SK, Cao B. New agents in HSC mobilization. Int J Hematol. 2017;105(2):141–52.

    Article  PubMed  CAS  Google Scholar 

  95. Karpova D, Ritchey JK, Holt MS, Abou-Ezzi G, Monlish D, Batoon L, et al. Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells. Blood. 2017;129(21):2939–49.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Ogle ME, Olingy CE, Awojoodu AO, et al. Sphingosine-1-phosphate receptor-3 supports hematopoietic stem and progenitor cell residence within the bone marrow niche. Stem Cells 2017;35:1040–52.

  97. Cao B, Zhang Z, Grassinger J, Williams B, Heazlewood CK, Churches QI, et al. Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. Nat Commun. 2016;7:11007.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  98. Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature. 2013;495(7441):365–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  99. Wang W, Yu S, Myers J, Wang Y, Xin WW, Albakri M, et al. Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica. 2017;102(10):1785–95.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  100. He S, Chu J, Vasu S, Deng Y, Yuan S, Zhang J, et al. FLT3L and plerixafor combination increases hematopoietic stem cell mobilization and leads to improved transplantation outcome. Biol Blood Marrow Transplant. 2014;20(3):309–13.

    Article  PubMed  CAS  Google Scholar 

  101. Anandasabapathy N, Breton G, Hurley A, Caskey M, Trumpfheller C, Sarma P, et al. Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers. Bone Marrow Transplant. 2015;50(7):924–30.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Di Giacomo F, Lewandowski D, Cabannes E, Nancy-Portebois V, Petitou M, Fichelson S, et al. Heparan sulfate mimetics can efficiently mobilize long-term hematopoietic stem cells. Haematologica. 2012;97(4):491–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  103. Frenette PS, Weiss L. Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms. Blood. 2000;96(7):2460–8.

    PubMed  CAS  Google Scholar 

  104. King AG, Horowitz D, Dillon SB, Levin R, Farese AM, MacVittie TJ, et al. Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood. 2001;97(6):1534–42.

    Article  PubMed  CAS  Google Scholar 

  105. Yahata T, Ibrahim AA, Muguruma Y, Eren M, Shaffer AM, Watanabe N, et al. TGF-beta-induced intracellular PAI-1 is responsible for retaining hematopoietic stem cells in the niche. Blood. 2017;130(21):2283–94.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  106. Mehta RS, Dave H, Bollard CM, Shpall EJ. Engineering cord blood to improve engraftment after cord blood transplant. Stem Cell Investig. 2017;4:41.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  107. de Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M, et al. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med. 2012;367(24):2305–15.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  108. Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, et al. Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest. 2014;124(7):3121–8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. 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.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  110. Wagner JE Jr, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, et al. Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell. 2016;18(1):144–55.

    Article  PubMed  CAS  Google Scholar 

  111. Ko KH, Holmes T, Palladinetti P, Song E, Nordon R, O'Brien TA, et al. GSK-3beta inhibition promotes engraftment of ex vivo-expanded hematopoietic stem cells and modulates gene expression. Stem Cells. 2011;29(1):108–18.

    Article  PubMed  CAS  Google Scholar 

  112. van der Loo JC, Ploemacher RE. Marrow- and spleen-seeding efficiencies of all murine hematopoietic stem cell subsets are decreased by preincubation with hematopoietic growth factors. Blood. 1995;85(9):2598–606.

    PubMed  Google Scholar 

  113. Frassoni F, Gualandi F, Podesta M, Raiola AM, Ibatici A, Piaggio G, et al. Direct intrabone transplant of unrelated cord-blood cells in acute leukaemia: a phase I/II study. Lancet Oncol. 2008;9(9):831–9.

    Article  PubMed  CAS  Google Scholar 

  114. Hagglund H, Remberger M, Ringden O. Twenty-year follow-up of a randomized trial comparing intraosseous and i.v. BM transplantation. Bone Marrow Transplant. 2014;49(12):1541–2.

    Article  PubMed  CAS  Google Scholar 

  115. Kurita N, Gosho M, Yokoyama Y, Kato T, Obara N, Sakata-Yanagimoto M, et al. A phase I/II trial of intrabone marrow cord blood transplantation and comparison of the hematological recovery with the Japanese nationwide database. Bone Marrow Transplant. 2017;52(4):574–9.

    Article  PubMed  CAS  Google Scholar 

  116. Wang X, Shin SC, Chiang AF, Khan I, Pan D, Rawlings DJ, et al. Intraosseous delivery of lentiviral vectors targeting factor VIII expression in platelets corrects murine hemophilia A. Mol Ther. 2015;23(4):617–26.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  117. Cutler C, Multani P, Robbins D, Kim HT, Le T, Hoggatt J, et al. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013;122(17):3074–81.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  118. Chaurasia P, Gajzer DC, Schaniel C, D'Souza S, Hoffman R. Epigenetic reprogramming induces the expansion of cord blood stem cells. J Clin Invest. 2014;124(6):2378–95.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  119. Christopherson KW 2nd, Hangoc G, Mantel CR, Broxmeyer HE. Modulation of hematopoietic stem cell homing and engraftment by CD26. Science. 2004;305(5686):1000–3.

    Article  PubMed  CAS  Google Scholar 

  120. Farag SS, Srivastava S, Messina-Graham S, Schwartz J, Robertson MJ, Abonour R, et al. In vivo DPP-4 inhibition to enhance engraftment of single-unit cord blood transplants in adults with hematological malignancies. Stem Cells Dev. 2013;22(7):1007–15.

    Article  PubMed  CAS  Google Scholar 

  121. Farag SS, Nelson R, Cairo MS, O'Leary HA, Zhang S, Huntley C, et al. High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation. Oncotarget. 2017;8(66):110350–7.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Brunstein CG, McKenna DH, DeFor TE, Sumstad D, Paul P, Weisdorf DJ, et al. Complement fragment 3a priming of umbilical cord blood progenitors: safety profile. Biol Blood Marrow Transplant. 2013;19(10):1474–9.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  123. Popat U, Mehta RS, Rezvani K, Fox P, Kondo K, Marin D, et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood. 2015;125(19):2885–92.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  124. •• Shimoto M, Sugiyama T, Nagasawa T. Numerous niches for hematopoietic stem cells remain empty during homeostasis. Blood. 2017;129(15):2124–31. Intriguing recent study demonstrating that during homeostasis, many HSC niches are unoccupied, contradicting the long-held concept that stem cell clearance and "space making" is a necessary function of HSCT conditioning.

    Article  PubMed  CAS  Google Scholar 

  125. Palchaudhuri R, Saez B, Hoggatt J, Schajnovitz A, Sykes DB, Tate TA, et al. Non-genotoxic conditioning for hematopoietic stem cell transplantation using a hematopoietic-cell-specific internalizing immunotoxin. Nat Biotechnol. 2016;34(7):738–45.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  126. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540–50.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  127. Ali S, Gassas A, Kirby-Allen M, Krueger J, Ali M, Schechter T. Eltrombopag for secondary failure of platelet recovery post-allogeneic hematopoietic stem cell transplant in children. Pediatr Transplant. 2017;21(6). https://doi.org/10.1111/petr.13017.

  128. Abbuehl JP, Tatarova Z, Held W, Huelsken J. Long-term engraftment of primary bone marrow stromal cells repairs niche damage and improves hematopoietic stem cell transplantation. Cell Stem Cell. 2017;21(2):241–55 e6.

  129. Bernardo ME, Cometa AM, Locatelli F. Mesenchymal stromal cells: a novel and effective strategy for facilitating engraftment and accelerating hematopoietic recovery after transplantation? Bone Marrow Transplant. 2012;47(3):323–9.

    Article  PubMed  CAS  Google Scholar 

  130. Petinati N, Drize N, Sats N, Risinskaya N, Sudarikov A, Drokov M, et al. Recovery of donor hematopoiesis after graft failure and second hematopoietic stem cell transplantation with intraosseous administration of mesenchymal stromal cells. Stem Cells Int. 2018;2018:6495018.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Wang Y, Hayes V, Jarocha D, Sim X, Harper DC, Fuentes R, et al. Comparative analysis of human ex vivo-generated platelets vs megakaryocyte-generated platelets in mice: a cautionary tale. Blood. 2015;125(23):3627–36.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  132. Brenet F, Kermani P, Spektor R, Rafii S, Scandura JM. TGFbeta restores hematopoietic homeostasis after myelosuppressive chemotherapy. J Exp Med. 2013;210(3):623–39.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  133. Schuettpelz LG, Link DC. Regulation of hematopoietic stem cell activity by inflammation. Front Immunol. 2013;4:204.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  134. Balderman SR, Calvi LM. Biology of BM failure syndromes: role of microenvironment and niches. Hematology Am Soc Hematol Educ Program. 2014;2014(1):71–6.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Hamzic E, Whiting K, Gordon Smith E, Pettengell R. Characterization of bone marrow mesenchymal stromal cells in aplastic anaemia. Br J Haematol. 2015;169(6):804–13.

    Article  PubMed  Google Scholar 

  136. Li J, Yang S, Lu S, Zhao H, Feng J, Li W, et al. Differential gene expression profile associated with the abnormality of bone marrow mesenchymal stem cells in aplastic anemia. PLoS One. 2012;7(11):e47764.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  137. Bueno C, Roldan M, Anguita E, Romero-Moya D, Martin-Antonio B, Rosu-Myles M, et al. Bone marrow mesenchymal stem cells from patients with aplastic anemia maintain functional and immune properties and do not contribute to the pathogenesis of the disease. Haematologica. 2014;99(7):1168–75.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  138. Blau O, Hofmann WK, Baldus CD, Thiel G, Serbent V, Schumann E, et al. Chromosomal aberrations in bone marrow mesenchymal stroma cells from patients with myelodysplastic syndrome and acute myeloblastic leukemia. Exp Hematol. 2007;35(2):221–9.

    Article  PubMed  CAS  Google Scholar 

  139. Cogle CR, Saki N, Khodadi E, Li J, Shahjahani M, Azizidoost S. Bone marrow niche in the myelodysplastic syndromes. Leuk Res. 2015;39(10):1020–7.

    Article  PubMed  Google Scholar 

  140. Medyouf H, Mossner M, Jann JC, Nolte F, Raffel S, Herrmann C, et al. Myelodysplastic cells in patients reprogram mesenchymal stromal cells to establish a transplantable stem cell niche disease unit. Cell Stem Cell. 2014;14(6):824–37.

    Article  PubMed  CAS  Google Scholar 

  141. Raaijmakers MH. Disease progression in myelodysplastic syndromes: do mesenchymal cells pave the way? Cell Stem Cell. 2014;14(6):695–7.

    Article  PubMed  CAS  Google Scholar 

  142. Bardelli D, Dander E, Bugarin C, Cappuzzello C, Pievani A, Fazio G, et al. Mesenchymal stromal cells from Shwachman-Diamond syndrome patients fail to recreate a bone marrow niche in vivo and exhibit impaired angiogenesis. Br J Haematol. 2018;182(1):114–24.

    Article  PubMed  CAS  Google Scholar 

  143. Zhou Y, He Y, Xing W, Zhang P, Shi H, Chen S, et al. An abnormal bone marrow microenvironment contributes to hematopoietic dysfunction in Fanconi anemia. Haematologica. 2017;102(6):1017–27.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Cle DV, Santana-Lemos B, Tellechea MF, Prata KL, Orellana MD, Covas DT, et al. Intravenous infusion of allogeneic mesenchymal stromal cells in refractory or relapsed aplastic anemia. Cytotherapy. 2015;17(12):1696–705.

    Article  PubMed  CAS  Google Scholar 

  145. Liu Z, Zhang Y, Xiao H, Yao Z, Zhang H, Liu Q, et al. Cotransplantation of bone marrow-derived mesenchymal stem cells in haploidentical hematopoietic stem cell transplantation in patients with severe aplastic anemia: an interim summary for a multicenter phase II trial results. Bone Marrow Transplant. 2017;52(5):704–10.

    Article  PubMed  CAS  Google Scholar 

  146. Schneider RK, Mullally A, Dugourd A, Peisker F, Hoogenboezem R, Van Strien PMH, et al. Gli1(+) mesenchymal stromal cells are a key driver of bone marrow fibrosis and an important cellular therapeutic target. Cell Stem Cell. 2017;20(6):785–800 e8.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  147. Stoddart A, Wang J, Hu C, Fernald AA, Davis EM, Cheng JX, et al. Inhibition of WNT signaling in the bone marrow niche prevents the development of MDS in the Apc(del/+) MDS mouse model. Blood. 2017;129(22):2959–70.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  148. Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, et al. Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature. 2014;506(7487):240–4.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  149. Zhang QS, Tang W, Deater M, Phan N, Marcogliese AN, Li H, et al. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice. Blood. 2016;128(24):2774–84.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  150. Zhang QS, Benedetti E, Deater M, Schubert K, Major A, Pelz C, et al. Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. Stem Cell Rep. 2015;4(1):90–102.

    Article  CAS  Google Scholar 

  151. Calado RT, Cle DV. Treatment of inherited bone marrow failure syndromes beyond transplantation. Hematology Am Soc Hematol Educ Program. 2017;2017(1):96–101.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Khincha PP, Wentzensen IM, Giri N, Alter BP, Savage SA. Response to androgen therapy in patients with dyskeratosis congenita. Br J Haematol. 2014;165(3):349–57.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  153. Woo DH, Chen Q, Yang TL, Glineburg MR, Hoge C, Leu NA, et al. Enhancing a Wnt-telomere feedback loop restores intestinal stem cell function in a human organotypic model of dyskeratosis congenita. Cell Stem Cell. 2016;19(3):397–405.

    Article  PubMed  CAS  Google Scholar 

  154. Fernandez RJ 3rd, Johnson FB. A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita. Ann N Y Acad Sci. 2018;1418(1):56–68.

    Article  PubMed  CAS  Google Scholar 

  155. Krause DS, Scadden DT. A hostel for the hostile: the bone marrow niche in hematologic neoplasms. Haematologica. 2015;100(11):1376–87.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  156. Hira VVV, Van Noorden CJF, Carraway HE, Maciejewski JP, Molenaar RJ. Novel therapeutic strategies to target leukemic cells that hijack compartmentalized continuous hematopoietic stem cell niches. Biochim Biophys Acta. 2017;1868(1):183–98.

    CAS  Google Scholar 

  157. Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, et al. A phase 1/2 study of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute myeloid leukemia. Blood. 2012;119(17):3917–24.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  158. Bowers M, Zhang B, Ho Y, Agarwal P, Chen CC, Bhatia R. Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development. Blood. 2015;125(17):2678–88.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  159. Poulos MG, Gars EJ, Gutkin MC, Kloss CC, Ginsberg M, Scandura JM, et al. Activation of the vascular niche supports leukemic progression and resistance to chemotherapy. Exp Hematol. 2014;42(11):976–86 e3.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  160. Krause DS, Fulzele K, Catic A, Sun CC, Dombkowski D, Hurley MP, et al. Differential regulation of myeloid leukemias by the bone marrow microenvironment. Nat Med. 2013;19(11):1513–7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  161. Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  162. Micallef IN, Stiff PJ, Nademanee AP, Maziarz RT, Horwitz ME, Stadtmauer EA, et al. Plerixafor plus granulocyte colony-stimulating factor for patients with non-Hodgkin lymphoma and multiple myeloma: long-term follow-up report. Biol Blood Marrow Transplant. 2018;24(6):1187–95.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  163. Zhang B, Ho YW, Huang Q, Maeda T, Lin A, Lee SU, et al. Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia. Cancer Cell. 2012;21(4):577–92.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author would like to acknowledge past and current research support from NIH/NHLBI K08 HL122306, the United States Department of Defense Bone Marrow Failure Research Program Idea Development Award, the American Society of Hematology Scholar Award Program, the Canuso Foundation, and the W.W. Smith Charitable Trust.

Author information

Authors and Affiliations

  1. Cellular Therapy and Transplant Section, Division of Oncology, Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Abramson Research Center, Suite 302, Philadelphia, PA, 19104, USA

    Timothy S. Olson

  2. Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    Timothy S. Olson

Authors
  1. Timothy S. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Timothy S. Olson.

Ethics declarations

Conflict of Interest

The author declares no competing financial interests. Dr. Olson has served on advisory boards for Novartis, BlueBirdBio, and Merck, but has not received research funding from these entities.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cellular Therapies: Preclinical and Clinical

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Olson, T.S. Translating HSC Niche Biology for Clinical Applications. Curr Stem Cell Rep 5, 38–52 (2019). https://doi.org/10.1007/s40778-019-0152-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40778-019-0152-1

Keywords

Search

Navigation