Developments in Hematopoietic Stem Cell Expansion and Gene Editing Technologies

  • Dogacan YucelEmail author
  • Fatih KocabasEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1079)


Hematopoietic stem cells (HSCs) are rare cells, which housed in the adult bone marrow. They maintain all types of differentiated blood cells throughout life. Due to limited availability of HSCs for transplantation, treatment of various inherited bone marrow disorders and anemia requires the development of HSC expansion and gene editing technologies. To this end, various studies addressed the use of cytokines and growth factors for HSC expansion. Major hurdle with these studies was found to be spontaneous differentiation of HSCs into different lineages during ex vivo procedure. In addition, cost efficient approaches were needed. Thus, studies move on to the identification of small molecules and development of RNA interference technologies with potential to enhance cell cycle progression and block inhibitory signaling mechanisms during ex vivo HSC expansion as well as single cell expansion of HSCs following gene editing studies. This review aims to highlight developments in hematopoietic stem cells expansion and gene editing technologies.


HSC expansion Small molecules Cell cycle progression Single cell expansion Gene editing 



We apologize to colleagues whose work could not be cited and discussed because of space limitations. We like to thank Dolay Damla Celik (Department of Biotechnology, Institute of Science, Yeditepe University, Istanbul, Turkey) for her critical reading of manuscript. We thank the support from Co-Funded Brain Circulation Scheme by The Scientific and Technological Research Council of Turkey (TÜBİTAK) and The Marie Curie Action COFUND of the 7th. Framework Programme (FP7) of the European Commission [grant number 115C039], TÜBİTAK ARDEB 1001 [grant numbers 115S185 & 215Z069], TÜBİTAK ARDEB 3501 [grant number 215Z071], TÜBİTAK ARDEB 1002 [grant number 216S317], The Science Academy Young Scientist Award Program (BAGEP-2015, Turkey), The International Centre for Genetic Engineering and Biotechnology – ICGEB 2015 Early Career Return Grant [grant number CRP/TUR15-02_EC], Medicines for Malaria Venture – Pathogenbox Award (supported by Bill & Melinda Gates Foundation) and funds provided by Yeditepe University, Istanbul, Turkey.

Conflict of Interest Statement

All authors declare that they have no conflicts of interest concerning this work.

Ethical Approval

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

Informed Consent

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


  1. Aggarwal R, Lu J, Pompili VJ, Das H (2012) Hematopoietic stem cells: transcriptional regulation, ex vivo expansion and clinical application. Curr Mol Med 12(1):34–49PubMedCentralPubMedCrossRefGoogle Scholar
  2. Akhter S, Rahman MM, Lee HS, Kim HJ, Hong ST (2013) Dynamic roles of angiopoietin-like proteins 1, 2, 3, 4, 6 and 7 in the survival and enhancement of ex vivo expansion of bone-marrow hematopoietic stem cells. Protein Cell 4(3):220–230PubMedCentralPubMedCrossRefGoogle Scholar
  3. Alemdehy MF, Haanstra JR, de Looper HW, van Strien PM, Verhagen-Oldenampsen J, Caljouw Y, Sanders MA, Hoogenboezem R, de Ru AH, Janssen GM, Smetsers SE, Bierings MB, van Veelen PA, Lindern M v, Touw IP, Erkeland SJ (2015) ICL-induced miR139-3p and miR199a-3p have opposite roles in hematopoietic cell expansion and leukemic transformation. Blood 125(25):3937–3948CrossRefPubMedGoogle Scholar
  4. Allouche M, Bikfalvi A (1995) The role of fibroblast growth factor-2 (FGF-2) in hematopoiesis. Prog Growth Factor Res 6(1):35–48CrossRefPubMedGoogle Scholar
  5. Andrews RG, Bartelmez SH, Knitter GH, Myerson D, Bernstein ID, Appelbaum FR, Zsebo KM (1992) A c-kit ligand, recombinant human stem cell factor, mediates reversible expansion of multiple CD34+ colony-forming cell types in blood and marrow of baboons. Blood 80(4):920–927PubMedGoogle Scholar
  6. Antonchuk J, Sauvageau G, Humphries RK (2002) HOXB4-induced expansion of adult hematopoietic stem cells ex vivo. Cell 109(1):39–45CrossRefPubMedGoogle Scholar
  7. Araki H, Mahmud N, Milhem M, Nunez R, Xu M, Beam CA, Hoffman R (2006) Expansion of human umbilical cord blood SCID-repopulating cells using chromatin-modifying agents. Exp Hematol 34(2):140–149CrossRefPubMedGoogle Scholar
  8. Asai T, Liu Y, Bae N, Nimer SD (2011) The p53 tumor suppressor protein regulates hematopoietic stem cell fate. J Cell Physiol 226(9):2215–2221PubMedCentralPubMedCrossRefGoogle Scholar
  9. Audet J, Miller CL, Eaves CJ, Piret JM (2002) Common and distinct features of cytokine effects on hematopoietic stem and progenitor cells revealed by dose-response surface analysis. Biotechnol Bioeng 80(4):393–404CrossRefPubMedGoogle Scholar
  10. Ballen KK, Gluckman E, Broxmeyer HE (2013) Umbilical cord blood transplantation: the first 25 years and beyond. Blood 122(4):491–498PubMedCentralPubMedCrossRefGoogle Scholar
  11. Barker JN (2007) Umbilical Cord Blood (UCB) transplantation: an alternative to the use of unrelated volunteer donors? Hematology Am Soc Hematol Educ Program 2007:55–61Google Scholar
  12. Berardi AC, Wang A, Abraham J, Scadden DT (1995) Basic fibroblast growth factor mediates its effects on committed myeloid progenitors by direct action and has no effect on hematopoietic stem cells. Blood 86(6):2123–2129PubMedGoogle Scholar
  13. Bhardwaj G, Murdoch B, Wu D, Baker DP, Williams KP, Chadwick K, Ling LE, Karanu FN, Bhatia M (2001) Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2(2):172–180CrossRefPubMedGoogle Scholar
  14. Bhatia M, Bonnet D, Wu D, Murdoch B, Wrana J, Gallacher L, Dick JE (1999) Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J Exp Med 189(7):1139–1148PubMedCentralPubMedCrossRefGoogle Scholar
  15. Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, Walker JR, Flaveny CA, Perdew GH, Denison MS, Schultz PG, Cooke MP (2010) Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science 329(5997):1345–1348PubMedCentralPubMedCrossRefGoogle Scholar
  16. Bordeaux-Rego P, Luzo A, Costa FF, Olalla Saad ST, Crosara-Alberto DP (2010) Both interleukin-3 and interleukin-6 are necessary for better ex vivo expansion of CD133+ cells from umbilical cord blood. Stem Cells Dev 19(3):413–422CrossRefPubMedGoogle Scholar
  17. Breems DA, Blokland EA, Ploemacher RE (1997) Stroma-conditioned media improve expansion of human primitive hematopoietic stem cells and progenitor cells. Leukemia 11(1):142–150CrossRefPubMedGoogle Scholar
  18. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, Arny M, Thomas L, Boyse EA (1989) Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci U S A 86(10):3828–3832PubMedCentralPubMedCrossRefGoogle Scholar
  19. Brun AC, Bjornsson JM, Magnusson M, Larsson N, Leveen P, Ehinger M, Nilsson E, Karlsson S (2004) Hoxb4-deficient mice undergo normal hematopoietic development but exhibit a mild proliferation defect in hematopoietic stem cells. Blood 103(11):4126–4133CrossRefPubMedGoogle Scholar
  20. Cavazzana-Calvo M, Fischer A, Hacein-Bey-Abina S, Aiuti A (2012) Gene therapy for primary immunodeficiencies: Part 1. Curr Opin Immunol 24(5):580–584CrossRefPubMedGoogle Scholar
  21. Chen X, Skutt-Kakaria K, Davison J, Ou YL, Choi E, Malik P, Loeb K, Wood B, Georges G, Torok-Storb B, Paddison PJ (2012) G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev 26(22):2499–2511PubMedCentralPubMedCrossRefGoogle Scholar
  22. Chitteti BR, Cheng YH, Poteat B, Rodriguez-Rodriguez S, Goebel WS, Carlesso N, Kacena MA, Srour EF (2010) Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood 115(16):3239–3248PubMedCentralPubMedCrossRefGoogle Scholar
  23. Choi YJ, Lin CP, Ho JJ, He X, Okada N, Bu P, Zhong Y, Kim SY, Bennett MJ, Chen C, Ozturk A, Hicks GG, Hannon GJ, He L (2011) miR-34 miRNAs provide a barrier for somatic cell reprogramming. Nat Cell Biol 13(11):1353–1360PubMedCentralPubMedCrossRefGoogle Scholar
  24. Choi E, Choi E, Hwang KC (2013) MicroRNAs as novel regulators of stem cell fate. World J Stem Cells 5(4):172–187PubMedCentralPubMedCrossRefGoogle Scholar
  25. Christoffersen NR, Shalgi R, Frankel LB, Leucci E, Lees M, Klausen M, Pilpel Y, Nielsen FC, Oren M, Lund AH (2010) p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC. Cell Death Differ 17(2):236–245CrossRefPubMedGoogle Scholar
  26. Chung SS, Hu W, Park CY (2011) The role of MicroRNAs in hematopoietic stem cell and leukemic stem cell function. Ther Adv Hematol 2(5):317–334PubMedCentralPubMedCrossRefGoogle Scholar
  27. Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, McDonnell DP (2006) Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci U S A 103(31):11707–11712PubMedCentralPubMedCrossRefGoogle Scholar
  28. Cicuttini FM, Begley CG, Boyd AW (1992) The effect of recombinant stem cell factor (SCF) on purified CD34-positive human umbilical cord blood progenitor cells. Growth Factors 6(1):31–39CrossRefPubMedGoogle Scholar
  29. Copley MR, Babovic S, Benz C, Knapp DJ, Beer PA, Kent DG, Wohrer S, Treloar DQ, Day C, Rowe K, Mader H, Kuchenbauer F, Humphries RK, Eaves CJ (2013) The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nat Cell Biol 15(8):916–925CrossRefPubMedGoogle Scholar
  30. Costinean S, Sandhu SK, Pedersen IM, Tili E, Trotta R, Perrotti D, Ciarlariello D, Neviani P, Harb J, Kauffman LR, Shidham A, Croce CM (2009) Src homology 2 domain-containing inositol-5-phosphatase and CCAAT enhancer-binding protein beta are targeted by miR-155 in B cells of Emicro-MiR-155 transgenic mice. Blood 114(7):1374–1382PubMedCentralPubMedCrossRefGoogle Scholar
  31. Csaszar E, Kirouac DC, Yu M, Wang W, Qiao W, Cooke MP, Boitano AE, Ito C, Zandstra PW (2012) Rapid expansion of human hematopoietic stem cells by automated control of inhibitory feedback signaling. Cell Stem Cell 10(2):218–229CrossRefPubMedGoogle Scholar
  32. D’Souza SS, Maufort J, Kumar A, Zhang J, Smuga-Otto K, Thomson JA, Slukvin II (2016) GSK3beta inhibition promotes efficient myeloid and lymphoid hematopoiesis from non-human primate-induced pluripotent stem cells. Stem Cell Rep 6(2):243–256CrossRefGoogle Scholar
  33. Dahlberg A, Brashem-Stein C, Delaney C, Bernstein ID (2014) Enhanced generation of cord blood hematopoietic stem and progenitor cells by culture with StemRegenin1 and Delta1(Ext-IgG.) Leukemia 28(10):2097–2101PubMedCentralPubMedCrossRefGoogle Scholar
  34. De Felice L, Tatarelli C, Mascolo MG, Gregorj C, Agostini F, Fiorini R, Gelmetti V, Pascale S, Padula F, Petrucci MT, Arcese W, Nervi C (2005) Histone deacetylase inhibitor valproic acid enhances the cytokine-induced expansion of human hematopoietic stem cells. Cancer Res 65(4):1505–1513CrossRefPubMedGoogle Scholar
  35. de Haan G, Weersing E, Dontje B, van Os R, Bystrykh LV, Vellenga E, Miller G (2003) In vitro generation of long-term repopulating hematopoietic stem cells by fibroblast growth factor-1. Dev Cell 4(2):241–251CrossRefPubMedGoogle Scholar
  36. de Lima M, McMannis J, Gee A, Komanduri K, Couriel D, Andersson BS, Hosing C, Khouri I, Jones R, Champlin R, Karandish S, Sadeghi T, Peled T, Grynspan F, Daniely Y, Nagler A, Shpall EJ (2008) Transplantation of ex vivo expanded cord blood cells using the copper chelator tetraethylenepentamine: a phase I/II clinical trial. Bone Marrow Transplant 41(9):771–778PubMedCentralPubMedCrossRefGoogle Scholar
  37. de Vries P, Brasel KA, Eisenman JR, Alpert AR, Williams DE (1991) The effect of recombinant mast cell growth factor on purified murine hematopoietic stem cells. J Exp Med 173(5):1205–1211CrossRefPubMedGoogle Scholar
  38. Delaney C, Heimfeld S, Brashem-Stein C, Voorhies H, Manger RL, Bernstein ID (2010a) Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution. Nat Med 16(2):232–236PubMedCentralPubMedCrossRefGoogle Scholar
  39. Delaney C, Ratajczak MZ, Laughlin MJ (2010b) Strategies to enhance umbilical cord blood stem cell engraftment in adult patients. Expert Rev Hematol 3(3):273–283PubMedCentralPubMedCrossRefGoogle Scholar
  40. Desponts C, Hazen AL, Paraiso KH, Kerr WG (2006) SHIP deficiency enhances HSC proliferation and survival but compromises homing and repopulation. Blood 107(11):4338–4345PubMedCentralPubMedCrossRefGoogle Scholar
  41. Dickstein J, Senyuk V, Premanand K, Laricchia-Robbio L, Xu P, Cattaneo F, Fazzina R, Nucifora G (2010) Methylation and silencing of miRNA-124 by EVI1 and self-renewal exhaustion of hematopoietic stem cells in murine myelodysplastic syndrome. Proc Natl Acad Sci U S A 107(21):9783–9788PubMedCentralPubMedCrossRefGoogle Scholar
  42. DiFalco MR, Ali S, Congote LF (2003) The improved survival of hematopoietic cells cultured with a fusion protein of insulin-like growth factor II (IGF-II) and interleukin 3 (IL-3) is associated with increases in Bcl-xL and phosphatidylinositol-3 kinase activity. J Leukoc Biol 73(2):297–305CrossRefPubMedGoogle Scholar
  43. Duyvestyn JM, Taylor SJ, Dagger SA, Langdon WY (2016) Dasatinib promotes the activation of quiescent hematopoietic stem cells in mice. Exp Hematol 44(5):410–421CrossRefPubMedGoogle Scholar
  44. Eaton DL, de Sauvage FJ (1997) Thrombopoietin: the primary regulator of megakaryocytopoiesis and thrombopoiesis. Exp Hematol 25(1):1–7PubMedGoogle Scholar
  45. Eaves CJ (2015) Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125(17):2605–2613PubMedCentralPubMedCrossRefGoogle Scholar
  46. Elizalde C, Fernandez-Rueda J, Salcedo JM, Dorronsoro A, Ferrin I, Jakobsson E, Trigueros C (2012) Histone deacetylase 3 modulates the expansion of human hematopoietic stem cells. Stem Cells Dev 21(14):2581–2591CrossRefPubMedGoogle Scholar
  47. Ema H, Takano H, Sudo K, Nakauchi H (2000) In vitro self-renewal division of hematopoietic stem cells. J Exp Med 192(9):1281–1288PubMedCentralPubMedCrossRefGoogle Scholar
  48. Endele M, Etzrodt M, Schroeder T (2014) Instruction of hematopoietic lineage choice by cytokine signaling. Exp Cell Res 329(2):207–213CrossRefPubMedGoogle Scholar
  49. Farahbakhshian E, Verstegen MM, Visser TP, Kheradmandkia S, Geerts D, Arshad S, Riaz N, Grosveld F, van Til NP, Meijerink JP (2014) Angiopoietin-like protein 3 promotes preservation of stemness during ex vivo expansion of murine hematopoietic stem cells. PLoS One 9(8):e105642PubMedCentralPubMedCrossRefGoogle Scholar
  50. Fares I, Chagraoui J, Gareau Y, Gingras S, Ruel R, Mayotte N, Csaszar E, Knapp DJ, Miller P, Ngom M, Imren S, Roy DC, Watts KL, Kiem HP, Herrington R, Iscove NN, Humphries RK, Eaves CJ, Cohen S, Marinier A, Zandstra PW, Sauvageau G (2014) Cord blood expansion. Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal. Science 345(6203):1509–1512PubMedCentralPubMedCrossRefGoogle Scholar
  51. Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M, Rivella S, Gambari R (2015) Recent trends in the gene therapy of beta-thalassemia. J Blood Med 6:69–85PubMedCentralPubMedGoogle Scholar
  52. Friedmann T, Roblin R (1972) Gene therapy for human genetic disease? Science 175(4025):949–955CrossRefGoogle Scholar
  53. Frisch BJ, Calvi LM (2014) Hematopoietic stem cell cultures and assays. Methods Mol Biol 1130:315–324PubMedCentralPubMedCrossRefGoogle Scholar
  54. Gaj T, Gersbach CA, Barbas CF 3rd (2013) ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol 31(7):397–405PubMedCentralPubMedCrossRefGoogle Scholar
  55. Gal H, Amariglio N, Trakhtenbrot L, Jacob-Hirsh J, Margalit O, Avigdor A, Nagler A, Tavor S, Ein-Dor L, Lapidot T, Domany E, Rechavi G, Givol D (2006) Gene expression profiles of AML derived stem cells; similarity to hematopoietic stem cells. Leukemia 20(12):2147–2154CrossRefPubMedGoogle Scholar
  56. Galli SJ, Iemura A, Garlick DS, Gamba-Vitalo C, Zsebo KM, Andrews RG (1993) Reversible expansion of primate mast cell populations in vivo by stem cell factor. J Clin Invest 91(1):148–152PubMedCentralPubMedCrossRefGoogle Scholar
  57. Gallicchio VS, Hughes NK, Hulette BC, DellaPuca R, Noblitt L (1991) Basic fibroblast growth factor (B-FGF) induces early- (CFU-s) and late-stage hematopoietic progenitor cell colony formation (CFU-gm, CFU-meg, and BFU-e) by synergizing with GM-CSF, Meg-CSF, and erythropoietin, and is a radioprotective agent in vitro. Int J Cell Cloning 9(3):220–232CrossRefPubMedGoogle Scholar
  58. Gammaitoni L, Bruno S, Sanavio F, Gunetti M, Kollet O, Cavalloni G, Falda M, Fagioli F, Lapidot T, Aglietta M, Piacibello W (2003) Ex vivo expansion of human adult stem cells capable of primary and secondary hemopoietic reconstitution. Exp Hematol 31(3):261–270CrossRefPubMedGoogle Scholar
  59. Gao Y, Yang P, Shen H, Yu H, Song X, Zhang L, Zhang P, Cheng H, Xie Z, Hao S, Dong F, Ma S, Ji Q, Bartlow P, Ding Y, Wang L, Liu H, Li Y, Cheng H, Miao W, Yuan W, Yuan Y, Cheng T, Xie XQ (2015) Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells. Nat Commun 6:6328PubMedCentralPubMedCrossRefGoogle Scholar
  60. Gentner B, Visigalli I, Hiramatsu H, Lechman E, Ungari S, Giustacchini A, Schira G, Amendola M, Quattrini A, Martino S, Orlacchio A, Dick JE, Biffi A, Naldini L (2010) Identification of hematopoietic stem cell-specific miRNAs enables gene therapy of globoid cell leukodystrophy. Sci Transl Med 2(58):58ra84CrossRefPubMedGoogle Scholar
  61. Gentner B, Pochert N, Rouhi A, Boccalatte F, Plati T, Berg T, Sun SM, Mah SM, Mirkovic-Hosle M, Ruschmann J, Muranyi A, Leierseder S, Argiropoulos B, Starczynowski DT, Karsan A, Heuser M, Hogge D, Camargo FD, Engelhardt S, Dohner H, Buske C, Jongen-Lavrencic M, Naldini L, Humphries RK, Kuchenbauer F (2015) MicroRNA-223 dose levels fine tune proliferation and differentiation in human cord blood progenitors and acute myeloid leukemia. Exp Hematol 43(10):858–868. e857PubMedCentralPubMedCrossRefGoogle Scholar
  62. Gilmore GL, DePasquale DK, Lister J, Shadduck RK (2000) Ex vivo expansion of human umbilical cord blood and peripheral blood CD34(+) hematopoietic stem cells. Exp Hematol 28(11):1297–1305CrossRefPubMedGoogle Scholar
  63. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P et al (1989) Hematopoietic reconstitution in a patient with Fanconi’s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 321(17):1174–1178CrossRefPubMedGoogle Scholar
  64. Goff JP, Shields DS, Greenberger JS (1998) Influence of cytokines on the growth kinetics and immunophenotype of daughter cells resulting from the first division of single CD34(+)Thy-1(+)lin- cells. Blood 92(11):4098–4107PubMedGoogle Scholar
  65. Gori JL, Chandrasekaran D, Kowalski JP, Adair JE, Beard BC, D’Souza SL, Kiem HP (2012) Efficient generation, purification, and expansion of CD34(+) hematopoietic progenitor cells from nonhuman primate-induced pluripotent stem cells. Blood 120(13):e35–e44PubMedCentralPubMedCrossRefGoogle Scholar
  66. Grassinger J, Simon M, Mueller G, Drewel D, Andreesen R, Hennemann B (2007) Bone morphogenetic protein (BMP)-7 but not BMP-2 and BMP-4 improves maintenance of primitive peripheral blood-derived hematopoietic progenitor cells (HPC) cultured in serum-free medium supplemented with early acting cytokines. Cytokine 40(3):165–171CrossRefPubMedGoogle Scholar
  67. Hager M, Pedersen CC, Larsen MT, Andersen MK, Hother C, Gronbaek K, Jarmer H, Borregaard N, Cowland JB (2011) MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-beta1 stimulation in granulocytic precursors. Blood 118(25):6649–6659CrossRefPubMedGoogle Scholar
  68. Han S, Wang Y, Wang B, Patel E, Okada S, Yang LJ, Moreb JS, Chang LJ (2010a) Ex vivo development, expansion and in vivo analysis of a novel lineage of dendritic cells from hematopoietic stem cells. J Immune Based Ther Vaccin 8:8CrossRefGoogle Scholar
  69. Han YC, Park CY, Bhagat G, Zhang J, Wang Y, Fan JB, Liu M, Zou Y, Weissman IL, Gu H (2010b) microRNA-29a induces aberrant self-renewal capacity in hematopoietic progenitors, biased myeloid development, and acute myeloid leukemia. J Exp Med 207(3):475–489PubMedCentralPubMedCrossRefGoogle Scholar
  70. Hershkovitz-Rokah O, Modai S, Pasmanik-Chor M, Toren A, Shomron N, Raanani P, Shpilberg O, Granot G (2015) MiR-30e induces apoptosis and sensitizes K562 cells to imatinib treatment via regulation of the BCR-ABL protein. Cancer Lett 356(2 Pt B):597–605CrossRefPubMedGoogle Scholar
  71. Hoggatt J, Singh P, Sampath J, Pelus LM (2009) Prostaglandin E2 enhances hematopoietic stem cell homing, survival, and proliferation. Blood 113(22):5444–5455PubMedCentralPubMedCrossRefGoogle Scholar
  72. Horwitz ME, Chao NJ, Rizzieri DA, Long GD, Sullivan KM, Gasparetto C, Chute JP, Morris A, McDonald C, Waters-Pick B, Stiff P, Wease S, Peled A, Snyder D, Cohen EG, Shoham H, Landau E, Friend E, Peleg I, Aschengrau D, Yackoubov D, Kurtzberg J, Peled T (2014) Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment. J Clin Invest 124(7):3121–3128PubMedCentralPubMedCrossRefGoogle Scholar
  73. Huang J, Nguyen-McCarty M, Hexner EO, Danet-Desnoyers G, Klein PS (2012) Maintenance of hematopoietic stem cells through regulation of Wnt and mTOR pathways. Nat Med 18(12):1778–1785PubMedCentralPubMedCrossRefGoogle Scholar
  74. Hutton JF, Rozenkov V, Khor FS, D’Andrea RJ, Lewis ID (2006) Bone morphogenetic protein 4 contributes to the maintenance of primitive cord blood hematopoietic progenitors in an ex vivo stroma-noncontact co-culture system. Stem Cells Dev 15(6):805–813CrossRefPubMedGoogle Scholar
  75. Hydbring P, Badalian-Very G (2013) Clinical applications of microRNAs. F1000Res 2:136PubMedCentralPubMedGoogle Scholar
  76. Isufi I, Seetharam M, Zhou L, Sohal D, Opalinska J, Pahanish P, Verma A (2007) Transforming growth factor-beta signaling in normal and malignant hematopoiesis. J Interferon Cytokine Res 27(7):543–552CrossRefPubMedGoogle Scholar
  77. Jaroscak J, Goltry K, Smith A, Waters-Pick B, Martin PL, Driscoll TA, Howrey R, Chao N, Douville J, Burhop S, Fu P, Kurtzberg J (2003) Augmentation of umbilical cord blood (UCB) transplantation with ex vivo-expanded UCB cells: results of a phase 1 trial using the AastromReplicell system. Blood 101(12):5061–5067CrossRefPubMedGoogle Scholar
  78. Jenkins CR, Shevchuk OO, Giambra V, Lam SH, Carboni JM, Gottardis MM, Holzenberger M, Pollak M, Humphries RK, Weng AP (2012) IGF signaling contributes to malignant transformation of hematopoietic progenitors by the MLL-AF9 oncoprotein. Exp Hematol 40(9):715–723. e716CrossRefPubMedGoogle Scholar
  79. Jones P, May G, Healy L, Brown J, Hoyne G, Delassus S, Enver T (1998) Stromal expression of Jagged 1 promotes colony formation by fetal hematopoietic progenitor cells. Blood 92(5):1505–1511PubMedGoogle Scholar
  80. Kalaitzidis D, Sykes SM, Wang Z, Punt N, Tang Y, Ragu C, Sinha AU, Lane SW, Souza AL, Clish CB, Anastasiou D, Gilliland DG, Scadden DT, Guertin DA, Armstrong SA (2012) mTOR complex 1 plays critical roles in hematopoiesis and Pten-loss-evoked leukemogenesis. Cell Stem Cell 11(3):429–439PubMedCentralPubMedCrossRefGoogle Scholar
  81. Karanu FN, Murdoch B, Gallacher L, Wu DM, Koremoto M, Sakano S, Bhatia M (2000) The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med 192(9):1365–1372PubMedCentralPubMedCrossRefGoogle Scholar
  82. Karanu FN, Murdoch B, Miyabayashi T, Ohno M, Koremoto M, Gallacher L, Wu D, Itoh A, Sakano S, Bhatia M (2001) Human homologues of Delta-1 and Delta-4 function as mitogenic regulators of primitive human hematopoietic cells. Blood 97(7):1960–1967CrossRefPubMedGoogle Scholar
  83. Karlsson G, Blank U, Moody JL, Ehinger M, Singbrant S, Deng CX, Karlsson S (2007) Smad4 is critical for self-renewal of hematopoietic stem cells. J Exp Med 204(3):467–474PubMedCentralPubMedCrossRefGoogle Scholar
  84. Kaushansky K (1995) Thrombopoietin: the primary regulator of platelet production. Blood 86(2):419–431PubMedGoogle Scholar
  85. Kaushansky K (2003) Thrombopoietin: accumulating evidence for an important biological effect on the hematopoietic stem cell. Ann N Y Acad Sci 996:39–43CrossRefPubMedGoogle Scholar
  86. Kertesz Z, Vas V, Kiss J, Urban VS, Pozsonyi E, Kozma A, Paloczi K, Uher F (2006) In vitro expansion of long-term repopulating hematopoietic stem cells in the presence of immobilized Jagged-1 and early acting cytokines. Cell Biol Int 30(5):401–405CrossRefPubMedGoogle Scholar
  87. Kim SY, Le Rademacher J, Antin JH, Anderlini P, Ayas M, Battiwalla M, Carreras J, Kurtzberg J, Nakamura R, Eapen M, Deeg HJ (2014) Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation. Haematologica 99(12):1868–1875PubMedCentralPubMedCrossRefGoogle Scholar
  88. Kurtzberg J (2009) Update on umbilical cord blood transplantation. Curr Opin Pediatr 21(1):22–29PubMedCentralPubMedCrossRefGoogle Scholar
  89. Lam V, Tokusumi T, Tokusumi Y, Schulz RA (2014) bantam miRNA is important for Drosophila blood cell homeostasis and a regulator of proliferation in the hematopoietic progenitor niche. Biochem Biophys Res Commun 453(3):467–472PubMedCentralPubMedCrossRefGoogle Scholar
  90. Lechman ER, Gentner B, van Galen P, Giustacchini A, Saini M, Boccalatte FE, Hiramatsu H, Restuccia U, Bachi A, Voisin V, Bader GD, Dick JE, Naldini L (2012) Attenuation of miR-126 activity expands HSC in vivo without exhaustion. Cell Stem Cell 11(6):799–811PubMedCentralPubMedCrossRefGoogle Scholar
  91. Lehar SM, Dooley J, Farr AG, Bevan MJ (2005) Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors. Blood 105(4):1440–1447CrossRefPubMedGoogle Scholar
  92. Li Y, Vecchiarelli-Federico LM, Li YJ, Egan SE, Spaner D, Hough MR, Ben-David Y (2012) The miR-17-92 cluster expands multipotent hematopoietic progenitors whereas imbalanced expression of its individual oncogenic miRNAs promotes leukemia in mice. Blood 119(19):4486–4498CrossRefPubMedGoogle Scholar
  93. Liu Y, Zhang B, Zhang J, Wang S, Yao H, He L, Chen L, Yue W, Li Y, Pei X (2014) CAPE promotes the expansion of human umbilical cord blood-derived hematopoietic stem and progenitor cells in vitro. Sci China Life Sci 57(2):188–194CrossRefPubMedGoogle Scholar
  94. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810CrossRefGoogle Scholar
  95. Lui WC, Chan YF, Chan LC, Ng RK (2014) Cytokine combinations on the potential for ex vivo expansion of murine hematopoietic stem cells. Cytokine 68(2):127–132CrossRefPubMedGoogle Scholar
  96. Luo Y, Li L, Zou P, Wang J, Shao L, Zhou D, Liu L (2014) Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence. Transplantation 97(1):20–29CrossRefPubMedGoogle Scholar
  97. Maciejewski JP, Selleri C, Sato T, Cho HJ, Keefer LK, Nathan CF, Young NS (1995) Nitric oxide suppression of human hematopoiesis in vitro. Contribution to inhibitory action of interferon-gamma and tumor necrosis factor-alpha. J Clin Invest 96(2):1085–1092PubMedCentralPubMedCrossRefGoogle Scholar
  98. MacMillan ML, Weisdorf DJ, Brunstein CG, Cao Q, DeFor TE, Verneris MR, Blazar BR, Wagner JE (2009) Acute graft-versus-host disease after unrelated donor umbilical cord blood transplantation: analysis of risk factors. Blood 113(11):2410–2415PubMedCentralPubMedCrossRefGoogle Scholar
  99. Maeder ML, Gersbach CA (2016) Genome-editing technologies for gene and cell therapy. Mol Ther 24(3):430–446PubMedCentralPubMedCrossRefGoogle Scholar
  100. Mancini SJ, Mantei N, Dumortier A, Suter U, MacDonald HR, Radtke F (2005) Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood 105(6):2340–2342CrossRefPubMedGoogle Scholar
  101. Meenhuis A, van Veelen PA, de Looper H, van Boxtel N, van den Berge IJ, Sun SM, Taskesen E, Stern P, de Ru AH, van Adrichem AJ, Demmers J, Jongen-Lavrencic M, Lowenberg B, Touw IP, Sharp PA, Erkeland SJ (2011) MiR-17/20/93/106 promote hematopoietic cell expansion by targeting sequestosome 1-regulated pathways in mice. Blood 118(4):916–925PubMedCentralPubMedCrossRefGoogle Scholar
  102. Metcalf D, Nicola NA (1991) Direct proliferative actions of stem cell factor on murine bone marrow cells in vitro: effects of combination with colony-stimulating factors. Proc Natl Acad Sci U S A 88(14):6239–6243PubMedCentralPubMedCrossRefGoogle Scholar
  103. Migliaccio G, Migliaccio AR, Druzin ML, Giardina PJ, Zsebo KM, Adamson JW (1991) Effects of recombinant human stem cell factor (SCF) on the growth of human progenitor cells in vitro. J Cell Physiol 148(3):503–509CrossRefPubMedGoogle Scholar
  104. Migliaccio AR, Whitsett C, Migliaccio G (2009) Erythroid cells in vitro: from developmental biology to blood transfusion products. Curr Opin Hematol 16(4):259–268CrossRefPubMedGoogle Scholar
  105. Miharada K, Hiroyama T, Sudo K, Nagasawa T, Nakamura Y (2006) Efficient enucleation of erythroblasts differentiated in vitro from hematopoietic stem and progenitor cells. Nat Biotechnol 24(10):1255–1256CrossRefPubMedGoogle Scholar
  106. Mo XD, Xu LP, Zhang XH, Liu DH, Wang Y, Chen H, Yan CH, Chen YH, Han W, Wang FR, Wang JZ, Liu KY, Huang XJ (2015) Haploidentical hematopoietic stem cell transplantation in adults with Philadelphia-negative acute lymphoblastic leukemia: no difference in the high- and low-risk groups. Int J Cancer 136(7):1697–1707CrossRefPubMedGoogle Scholar
  107. Mohamed AA, Ibrahim AM, El-Masry MW, Mansour IM, Khroshied MA, Gouda HM, Riad RM (2006) Ex vivo expansion of stem cells: defining optimum conditions using various cytokines. Lab Hematol 12(2):86–93CrossRefPubMedGoogle Scholar
  108. Morishima Y, Kashiwase K, Matsuo K, Azuma F, Morishima S, Onizuka M, Yabe T, Murata M, Doki N, Eto T, Mori T, Miyamura K, Sao H, Ichinohe T, Saji H, Kato S, Atsuta Y, Kawa K, Kodera Y, Sasazuki T, Japan Marrow Donor P (2015) Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 125(7):1189–1197PubMedCentralPubMedCrossRefGoogle Scholar
  109. Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505(7483):327–334PubMedCentralPubMedCrossRefGoogle Scholar
  110. Morrison SJ, Wright DE, Weissman IL (1997) Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc Natl Acad Sci U S A 94(5):1908–1913PubMedCentralPubMedCrossRefGoogle Scholar
  111. Mountford JC, Olivier E, Jordanides NE, de Sousa P, Turner ML (2010) Red blood cells from pluripotent stem cells for use in transfusion. Regen Med 5(3):411–423CrossRefPubMedGoogle Scholar
  112. Murdoch B, Chadwick K, Martin M, Shojaei F, Shah KV, Gallacher L, Moon RT, Bhatia M (2003) Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc Natl Acad Sci U S A 100(6):3422–3427PubMedCentralPubMedCrossRefGoogle Scholar
  113. Murray LJ, Young JC, Osborne LJ, Luens KM, Scollay R, Hill BL (1999) Thrombopoietin, flt3, and kit ligands together suppress apoptosis of human mobilized CD34+ cells and recruit primitive CD34+ Thy-1+ cells into rapid division. Exp Hematol 27(6):1019–1028CrossRefPubMedGoogle Scholar
  114. Narimatsu H, Matsumura T, Kami M, Miyakoshi S, Kusumi E, Takagi S, Miura Y, Kato D, Inokuchi C, Myojo T, Kishi Y, Murashige N, Yuji K, Masuoka K, Yoneyama A, Wake A, Morinaga S, Kanda Y, Taniguchi S (2005) Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients. Biol Blood Marrow Transplant 11(6):429–436CrossRefPubMedGoogle Scholar
  115. Negishi N, Suzuki D, Ito R, Irie N, Matsuo K, Yahata T, Nagano K, Aoki K, Ohya K, Hozumi K, Ando K, Tamaoki N, Ito M, Habu S (2014) Effective expansion of engrafted human hematopoietic stem cells in bone marrow of mice expressing human Jagged1. Exp Hematol 42(6):487–494. e481CrossRefPubMedGoogle Scholar
  116. Ng YY, Baert MR, de Haas EF, Pike-Overzet K, Staal FJ (2009) Isolation of human and mouse hematopoietic stem cells. Methods Mol Biol 506:13–21CrossRefPubMedGoogle Scholar
  117. Nienhuis AW (2013) Development of gene therapy for blood disorders: an update. Blood 122(9):1556–1564PubMedCentralPubMedCrossRefGoogle Scholar
  118. Nikougoftar Zarif M, Soleimani M, Abolghasemi H, Amirizade N, Abroun S, Kaviani S (2011) The high yield expansion and megakaryocytic differentiation of human umbilical cord blood CD133(+) cells. Cell J 13(3):173–178PubMedCentralPubMedGoogle Scholar
  119. Nishino T, Miyaji K, Ishiwata N, Arai K, Yui M, Asai Y, Nakauchi H, Iwama A (2009) Ex vivo expansion of human hematopoietic stem cells by a small-molecule agonist of c-MPL. Exp Hematol 37(11):1364–1377. e1364CrossRefPubMedGoogle Scholar
  120. Nishino T, Wang C, Mochizuki-Kashio M, Osawa M, Nakauchi H, Iwama A (2011) Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase. PLoS One 6(9):e24298PubMedCentralPubMedCrossRefGoogle Scholar
  121. Nogueira-Pedro A, Barbosa CM, Segreto HR, Lungato L, D’Almeida V, Moraes AA, Miranda A, Paredes-Gamero EJ, Ferreira AT (2011) alpha-Tocopherol induces hematopoietic stem/progenitor cell expansion and ERK1/2-mediated differentiation. J Leukoc Biol 90(6):1111–1117CrossRefPubMedGoogle Scholar
  122. Notta F, Doulatov S, Laurenti E, Poeppl A, Jurisica I, Dick JE (2011) Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science 333(6039):218–221CrossRefPubMedGoogle Scholar
  123. O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, Paquette RL, Baltimore D (2008) Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med 205(3):585–594PubMedCentralPubMedCrossRefGoogle Scholar
  124. Ohishi K, Varnum-Finney B, Flowers D, Anasetti C, Myerson D, Bernstein ID (2000) Monocytes express high amounts of Notch and undergo cytokine specific apoptosis following interaction with the Notch ligand, Delta-1. Blood 95(9):2847–2854PubMedGoogle Scholar
  125. Okajima Y, Matsumura I, Nishiura T, Hashimoto K, Yoshida H, Ishikawa J, Wakao H, Yoshimura A, Kanakura Y, Tomiyama Y, Matsuzawa Y (1998) Insulin-like growth factor-I augments erythropoietin-induced proliferation through enhanced tyrosine phosphorylation of STAT5. J Biol Chem 273(36):22877–22883CrossRefPubMedGoogle Scholar
  126. Ott MG, Merget-Millitzer H, Ottmann OG, Martin H, Bruggenolte N, Bialek H, Seger R, Hossle JP, Hoelzer D, Grez M (2002) Mobilization and transduction of CD34(+) peripheral blood stem cells in patients with X-linked chronic granulomatous disease. J Hematother Stem Cell Res 11(4):683–694CrossRefPubMedGoogle Scholar
  127. Park JR (1996) Cytokine regulation of apoptosis in hematopoietic precursor cells. Curr Opin Hematol 3(3):191–196CrossRefPubMedGoogle Scholar
  128. Park M, Seo JJ (2012) Role of HLA in hematopoietic stem cell transplantation. Bone Marrow Res 2012:680841PubMedCentralPubMedCrossRefGoogle Scholar
  129. Peled T, Landau E, Mandel J, Glukhman E, Goudsmid NR, Nagler A, Fibach E (2004) Linear polyamine copper chelator tetraethylenepentamine augments long-term ex vivo expansion of cord blood-derived CD34+ cells and increases their engraftment potential in NOD/SCID mice. Exp Hematol 32(6):547–555CrossRefPubMedGoogle Scholar
  130. Peled T, Shoham H, Aschengrau D, Yackoubov D, Frei G, Rosenheimer GN, Lerrer B, Cohen HY, Nagler A, Fibach E, Peled A (2012) Nicotinamide, a SIRT1 inhibitor, inhibits differentiation and facilitates expansion of hematopoietic progenitor cells with enhanced bone marrow homing and engraftment. Exp Hematol 40(4):342–355. e341CrossRefPubMedGoogle Scholar
  131. Pelus LM, Singh P (2014) Delta-1 provides pleasant stem cell environs. Blood 123(5):605–606PubMedCentralPubMedCrossRefGoogle Scholar
  132. Purton LE, Bernstein ID, Collins SJ (1999) All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1(+)) while enhancing the terminal maturation of committed granulocyte/monocyte progenitors. Blood 94(2):483–495PubMedGoogle Scholar
  133. Purton LE, Bernstein ID, Collins SJ (2000) All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells. Blood 95(2):470–477PubMedGoogle Scholar
  134. Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL (2003) A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423(6938):409–414CrossRefPubMedGoogle Scholar
  135. Reykdal S, Abboud C, Liesveld J (1999) Effect of nitric oxide production and oxygen tension on progenitor preservation in ex vivo culture. Exp Hematol 27(3):441–450CrossRefPubMedGoogle Scholar
  136. Roeven MW, Thordardottir S, Kohela A, Maas F, Preijers F, Jansen JH, Blijlevens NM, Cany J, Schaap N, Dolstra H (2015) The Aryl hydrocarbon receptor antagonist StemRegenin1 Improves In Vitro generation of highly functional natural killer cells from CD34(+) hematopoietic stem and progenitor cells. Stem Cells Dev 24(24):2886–2898CrossRefPubMedGoogle Scholar
  137. Rosenberg PS, Alter BP, Bolyard AA, Bonilla MA, Boxer LA, Cham B, Fier C, Freedman M, Kannourakis G, Kinsey S, Schwinzer B, Zeidler C, Welte K, Dale DC, R. Severe Chronic Neutropenia International (2006) The incidence of leukemia and mortality from sepsis in patients with severe congenital neutropenia receiving long-term G-CSF therapy. Blood 107(12):4628–4635PubMedCentralPubMedCrossRefGoogle Scholar
  138. Rossi B, Zanolin E, Vincenzi C, Diani F, Pizzolo G, de Wynter E, Nadali G (2004) Effect of addition of FLT-3 ligand and megakaryocyte growth and development factor on hemopoietic cells in serum-free conditions. Stem Cells Dev 13(4):362–371CrossRefPubMedGoogle Scholar
  139. Sadelain M (2004) Insertional oncogenesis in gene therapy: how much of a risk? Gene Ther 11(7):569–573CrossRefPubMedGoogle Scholar
  140. Sanders M, Sorba S, Dainiak N (1993) Insulin-like growth factors stimulate erythropoiesis in serum-substituted umbilical cord blood cultures. Exp Hematol 21(1):25–30PubMedGoogle Scholar
  141. Sauvageau G, Thorsteinsdottir U, Eaves CJ, Lawrence HJ, Largman C, Lansdorp PM, Humphries RK (1995) Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 9(14):1753–1765CrossRefPubMedGoogle Scholar
  142. Sauvageau G, Iscove NN, Humphries RK (2004) In vitro and in vivo expansion of hematopoietic stem cells. Oncogene 23(43):7223–7232CrossRefPubMedGoogle Scholar
  143. Seita J, Weissman IL (2010) Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med 2(6):640–653PubMedCentralPubMedCrossRefGoogle Scholar
  144. Shaughnessy P, Chao N, Shapiro J, Walters K, McCarty J, Abhyankar S, Shayani S, Helmons P, Leather H, Pazzalia A, Pickard S (2013) Pharmacoeconomics of hematopoietic stem cell mobilization: an overview of current evidence and gaps in the literature. Biol Blood Marrow Transplant 19(9):1301–1309CrossRefPubMedGoogle Scholar
  145. Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y, Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D, Hild E, Malcolm J, Ward W, McNiece IK (2002) Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant 8(7):368–376CrossRefPubMedGoogle Scholar
  146. Sirin O, Lukov GL, Mao R, Conneely OM, Goodell MA (2010) The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol 12(12):1213–1219PubMedCentralPubMedCrossRefGoogle Scholar
  147. Sitnicka E, Lin N, Priestley GV, Fox N, Broudy VC, Wolf NS, Kaushansky K (1996) The effect of thrombopoietin on the proliferation and differentiation of murine hematopoietic stem cells. Blood 87(12):4998–5005PubMedGoogle Scholar
  148. Skarn M, Baroy T, Stratford EW, Myklebost O (2013) Epigenetic regulation and functional characterization of microRNA-142 in mesenchymal cells. PLoS One 8(11):e79231PubMedCentralPubMedCrossRefGoogle Scholar
  149. Song SJ, Ito K, Ala U, Kats L, Webster K, Sun SM, Jongen-Lavrencic M, Manova-Todorova K, Teruya-Feldstein J, Avigan DE, Delwel R, Pandolfi PP (2013) The oncogenic microRNA miR-22 targets the TET2 tumor suppressor to promote hematopoietic stem cell self-renewal and transformation. Cell Stem Cell 13(1):87–101PubMedCentralPubMedCrossRefGoogle Scholar
  150. Souza LR, Silva E, Calloway E, Kucuk O, Rossi M, McLemore ML (2014) Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage. Cancer Prev Res (Phila) 7(5):534–544CrossRefGoogle Scholar
  151. Sun W, Shen W, Yang S, Hu F, Li H, Zhu TH (2010) miR-223 and miR-142 attenuate hematopoietic cell proliferation, and miR-223 positively regulates miR-142 through LMO2 isoforms and CEBP-beta. Cell Res 20(10):1158–1169CrossRefPubMedGoogle Scholar
  152. Surdziel E, Cabanski M, Dallmann I, Lyszkiewicz M, Krueger A, Ganser A, Scherr M, Eder M (2011) Enforced expression of miR-125b affects myelopoiesis by targeting multiple signaling pathways. Blood 117(16):4338–4348CrossRefPubMedGoogle Scholar
  153. Szatmari I, Iacovino M, Kyba M (2010) The retinoid signaling pathway inhibits hematopoiesis and uncouples from the Hox genes during hematopoietic development. Stem Cells 28(9):1518–1529PubMedCentralPubMedCrossRefGoogle Scholar
  154. Talano JA, Cairo MS (2015) Hematopoietic stem cell transplantation for sickle cell disease: state of the science. Eur J Haematol 94(5):391–399CrossRefPubMedGoogle Scholar
  155. Thordardottir S, Hangalapura BN, Hutten T, Cossu M, Spanholtz J, Schaap N, Radstake TR, van der Voort R, Dolstra H (2014) The aryl hydrocarbon receptor antagonist StemRegenin 1 promotes human plasmacytoid and myeloid dendritic cell development from CD34+ hematopoietic progenitor cells. Stem Cells Dev 23(9):955–967CrossRefPubMedGoogle Scholar
  156. Tian C, You MJ, Yu Y, Zhu L, Zheng G, Zhang Y (2015) MicroRNA-9 promotes proliferation of leukemia cells in adult CD34-positive acute myeloid leukemia with normal karyotype by downregulation of Hes1. Tumour Biol 29(12):2442–2445Google Scholar
  157. Toda H, Yamamoto M, Kohara H, Tabata Y (2011) Orientation-regulated immobilization of Jagged1 on glass substrates for ex vivo proliferation of a bone marrow cell population containing hematopoietic stem cells. Biomaterials 32(29):6920–6928CrossRefPubMedGoogle Scholar
  158. Trowbridge JJ, Xenocostas A, Moon RT, Bhatia M (2006) Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat Med 12(1):89–98CrossRefPubMedGoogle Scholar
  159. Uchida N, He D, Friera AM, Reitsma M, Sasaki D, Chen B, Tsukamoto A (1997) The unexpected G0/G1 cell cycle status of mobilized hematopoietic stem cells from peripheral blood. Blood 89(2):465–472PubMedGoogle Scholar
  160. Varnum-Finney B, Purton LE, Yu M, Brashem-Stein C, Flowers D, Staats S, Moore KA, Le Roux I, Mann R, Gray G, Artavanis-Tsakonas S, Bernstein ID (1998) The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells. Blood 91(11):4084–4091PubMedGoogle Scholar
  161. Von Drygalski A, Alespeiti G, Ren L, Adamson JW (2004) Murine bone marrow cells cultured ex vivo in the presence of multiple cytokine combinations lose radioprotective and long-term engraftment potential. Stem Cells Dev 13(1):101–111CrossRefGoogle Scholar
  162. Wagner JE Jr, Brunstein CG, Boitano AE, DeFor TE, McKenna D, Sumstad D, Blazar BR, Tolar J, Le C, Jones J, Cooke MP, Bleul CC (2016) Phase I/II trial of StemRegenin-1 expanded umbilical cord blood hematopoietic stem cells supports testing as a stand-alone graft. Cell Stem Cell 18(1):144–155CrossRefPubMedGoogle Scholar
  163. Walasek MA, van Os R, de Haan G (2012) Hematopoietic stem cell expansion: challenges and opportunities. Ann N Y Acad Sci 1266:138–150CrossRefPubMedGoogle Scholar
  164. Walker L, Lynch M, Silverman S, Fraser J, Boulter J, Weinmaster G, Gasson JC (1999) The Notch/Jagged pathway inhibits proliferation of human hematopoietic progenitors in vitro. Stem Cells 17(3):162–171CrossRefPubMedGoogle Scholar
  165. Wang YF, Li Q, Meng HX, Yu Z, Liu JH, Cui W, Zhou Y, Mai YJ, You SG, Qiu LG (2004) Preliminary study on extensive amplification of human dendritic cells differentiated from cord blood CD34+ progenitor cells by two-step culture. Zhonghua Xue Ye Xue Za Zhi 25(2):70–73PubMedGoogle Scholar
  166. Wang Y, Kellner J, Liu L, Zhou D (2011) Inhibition of p38 mitogen-activated protein kinase promotes ex vivo hematopoietic stem cell expansion. Stem Cells Dev 20(7):1143–1152PubMedCentralPubMedCrossRefGoogle Scholar
  167. Watts KL, Delaney C, Nelson V, Trobridge GD, Beard BC, Humphries RK, Kiem HP (2013) CD34(+) expansion with Delta-1 and HOXB4 promotes rapid engraftment and transfusion independence in a Macaca nemestrina cord blood transplant model. Mol Ther 21(6):1270–1278PubMedCentralPubMedCrossRefGoogle Scholar
  168. Wei C, Liu J, Yu Z, Zhang B, Gao G, Jiao R (2013) TALEN or Cas9 - rapid, efficient and specific choices for genome modifications. J Genet Genomics 40(6):281–289CrossRefPubMedGoogle Scholar
  169. Wisniewski D, Affer M, Willshire J, Clarkson B (2011) Further phenotypic characterization of the primitive lineage- CD34+CD38-CD90+CD45RA- hematopoietic stem cell/progenitor cell sub-population isolated from cord blood, mobilized peripheral blood and patients with chronic myelogenous leukemia. Blood Cancer J 1(9):e36PubMedCentralPubMedCrossRefGoogle Scholar
  170. Wojtowicz EE, Walasek MA, Broekhuis MJ, Weersing E, Ritsema M, Ausema A, Bystrykh LV, de Haan G (2014) MicroRNA-125 family members exert a similar role in the regulation of murine hematopoiesis. Exp Hematol 42(10):909–918. e901CrossRefPubMedGoogle Scholar
  171. Wright AV, Sternberg SH, Taylor DW, Staahl BT, Bardales JA, Kornfeld JE, Doudna JA (2015) Rational design of a split-Cas9 enzyme complex. Proc Natl Acad Sci U S A 112(10):2984–2989PubMedCentralPubMedCrossRefGoogle Scholar
  172. Wu JM, Hsueh YC, Ch’ang HJ, Luo CY, Wu LW, Nakauchi H, Hsieh PC (2015) Circulating cells contribute to cardiomyocyte regeneration after injury. Circ Res 116(4):633–641CrossRefPubMedGoogle Scholar
  173. Xiao Y, Wei X, Jiang Z, Wang X, Ye W, Liu X, Zhang M, Xu Y, Wu D, Lai L, Yao H, Liu Z, Cao S, Liu P, Xu B, Li Y, Yao Y, Pei D, Li P (2015) Loss of Angiopoietin-like 7 diminishes the regeneration capacity of hematopoietic stem and progenitor cells. J Hematol Oncol 8:7PubMedCentralPubMedCrossRefGoogle Scholar
  174. Xie J, Chen X, Zheng J, Li C, Stacy S, Holzenberger M, Hu X, Zhang CC (2015a) IGF-IR determines the fates of BCR/ABL leukemia. J Hematol Oncol 8:3PubMedCentralPubMedCrossRefGoogle Scholar
  175. Xie XQ, Yang P, Zhang Y, Zhang P, Wang L, Ding Y, Yang M, Tong Q, Cheng H, Ji Q, McGuire T, Yuan W, Cheng T, Gao Y (2015b) Discovery of novel INK4C small-molecule inhibitors to promote human and murine hematopoietic stem cell ex vivo expansion. Sci Rep 5:18115PubMedCentralPubMedCrossRefGoogle Scholar
  176. Xu L, Xu Y, Jing Z, Wang X, Zha X, Zeng C, Chen S, Yang L, Luo G, Li B, Li Y (2014) Altered expression pattern of miR-29a, miR-29b and the target genes in myeloid leukemia. Exp Hematol Oncol 3:17PubMedCentralPubMedCrossRefGoogle Scholar
  177. Yagi M, Ritchie KA, Sitnicka E, Storey C, Roth GJ, Bartelmez S (1999) Sustained ex vivo expansion of hematopoietic stem cells mediated by thrombopoietin. Proc Natl Acad Sci U S A 96(14):8126–8131PubMedCentralPubMedCrossRefGoogle Scholar
  178. Yeoh JS, van Os R, Weersing E, Ausema A, Dontje B, Vellenga E, de Haan G (2006) Fibroblast growth factor-1 and -2 preserve long-term repopulating ability of hematopoietic stem cells in serum-free cultures. Stem Cells 24(6):1564–1572CrossRefPubMedGoogle Scholar
  179. Yuan X, Wu H, Xu H, Xiong H, Chu Q, Yu S, Wu GS, Wu K (2015) Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett 369(1):20–27CrossRefPubMedGoogle Scholar
  180. Zhang CC, Lodish HF (2005) Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105(11):4314–4320PubMedCentralPubMedCrossRefGoogle Scholar
  181. Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, Lodish HF (2006) Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nat Med 12(2):240–245PubMedCentralPubMedCrossRefGoogle Scholar
  182. Zhang CC, Kaba M, Iizuka S, Huynh H, Lodish HF (2008) Angiopoietin-like 5 and IGFBP2 stimulate ex vivo expansion of human cord blood hematopoietic stem cells as assayed by NOD/SCID transplantation. Blood 111(7):3415–3423PubMedCentralPubMedCrossRefGoogle Scholar
  183. Zheng J, Huynh H, Umikawa M, Silvany R, Zhang CC (2011) Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood 117(2):470–479PubMedCentralPubMedCrossRefGoogle Scholar
  184. Zou J, Zou P, Lou Y, Xiao Y, Wang J, Liu L (2011) The cross-talk between ROS and p38MAPKalpha in the Ex Vivo expanded human umbilical cord blood CD133(+) cells. J Huazhong Univ Sci Technolog Med Sci 31(5):591–595CrossRefPubMedGoogle Scholar
  185. Zsebo KM, Williams DA, Geissler EN, Broudy VC, Martin FH, Atkins HL, Hsu RY, Birkett NC, Okino KH, Murdock DC et al (1990) Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell 63(1):213–224CrossRefPubMedGoogle Scholar
  186. Zumkeller W (2002) The insulin-like growth factor system in hematopoietic cells. Leuk Lymphoma 43(3):487–491CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Faculty of MedicineUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of Biotechnology, Institute of ScienceYeditepe UniversityIstanbulTurkey
  3. 3.Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of EngineeringYeditepe UniversityIstanbulTurkey

Personalised recommendations