Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 238-240).
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In this study, treatment of mice with PTH for 5 weeks prior to a 5-day mobilization with G-CSF increased the number of HSCs in circulation. PTH treatment after chemotherapy in mice also leads to a faster and more robust recovery of the HSC pool. These data validate the niche as a potential therapeutic target.
8. Calvi LM, Adams GB, Weibrecht KW, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–846. [PubMed] 9. Zhang J, Niu C, Ye L, et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–841. [PubMed] 10. Visnjic D, Kalajzic Z, Rowe DW, et al. Hematopoiesis is severely altered in mice with an induced osteoblast deficiency. Blood. 2004;103:3258–3264. [PubMed] 11••. Haylock DN, Williams B, Johnston HM, et al. Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum. Stem Cells. 2007;25:1062–1069. [PubMed]
HSCs adhered tightly to the endosteum are not recovered by conventional methods of flushing the marrow. Liberating these HSCs requires grinding of the bone with subsequent enzymatic digestion. HSCs isolated in this way demonstrate increased proliferative and long-term engraftment potential.
12. Kiel MJ, Yilmaz OH, Iwashita T, et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121:1109–1121. [PubMed] 13. Sipkins DA, Wei X, Wu JW, et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature. 2005;435:969–973. [PMC free article] [PubMed] 14. Chute JP, Muramoto GG, Dressman HK, et al. Molecular profile and partial functional analysis of novel endothelial cell-derived growth factors that regulate hematopoiesis. Stem Cells. 2006;24:1315–1327. [PubMed] 15. Kollet O, Dar A, Shivtiel S, et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med. 2006;12:657–664. [PubMed] 16•. Lymperi S, Horwood N, Marley S, et al. Strontium can increase some osteoblasts without increasing hematopoietic stem cells. Blood. 2008;111:1173–1181. [PubMed]
In-vivo treatment of mice with strontium increases osteoblastic number and bone volume. However, it fails to increase N-CAD expressing osteoblasts and HSCs. Suggesting N-CAD expressing osteoblastic involvement in HSCs support. Also it may suggest that osteoclasts (which are inhibited by strontium) may be involved in HSCs expansion and regulation.
17. Katayama Y, Battista M, Kao WM, et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006;124:407–421. [PubMed] 18••. Mendez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452:442–447. [PubMed]
The CXCL12 concentration is shown to be controlled by the circadian rhythm. This control regulated by photic cues is matched by circadian oscillations in circulating HSCs released from the bone marrow.
19•. DiMascio L, Voermans C, Uqoezwa M, et al. Identification of adiponectin as a novel hemopoietic stem cell growth factor. J Immunol. 2007;178:3511–3520. [PubMed]
Adiponectin is identified as a regulator of HSCs both in vivo and in vitro. Competitive transplants show that culture of HSCs with adiponectin prior to transplant increases their repopulation of lethally irradiated mice.
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The authors showed that the maintenance of normal adult hematopoiesis is not dependent on canonical Notch signaling. However, it remains to be shown whether Notch signaling is required for osteoblast-dependent HSC expansion.
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Binding of human CD34+ bone marrow cells to fibronectin in vitro in addition to specific cytokines results in upregulation of GATA-2, c-myb as well as CD34 total protein but not cell surface expression. These genes have previously been shown to maintain hematopoietic progenitor quiescence.
52•. Gottschling S, Saffrich R, Seckinger A, et al. Human mesenchymal stromal cells regulate initial self-renewing divisions of hematopoietic progenitor cells by a beta1-integrin-dependent mechanism. Stem Cells. 2007;25:798–806. [PubMed]
β1-Integrins are shown to be critical in regulating self-renewal of human hematopoietic progenitor cells verifying what has been shown in animal models.
53. Arai F, Hirao A, Ohmura M, et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118:149–161. [PubMed] 54. Wilson A, Murphy MJ, Oskarsson T, et al. c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation. Genes Dev. 2004;18:2747–2763. [PubMed] 55••. Haug JS, He XC, Grindley JC, et al. N-cadherin expression level distinguishes reserved versus primed states of hematopoietic stem cells. Cell Stem Cell. 2008;2:367–379. [PubMed]
N-CAD expression levels were shown to vary among bone marrow cells between low, intermediate and high. The greatest reconstitution potential from freshly isolated HSCs is contained in the N-CAD low population though if cultured overnight the reconstitution potential of N-CAD intermediate is greatly improved.
56••. 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;1:204–217. [PubMed]
In this study, all of the cells displaying HSC activity in irradiated mice are contained in the N-cadherin negative population of bone marrow cells. They were also unable to detect N-cadherin by PCR, or Western blotting in cells purified in HSCs.
57••. Jung Y, Wang J, Song J, et al. Annexin II expressed by osteoblasts and endothelial cells regulates stem cell adhesion, homing, and engraftment following transplantation. Blood. 2007;110:82–90. [PubMed]
The authors show through genetic manipulation that Anxa2-deficient animals have fewer HSCs in the marrow and that osteoblasts derived from these animals show much reduced adhesion to HSCs. Further they show that inhibition of Anxa2 binding in irradiated mice after a whole marrow transplant reduces HSC engraftment and ultimately survival of the animals.
58. Hsu HC, Ema H, Osawa M, et al. Hematopoietic stem cells express Tie-2 receptor in the murine fetal liver. Blood. 2000;96:3757–3762. [PubMed] 59. Puri MC, Bernstein A. Requirement for the TIE family of receptor tyrosine kinases in adult but not fetal hematopoiesis. Proc Natl Acad Sci U S A. 2003;100:12753–12758. [PubMed] 60. Arai F, Ohneda O, Miyamoto T, et al. Mesenchymal stem cells in perichondrium express activated leukocyte cell adhesion molecule and participate in bone marrow formation. J Exp Med. 2002;195:1549–1563. [PMC free article] [PubMed] 61. Arai F, Hirao A, Suda T. Regulation of hematopoietic stem cells by the niche. Trends Cardiovasc Med. 2005;15:75–79. [PubMed] 62. Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106:1331–1339. [PMC free article] [PubMed] 63. Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318. [PMC free article] [PubMed] 64. Heissig B, Hattori K, Dias S, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–637. [PMC free article] [PubMed] 65. Larochelle A, Krouse A, Metzger M, et al. AMD3100 mobilizes hematopoietic stem cells with long-term repopulating capacity in nonhuman primates. Blood. 2006;107:3772–3778. [PubMed] 66. 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;25:977–988. [PubMed] 67. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science. 1999;283:845–848. [PubMed] 68. Jung Y, Wang J, Schneider A, et al. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone. 2006;38:497–508. [PubMed] 69. Ma Q, Jones D, Borghesani PR, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998;95:9448–9453. [PubMed] 70. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature. 1998;393:595–599. [PubMed] 71•. Rossi L, Manfredini R, Bertolini F, et al. The extracellular nucleotide UTP is a potent inducer of hematopoietic stem cell migration. Blood. 2007;109:533–542. [PubMed]
In-vitro UTP increases stem cell migration and cell adhesion mediated by fibronectin. In-vivo results show that pretreating bone marrow cells with UTP improves the homing of human CD34+ cells in immune-deficient mice.
72•. Sierro F, Biben C, Martinez-Munoz L, et al. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proc Natl Acad Sci U S A. 2007;104:14759–14764. [PubMed]
Conditional knockouts of CXCR7 in mice show no hematopoietic defects in contrast to CXCR4 and CXCL12 knockouts. CXCR7 is shown to form heterodimers with CXCR4 and enhance CXCL12 signaling but is not an essential component.
73. Rodan SB, Rodan GA, Simmons HA, et al. Bone resorptive factor produced by osteosarcoma cells with osteoblastic features is PGE2. Biochem Biophys Res Commun. 1981;102:1358–1365. [PubMed] 74••. North TE, Goessling W, Walkley CR, et al. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007;447:1007–1011. [PMC free article] [PubMed]
Treatment of zebrafish with chemicals known to stimulate PGE2 production subsequently increased HSCs. Coinciding with the zebrafish data are data in mice showing ex-vivo treatment of murine bone marrow increased spleen colony formation in subsequent transplants by three-fold at 12 days after transplantation.
75. Tetradis S, Pilbeam CC, Liu Y, et al. Parathyroid hormone increases prostaglandin G/H synthase-2 transcription by a cyclic adenosine 3′,5′-monophosphate-mediated pathway in murine osteoblastic MC3T3-E1 cells. Endocrinology. 1997;138:3594–3600. [PubMed] 76. Reya T, Duncan AW, Ailles L, et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature. 2003;423:409–414. [PubMed] 77. Willert K, Brown JD, Danenberg E, et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature. 2003;423:448–452. [PubMed] 78. Murdoch B, Chadwick K, Martin M, et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci U S A. 2003;100:3422–3427. [PubMed] 79. Zhou H, Mak W, Zheng Y, et al. Osteoblasts directly control lineage commitment of mesenchymal progenitor cells through Wnt signaling. J Biol Chem. 2008;283:1936–1945. [PubMed] 80••. Fleming HE, Janzen V, Lo Celso C, 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;2:274–283. [PMC free article] [PubMed]
In this study, authors used an osteoblast-specific promoter to drive the over-expression of Dkk1 a Wnt inhibitor. Wnt signaling was impaired in HSCs and resulted in HSCs cell cycling and impaired regeneration after transplantation, demonstrating microenvironmental control of HSCs proliferation.
81•. Nemeth MJ, Topol L, Anderson SM, et al. Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci U S A. 2007;104:15436–15441. [PubMed]
Wnt5a inhibits canonical Wnt signaling by destabilizing β-catenin. This results in decreased proliferation in HSCs as well as increased short-term repopulation due to a pool of quiescent stem cells after Wnt5a treatment.
82. Adams GB, Chabner KT, Alley IR, et al. Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature. 2006;439:599–603. [PubMed] 83. Silver IA, Murrills RJ, Etherington DJ. Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts. Exp Cell Res. 1988;175:266–276. [PubMed] 84••. Walkley CR, Shea JM, Sims NA, et al. Rb regulates interactions between hematopoietic stem cells and their bone marrow microenvironment. Cell. 2007;129:1081–1095. [PMC free article] [PubMed]
The authors demonstrated that loss of retinoblastoma in either the microenvironment or in HSCs alone is insufficient to disrupt hematopoiesis. However, loss of retinoblastoma in both the microenvironment and HSCs causes severe myeloproliferation and loss of HSCs from the marrow.
85••. Walkley CR, Olsen GH, Dworkin S, et al. A microenvironment-induced myeloproliferative syndrome caused by retinoic acid receptor gamma deficiency. Cell. 2007;129:1097–1110. [PMC free article] [PubMed]
The study showed that wild type bone marrow transplanted into RARγ-deficient mice resulted in a myeloproliferative syndrome mediated entirely by the RARγ-deficient microenvironment.
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Integrin-linked kinase is activated by binding of β-integrins, expressed by leukemic cells, to bone marrow stromal cells activating the Akt pathway. Further inhibitors of the Akt pathway result in increased apoptosis in leukemia cells.
92. Mohle R, Bautz F, Rafii S, et al. The chemokine receptor CXCR-4 is expressed on CD34+ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood. 1998;91:4523–4530. [PubMed] 93. Mohle R, Schittenhelm M, Failenschmid C, et al. Functional response of leukaemic blasts to stromal cell-derived factor-1 correlates with preferential expression of the chemokine receptor CXCR4 in acute myelomonocytic and lymphoblastic leukaemia. Br J Haematol. 2000;110:563–572. [PubMed] 94••. Ishikawa F, Yoshida S, Saito Y, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315–1321. [PubMed]
Primitive CD34+ human AML cells were shown to home to the endosteum of nonobese diabetic-severe combined immunodeficiency (NOD/SCID)/IL2rynull mice. Further AML cells engrafted within the endosteum were resistant to chemotherapy-induced apoptosis.
95••. Zhao C, Blum J, Chen A, et al. Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007;12:528–541. [PMC free article] [PubMed]
A conditional knockout of β-catenin in the hematopoietic system resulted in deficient self-renewal in both normal and leukemic stem cells. This defect impaired the development of CML in a BCR and ABL leukemogenesis model.
96•. Guo W, Lasky JL, Chang CJ, et al. Multigenetic events collaboratively contribute to Pten-null leukaemia stem-cell formation. Nature. 2008;453:529–533. [PMC free article] [PubMed]
Conditionally knocking out PTEN in the mouse hematopoietic system results in a myeloproliferative disorder and eventually leads to acute T lymphoblastic leukemia (T-ALL). Further, the deletion of just one allele of β-catenin results in reduced incidence and delayed onset of T-ALL in the PTEN null model indicating that β-catenin may play a role in the development of LSC.
97. Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature. 2006;441:475–482. [PubMed] 98. Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature. 2006;441:518–522. [PubMed] 99. Jin L, Hope KJ, Zhai Q, et al. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12:1167–1174. [PubMed] 100•. Matsunaga T, Fukai F, Miura S, et al. Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. Leukemia. 2008;22:353–360. [PubMed]
Primary leukemia cells with high expression of α4-integrins display resistance to the chemotherapeutic Ara C when adhered to fibronectin. Leukemia samples with low α4-integrin expression show little resistance to Ara C treatment. Disruption of fibronectin binding with the peptide FNIII14 resulted in sensitization of the leukemia samples to Ara C treatment and in a mouse model of minimal residual disease increased survival to 100%.
101•. Zhao Y, Bachelier R, Treilleux I, et al. Tumor alphavbeta3 integrin is a therapeutic target for breast cancer bone metastases. Cancer Res. 2007;67:5821–5830. [PubMed]
αvβ3 Integrin is expressed by breast cancer cells that preferentially metastasize to bone where they induce osteoclastic-mediated bone resorption. Treatment with an antagonist of αvβ3 integrin results in a decrease in bone resorption and skeletal tumor burden.