Cell and Tissue Research

, Volume 331, Issue 1, pp 79–90 | Cite as

Telomeres, senescence, and hematopoietic stem cells

  • Stefan ZimmermannEmail author
  • Uwe M. Martens


The replicative lifespan of normal somatic cells is restricted by the erosion of telomeres, which are protective caps at the ends of linear chromosomes. The loss of telomeres induces antiproliferative signals that eventually lead to cellular senescence. The enzyme complex telomerase can maintain telomeres, but its expression is confined to highly proliferative cells such as stem cells and tumor cells. The immense regenerative capacity of the hematopoietic system is provided by a distinct type of adult stem cell: hematopoietic stem cells (HSCs). Although blood cells have to be produced continuously throughout life, the HSC pool seems not to be spared by aging processes. Indeed, limited expression of telomerase is not sufficient to prevent telomere shortening in these cells, which is thought ultimately to limit their proliferative capacity. In this review, we discuss the relevance of telomere maintenance for the hematopoietic stem cell compartment and consider potential functions of telomerase in this context. We also present possible clinical applications of telomere manipulation in HSCs and new insights affecting the aging of the hematopoietic stem cell pool and replicative exhaustion.


Senescence Aging Telomerase Telomere Stem cells 



Grant support: European Community Grant LSHC-CT-2004-502943 (MOL CANCER MED).


  1. Abkowitz JL, Golinelli D, Harrison DE, Guttorp P (2000) In vivo kinetics of murine hemopoietic stem cells. Blood 96:3399–3405PubMedGoogle Scholar
  2. Akimov SS, Ramezani A, Hawley TS, Hawley RG (2005) Bypass of senescence, immortalization, and transformation of human hematopoietic progenitor cells. Stem Cells 23:1423–1433PubMedGoogle Scholar
  3. Akiyama M, Hoshi Y, Sakurai S, Yamada H, Yamada O, Mizoguchi H (1998) Changes of telomere length in children after hematopoietic stem cell transplantation. Bone Marrow Transplant 21:167–171PubMedGoogle Scholar
  4. Akiyama M, Asai O, Kuraishi Y, Urashima M, Hoshi Y, Sakamaki H, Yabe H, Furukawa T, Yamada O, Mizoguchi H, Yamada H (2000) Shortening of telomeres in recipients of both autologous and allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 25:441–447PubMedGoogle Scholar
  5. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai EV, Futcher AB, Greider CW, Harley CB (1992) Telomere length predicts replicative capacity of human fibroblasts. Proc Natl Acad Sci USA 89:10114–10118PubMedGoogle Scholar
  6. Allsopp RC, Cheshier S, Weissman IL (2001) Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med 193:917–924PubMedGoogle Scholar
  7. Allsopp RC, Cheshier S, Weissman IL (2002) Telomerase activation and rejuvenation of telomere length in stimulated T cells derived from serially transplanted hematopoietic stem cells. J Exp Med 196:1427–1433PubMedGoogle Scholar
  8. Allsopp RC, Morin GB, Horner JW, DePinho R, Harley CB, Weissman IL (2003a) Effect of TERT over-expression on the long-term transplantation capacity of hematopoietic stem cells. Nat Med 9:369–371Google Scholar
  9. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL (2003b) Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood 102:517–520Google Scholar
  10. Armanios M, Greider CW (2005) Telomerase and cancer stem cells. Cold Spring Harb Symp Quant Biol 70:205–208PubMedGoogle Scholar
  11. Armstrong L, Saretzki G, Peters H, Wappler I, Evans J, Hole N, von Zglinicki T, Lako M (2005) Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage. Stem Cells 23:516–529PubMedGoogle Scholar
  12. Artandi SE, Alson S, Tietze MK, Sharpless NE, Ye S, Greenberg RA, Castrillon DH, Horner JW, Weiler SR, Carrasco RD, DePinho RA (2002) Constitutive telomerase expression promotes mammary carcinomas in aging mice. Proc Natl Acad Sci USA 99:8191–8196PubMedGoogle Scholar
  13. Asai A, Oshima Y, Yamamoto Y, Uochi TA, Kusaka H, Akinaga S, Yamashita Y, Pongracz K, Pruzan R, Wunder E, Piatyszek M, Li S, Chin AC, Harley CB, Gryaznov S (2003) A novel telomerase template antagonist (GRN163) as a potential anticancer agent. Cancer Res 63:3931–3939PubMedGoogle Scholar
  14. Baerlocher GM, Lansdorp PM (2003) Telomere length measurements in leukocyte subsets by automated multicolor flow-FISH. Cytometry A 55:1–6PubMedGoogle Scholar
  15. Baerlocher GM, Rice K, Vulto I, Lansdorp PM (2006) Longitudinal data on telomere length in leukocytes from newborn baboons support a marked drop in stem cell turnover around 1 year of age. Aging Cell 6:121–123PubMedGoogle Scholar
  16. Ball SE, Gibson FM, Rizzo S, Tooze JA, Marsh JC, Gordon-Smith EC (1998) Progressive telomere shortening in aplastic anemia. Blood 91:3582–3592PubMedGoogle Scholar
  17. Beausejour CM, Campisi J (2006) Ageing: balancing regeneration and cancer. Nature 443:404–405PubMedGoogle Scholar
  18. Bhatia M, Wang J, Kapp U, Bonnet D, Dick JE (1997) Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. Proc Natl Acad Sci USA 94:5320–5325PubMedGoogle Scholar
  19. Blackburn EH (2001) Switching and signaling at the telomere. Cell 106:661–673PubMedGoogle Scholar
  20. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW (1997) Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91:25–34PubMedGoogle Scholar
  21. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE (1998) Extension of life-span by introduction of telomerase into normal human cells. Science 279:349–352PubMedGoogle Scholar
  22. Broccoli D, Young JW, de Lange T (1995) Telomerase activity in normal and malignant hematopoietic cells. Proc Natl Acad Sci USA 92:9082–9086PubMedGoogle Scholar
  23. Brummendorf TH, Rufer N, Baerlocher GM, Roosnek E, Lansdorp PM (2001a) Limited telomere shortening in hematopoietic stem cells after transplantation. Ann Acad Sci 938:1–8Google Scholar
  24. Brummendorf TH, Maciejewski JP, Mak J, Young NS, Lansdorp PM (2001b) Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 97:895–900Google Scholar
  25. Campisi J (2005) Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120:513–522PubMedGoogle Scholar
  26. Cao Y, Li H, Deb S, Liu JP (2002) TERT regulates cell survival independent of telomerase enzymatic activity. Oncogene 21:3130–3138PubMedGoogle Scholar
  27. Carlesso N, Aster JC, Sklar J, Scadden DT (1999) Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood 93:838–848PubMedGoogle Scholar
  28. Cech TR (2004) Beginning to understand the end of the chromosome. Cell 116:273–279PubMedGoogle Scholar
  29. Chiu CP, Dragowska W, Kim NW, Vaziri H, Yui J, Thomas TE, Harley CB, Lansdorp PM (1996) Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow. Stem Cells 14:239–248PubMedGoogle Scholar
  30. Choudhury AR, Ju Z, Djojosubroto MW, Schienke A, Lechel A, Schaetzlein S, Jiang H, Stepczynska A, Wang C, Buer J, Lee HW, von Zglinicki T, Ganser A, Schirmacher P, Nakauchi H, Rudolph KL (2007) Cdkn1a deletion improves stem cell function and lifespan of mice with dysfunctional telomeres without accelerating cancer formation. Nat Genet 39:99–105PubMedGoogle Scholar
  31. Collins K, Mitchell JR (2002) Telomerase in the human organism. Oncogene 21:564–579PubMedGoogle Scholar
  32. Collins CJ, Sedivy JM (2003) Involvement of the INK4a/Arf gene locus in senescence. Aging Cell 2:145–150PubMedGoogle Scholar
  33. Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Protein carbonylation in human diseases. Trends Mol Med 9:169–176PubMedGoogle Scholar
  34. Damm K, Hemmann U, Garin-Chesa P, Hauel N, Kauffmann I, Priepke H, Niestroj C, Daiber C, Enenkel B, Guilliard B, Lauritsch I, Muller E, Pascolo E, Sauter G, Pantic M, Martens UM, Wenz C, Lingner J, Kraut N, Rettig WJ, Schnapp A (2001) A highly selective telomerase inhibitor limiting human cancer cell proliferation. EMBO J 20:6958–6968PubMedGoogle Scholar
  35. Dikmen ZG, Gellert GC, Jackson S, Gryaznov S, Tressler R, Dogan P, Wright WE, Shay JW (2005) In vivo inhibition of lung cancer by GRN163L: a novel human telomerase inhibitor. Cancer Res 65:7866–7873PubMedGoogle Scholar
  36. Djojosubroto MW, Chin AC, Go N, Schaetzlein S, Manns MP, Gryaznov S, Harley CB, Rudolph KL (2005) Telomerase antagonists GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology 42:1127–1136PubMedGoogle Scholar
  37. dDokal I, Vulliamy T (2003) Dyskeratosis congenita: its link to telomerase and aplastic anaemia. Blood Rev 17:217–225PubMedGoogle Scholar
  38. El-Daly H, Kull M, Zimmermann S, Pantic M, Waller CF, Martens UM (2005) Selective cytotoxicity and telomere damage in leukemia cells using the telomerase inhibitor BIBR1532. Blood 105:1742–1749PubMedGoogle Scholar
  39. Elwood NJ, Jiang XR, Chiu CP, Lebkowski JS, Smith CA (2004) Enhanced long-term survival, but no increase in replicative capacity, following retroviral transduction of human cord blood CD34+ cells with human telomerase reverse transcriptase. Haematologica 89:377–378PubMedGoogle Scholar
  40. Engelhardt M, Kumar R, Albanell J, Pettengell R, Han W, Moore MA (1997) Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells. Blood 90:182–193PubMedGoogle Scholar
  41. Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, Read EJ, Lansdorp PM, Young NS (2003) Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet 362:1628–1630PubMedGoogle Scholar
  42. Folini M, Brambilla C, Villa R, Gandellini P, Vignati S, Paduano F, Daidone MG, Zaffaroni N (2005) Antisense oligonucleotide-mediated inhibition of hTERT, but not hTERC, induces rapid cell growth decline and apoptosis in the absence of telomere shortening in human prostate cancer cells. Eur J Cancer 41:624–634PubMedGoogle Scholar
  43. Frenck RW Jr, Blackburn EH, Shannon KM (1998) The rate of telomere sequence loss in human leukocytes varies with age. Proc Natl Acad Sci USA 95:5607–5610PubMedGoogle Scholar
  44. Gammaitoni L, Weisel KC, Gunetti M, Wu KD, Bruno S, Pinelli S, Bonati A, Aglietta M, Moore MA, Piacibello W (2004) Elevated telomerase activity and minimal telomere loss in cord blood long-term cultures with extensive stem cell replication. Blood 103:4440–4448PubMedGoogle Scholar
  45. Gellert GC, Dikmen ZG, Wright WE, Gryaznov S, Shay JW (2006) Effects of a novel telomerase inhibitor, GRN163L, in human breast cancer. Breast Cancer Res Treat 96:73–81PubMedGoogle Scholar
  46. Glimm H, Eisterer W, Lee K, Cashman J, Holyoake TL, Nicolini F, Shultz LD, von Kalle C, Eaves CJ (2001) Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD/SCID-beta2 microglobulin-null mice. J Clin Invest 107:199–206PubMedGoogle Scholar
  47. Goldman F, Bouarich R, Kulkarni S, Freeman S, Du HY, Harrington L, Mason PJ, Londono-Vallejo A, Bessler M (2005) The effect of TERC haploinsufficiency on the inheritance of telomere length. Proc Natl Acad Sci USA 102:17119—17124PubMedGoogle Scholar
  48. Gorbunova V, Seluanov A (2003) Telomerase as a growth-promoting factor. Cell Cycle 2:534–537PubMedGoogle Scholar
  49. Greider CW, Blackburn EH (1989) A telomeric sequence in the RNA of Tetrahymena telomerase required for telomere repeat synthesis. Nature 337:331–337PubMedGoogle Scholar
  50. Griffith JD, Comeau L, Rosenfield S, Stansel RM, Bianchi A, Moss H, de Lange T(1999) Mammalian telomeres end in a large duplex loop. Cell 97:503–514PubMedGoogle Scholar
  51. Hahn WC, Stewart SA, Brooks MW, York SG, Eaton E, Kurachi A, Beijersbergen RL, Knoll JH, Meyerson M, Weinberg RA (1999) Inhibition of telomerase limits the growth of human cancer cells. Nat Med 5:1164–1170PubMedGoogle Scholar
  52. Hande MP, Samper E, Lansdorp P, Blasco MA (1999) Telomere length dynamics and chromosomal instability in cells derived from telomerase null mice. J Cell Biol 144:589–601PubMedGoogle Scholar
  53. Hao LY, Armanios M, Strong MA, Karim B, Feldser DM, Huso D, Greider CW (2005) Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell 123:1121–1131PubMedGoogle Scholar
  54. Harle-Bachor C, Boukamp P (1996) Telomerase activity in the regenerative basal layer of the epidermis in human skin and in immortal and carcinoma-derived skin keratinocytes. Proc Natl Acad Sci USA 93:6476–6481PubMedGoogle Scholar
  55. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460PubMedGoogle Scholar
  56. Harley CB, Kim NW, Prowse KR, Weinrich SL, Hirsch KS, West MD, Bacchetti S, Hirte HW, Counter CM, Greider CW, et al (1994) Telomerase, cell immortality, and cancer. Cold Spring Harb Symp Quant Biol 59:307–315PubMedGoogle Scholar
  57. Harrison D, Astle C (1982) Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 156:1767–1779PubMedGoogle Scholar
  58. Harrison DE, Astle CM, Delaittre JA (1978) Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging. J Exp Med 147:1526–1531PubMedGoogle Scholar
  59. Herbert B, Pitts AE, Baker SI, Hamilton SE, Wright WE, Shay JW, Corey DR (1999) Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death. Proc Natl Acad Sci USA 96:14276–14281PubMedGoogle Scholar
  60. Herbig U, Ferreira M, Condel L, Carey D, Sedivy JM (2006) Cellular senescence in aging primates. Science 311:1257PubMedGoogle Scholar
  61. Herrera E, Samper E, Blasco MA (1999) Telomere shortening in mTR−/− embryos is associated with failure to close the neural tube. EMBO J 18:1172–1181PubMedGoogle Scholar
  62. Hiyama K, Hirai Y, Kyoizumi S, Akiyama M, Hiyama E, Piatyszek MA, Shay JW, Ishioka S, Yamakido M (1995) Activation of telomerase in human lymphocytes and hematopoietic progenitor cells. J Immunol 155:3711–3715PubMedGoogle Scholar
  63. Hooijberg E, Ruizendaal JJ, Snijders PJ, Kueter EW, Walboomers JM, Spits H (2000) Immortalization of human CD8+ T cell clones by ectopic expression of telomerase reverse transcriptase. J Immunol 165:4239–4245PubMedGoogle Scholar
  64. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N, Ikeda Y, Mak TW, Suda T (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431:997–1002PubMedGoogle Scholar
  65. Ivanova NB, Dimos JT, Schaniel C, Hackney JA, Moore KA, Lemischka IR (2002) A stem cell molecular signature. Science 298:601–604Google Scholar
  66. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT (2006) Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature 443:421–426PubMedGoogle Scholar
  67. Jaras M, Edqvist A, Rebetz J, Salford LG, Widegren B, Fan X (2006) Human short-term repopulating cells have enhanced telomerase reverse transcriptase expression. Blood 108:1084–1091PubMedGoogle Scholar
  68. 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 101:5061–5067PubMedGoogle Scholar
  69. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedGoogle Scholar
  70. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL (2007a) Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med 13:742–747PubMedGoogle Scholar
  71. Ju Z, Choudhury AR, Rudolph KL (2007b) A dual role of p21 in stem cell aging. Ann N Y Acad Sci 1100:333–344PubMedGoogle Scholar
  72. Kamminga LM, de Haan G (2006) Cellular memory and hematopoietic stem cell aging. Stem Cells 24:1143–1149PubMedGoogle Scholar
  73. Keith WN (2004) From stem cells to cancer: balancing immortality and neoplasia. Oncogene 23:5092–5094PubMedGoogle Scholar
  74. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015PubMedGoogle Scholar
  75. Kolquist KA, Ellisen LW, Counter CM, Meyerson M, Tan LK, Weinberg RA, Haber DA, Gerald WL (1998) Expression of TERT in early premalignant lesions and a subset of cells in normal tissues. Nat Genet 19:182–186PubMedGoogle Scholar
  76. Lansdorp PM (1995) Telomere length and proliferation potential of hematopoietic stem cells. J Cell Sci 108:1–6PubMedGoogle Scholar
  77. Lansdorp PM, Dragowska W, Thomas TE, Little MT, Mayani H (1994) Age-related decline in proliferative potential of purified stem cell candidates. Blood Cells 20:376–380PubMedGoogle Scholar
  78. Lansdorp PM, Poon S, Chavez E, Dragowska V, Zijlmans M, Bryan T, Reddel R, Egholm M, Bacchetti S, Martens U (1997) Telomeres in the haemopoietic system. Ciba Found Symp 211:209–222PubMedGoogle Scholar
  79. Lee J, Kook H, Chung I, Kim H, Park M, Kim C, Nah J, Hwang T (1999) Telomere length changes in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 24:411–415PubMedGoogle Scholar
  80. Lee JJ, Kook H, Chung IJ, Na JA, Park MR, Hwang TJ, Kwak JY, Sohn SK, Kim HJ (2001) Telomere length changes in patients with aplastic anaemia. Br J Haematol 112:1025–1030PubMedGoogle Scholar
  81. Lessard J, Sauvageau G (2003) Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells. Nature 423:255–260PubMedGoogle Scholar
  82. Li S, Ferguson MJ, Hawkins CJ, Smith C, Elwood NJ (2006) Human telomerase reverse transcriptase protects hematopoietic progenitor TF-1 cells from death and quiescence induced by cytokine withdrawal. Leukemia 20:1270–1278PubMedGoogle Scholar
  83. Liu K, Schoonmaker MM, Levine BL, June CH, Hodes RJ, Weng NP (1999) Constitutive and regulated expression of telomerase reverse transcriptase (hTERT) in human lymphocytes. Proc Natl Acad Sci USA 96:5147–5152PubMedGoogle Scholar
  84. Liu Y, Snow BE, Hande MP, Yeung D, Erdmann NJ, Wakeham A, Itie A, Siderovski DP, Lansdorp PM, Robinson MO, Harrington L (2000) The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo. Curr Biol 10:1459–1462PubMedGoogle Scholar
  85. Ly H, Calado RT, Allard P, Baerlocher GM, Lansdorp PM, Young NS, Parslow TG (2005) Functional characterization of telomerase RNA variants found in patients with hematologic disorders. Blood 105:2332–2339PubMedGoogle Scholar
  86. Maciejewski JP, Anderson S, Katevas P, Young NS (1994) Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol 87:227–234PubMedGoogle Scholar
  87. Marrone A, Stevens D, Vulliamy T, Dokal I, Mason PJ (2004) Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood 104:3936–3942PubMedGoogle Scholar
  88. Marsh JC, Chang J, Testa NG, Hows JM, Dexter TM (1990) The hematopoietic defect in aplastic anemia assessed by long-term marrow culture. Blood 76:1748–1757PubMedGoogle Scholar
  89. Martens UM, Zijlmans JM, Poon SS, Dragowska W, Yui J, Chavez EA, Ward RK, Lansdorp PM (1998) Short telomeres on human chromosome 17p. Nat Genet 18:76–80PubMedGoogle Scholar
  90. Martens UM, Brass V, Sedlacek L, Pantic M, Exner C, Guo Y, Engelhardt M, Lansdorp PM, Waller CF, Lange W (2002) Telomere maintenance in human B lymphocytes. Br J Haematol 119:810–818PubMedGoogle Scholar
  91. Marx J (2003) Cancer research. Mutant stem cells may seed cancer. Science 301:1308–1310PubMedGoogle Scholar
  92. Maser RS, DePinho RA (2002) Connecting chromosomes, crisis, and cancer. Science 297:565–569PubMedGoogle Scholar
  93. Massard C, Zermati Y, Pauleau AL, Larochette N, Metivier D, Sabatier L, Kroemer G, Soria JC (2006) hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene 25:4505–4514PubMedGoogle Scholar
  94. Masutomi K, Yu EY, Khurts S, Ben-Porath I, Currier JL, Metz GB, Brooks MW, Kaneko S, Murakami S, DeCaprio JA, Weinberg RA, Stewart SA, Hahn WC (2003) Telomerase maintains telomere structure in normal human cells. Cell 114:241–253PubMedGoogle Scholar
  95. Mitchell JR, Wood E, Collins K (1999) A telomerase component is defective in the human disease dyskeratosis congenita. Nature 402:551–555PubMedGoogle Scholar
  96. Moore MA (2000) Umbilical cord blood: an expandable resource. J Clin Invest 105:855–856PubMedGoogle Scholar
  97. Morrison SJ, Prowse KR, Ho P, Weissman IL (1996) Telomerase activity in hematopoietic cells is associated with self-renewal potential. Immunity 5:207–216PubMedGoogle Scholar
  98. Notaro R, Cimmino A, Tabarini D, Rotoli B, Luzzatto L (1997) In vivo telomere dynamics of human hematopoietic stem cells. Proc Natl Acad Sci USA 94:13782–13785PubMedGoogle Scholar
  99. Nystrom T (2005) Role of oxidative carbonylation in protein quality control and senescence. EMBO J 24:1311–1317PubMedGoogle Scholar
  100. Ohyashiki JH, Sashida G, Tauchi T, Ohyashiki K (2002) Telomeres and telomerase in hematologic neoplasia. Oncogene 21:680–687PubMedGoogle Scholar
  101. Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ, Clarke MF (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–305PubMedGoogle Scholar
  102. Pipes BL, Tsang T, Peng SX, Fiederlein R, Graham M, Harris DT (2006) Telomere length changes after umbilical cord blood transplant. Transfusion 46:1038–1043PubMedGoogle Scholar
  103. Prasher JM, Lalai AS, Heijmans-Antonissen C, Ploemacher RE, Hoeijmakers JH, Touw IP, Niedernhofer LJ (2005) Reduced hematopoietic reserves in DNA interstrand crosslink repair-deficient Ercc1−/− mice. EMBO J 24:861–871PubMedGoogle Scholar
  104. Ramalho-Santos M, Yoon S, Matsuzaki Y, Mulligan RC, Melton DA (2002) “Stemness”: transcriptional profiling of embryonic and adult stem cells. Science 298:597-600PubMedGoogle Scholar
  105. 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 423:409–414PubMedGoogle Scholar
  106. Robertson JD, Testa NG, Russell NH, Jackson G, Parker AN, Milligan DW, Stainer C, Chakrabarti S, Dougal M, Chopra R (2001) Accelerated telomere shortening following allogeneic transplantation is independent of the cell source and occurs within the first year post transplant. Bone Marrow Transplant 27:1283–1286PubMedGoogle Scholar
  107. Rocci A, Ricca I, Dellacasa C, Longoni P, Compagno M, Francese R, Lobetti Bodoni C, Manzini P, Caracciolo D, Boccadoro M, Ferrero D, Ladetto M, Carlo-Stella C, Tarella C (2007) Long-term lymphoma survivors following high-dose chemotherapy and autograft: evidence of permanent telomere shortening in myeloid cells, associated with marked reduction of bone marrow hematopoietic stem cell reservoir. Exp Hematol 35:673–681PubMedGoogle Scholar
  108. Roelofs H, de Pauw ES, Zwinderman AH, Opdam SM, Willemze R, Tanke HJ, Fibbe WE (2003) Homeostasis of telomere length rather than telomere shortening after allogeneic peripheral blood stem cell transplantation. Blood 101:358–362PubMedGoogle Scholar
  109. Roth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, Spits H, Luiten RM (2003) Telomerase levels control the lifespan of human T lymphocytes. Blood 102:849–857PubMedGoogle Scholar
  110. Roth A, Baerlcher GM, Schertzer M, Chavez E, Duhrsen U, Lansdorp PM (2005) Telomere loss senescence and genetic instability in CD4+ T lymphocytes overexpressing hTERT. Blood 106:43–50PubMedGoogle Scholar
  111. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA (1999) Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 96:701–712PubMedGoogle Scholar
  112. Rufer N, Dragowska W, Thornbury G, Roosnek E, Lansdorp PM (1998) Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry. Nat Biotechnol 16:743–747PubMedGoogle Scholar
  113. Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, Schulzer M, Lansdorp PM (1999) Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of hematopoietic stem cells and memory T cells in early childhood. J Exp Med 190:157–167PubMedGoogle Scholar
  114. Rufer N, Brummendorf TH, Chapuis B, Helg C, Lansdorp PM, Roosnek E (2001a) Accelerated telomere shortening in hematological lineages is limited to the first year following stem cell transplantation. Blood 97:575–577Google Scholar
  115. Rufer N, Migliaccio M, Antonchuk J, Humphries RK, Roosnek E, Lansdorp PM (2001b) Transfer of the human telomerase reverse transcriptase (TERT) gene into T lymphocytes results in extension of replicative potential. Blood 98:597–603Google Scholar
  116. Satija NK, Gurudutta GU, Sharma S, Afrin F, Gupta P, Verma YK, Singh VK, Tripathi RP (2007) Mesenchymal stem cells: molecular targets for tissue engineering. Stem Cells Dev 16:7–23PubMedGoogle Scholar
  117. 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 9:1753–1765PubMedGoogle Scholar
  118. Scopes J, Bagnara M, Gordon-Smith EC, Ball SE, Gibson FM (1994) Haemopoietic progenitor cells are reduced in aplastic anaemia. Br J Haematol 86:427–430Google Scholar
  119. Serakinci N, Guldberg P, Burns JS, Abdallah B, Schrodder H, Jensen T, Kassem M (2004) Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 23:5095–5098PubMedGoogle Scholar
  120. Shepherd BE, Guttorp P, Lansdorp PM, Abkowitz JL (2004) Estimating human hematopoietic stem cell kinetics using granulocyte telomere lengths. Exp Hematol 32:1040–1050PubMedGoogle Scholar
  121. Shi S, Gronthos S, Chen S, Reddi A, Counter CM, Robey PG, Wang CY (2002) Bone formation by human postnatal bone marrow stromal stem cells is enhanced by telomerase expression. Nat Biotechnol 20:587–591PubMedGoogle Scholar
  122. Siminovitch L, Till JE, McCulloch EA (1964) Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J Cell Physiol 64:23–31PubMedGoogle Scholar
  123. Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI, Jensen TG, Kassem M (2002) Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 20:592–596PubMedGoogle Scholar
  124. Slagboom PE, Droog S, Boomsma DI (1994) Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet 55:876–882PubMedGoogle Scholar
  125. Son NH, Joyce B, Hieatt A, Chrest FJ, Yanovski J, Weng NP (2003) Stable telomere length and telomerase expression from naive to memory B-lymphocyte differentiation. Mech Ageing Dev 124:427–432PubMedGoogle Scholar
  126. Stewart SA, Weinberg RA (2006) Telomeres: cancer to human aging. Annu Rev Cell Dev Biol 22:531–557PubMedGoogle Scholar
  127. Tanavde VM, Malehorn MT, Lumkul R, Gao Z, Wingard J, Garrett ES, Civin CI (2002) Human stem-progenitor cells from neonatal cord blood have greater hematopoietic expansion capacity than those from mobilized adult blood. Exp Hematol 30:816–823PubMedGoogle Scholar
  128. Terskikh AV, Miyamoto T, Chang C, Diatchenko L, Weissman IL (2003) Gene expression analysis of purified hematopoietic stem cells and committed progenitors. Blood 102:94–101PubMedGoogle Scholar
  129. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedGoogle Scholar
  130. Thornley I, Sutherland R, Wynn R, Nayar R, Sung L, Corpus G, Kiss T, Lipton J, Doyle J, Saunders F, Kamel-Reid S, Freedman M, Messner H (2002) Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss. Blood 99:2387–2396PubMedGoogle Scholar
  131. Traycoff CM, Kosak ST, Grigsby S, Srour EF (1995) Evaluation of ex vivo expansion potential of cord blood and bone marrow hematopoietic progenitor cells using cell tracking and limiting dilution analysis. Blood 85:2059–2068PubMedGoogle Scholar
  132. Van Ziffle JA, Baerlocher GM, Lansdorp PM (2003) Telomere length in subpopulations of human hematopoietic cells. Stem Cells 21:654–660PubMedGoogle Scholar
  133. Vaziri H, Benchimol S (1998) Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. Curr Biol 8:279–282PubMedGoogle Scholar
  134. Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667PubMedGoogle Scholar
  135. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley CB, Lansdorp PM (1994) Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proc Natl Acad Sci USA 91:9857–9860PubMedGoogle Scholar
  136. Verfaillie CM, Pera MF, Lansdorp PM (2002) Stem cells: hype and reality. Hematology Am Soc Hematol Educ Program 2002:369–391Google Scholar
  137. von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344Google Scholar
  138. Vulliamy T, Dokal I (2006) Dyskeratosis congenita. Semin Hematol 43:157–166PubMedGoogle Scholar
  139. Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I (2001) The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita. Nature 413:432–435PubMedGoogle Scholar
  140. Vulliamy T, Marrone A, Dokal I, Mason PJ (2002) Association between aplastic anaemia and mutations in telomerase RNA. Lancet 359:2168–2170PubMedGoogle Scholar
  141. Vulliamy T, Marrone A, Szydlo R, Walne A, Mason PJ, Dokal I (2004) Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC. Nat Genet 36:447–449PubMedGoogle Scholar
  142. Wang JC, Warner JK, Erdmann N, Lansdorp PM, Harrington L, Dick JE (2005) Dissociation of telomerase activity and telomere length maintenance in primitive human hematopoietic cells. Proc Natl Acad Sci USA 102:14398–14403PubMedGoogle Scholar
  143. Watson JD (1972) Origin of concatemeric T7 DNA. Nat New Biol 239:197–201PubMedGoogle Scholar
  144. Weng NP, Levine BL, June CH, Hodes RJ (1996) Regulated expression of telomerase activity in human T lymphocyte development and activation. J Exp Med 183:2471–2479PubMedGoogle Scholar
  145. Weng NP, Hathcock KS, Hodes RJ (1998) Regulation of telomere length and telomerase in T and B cells: a mechanism for maintaining replicative potential. Immunity 9:151–157PubMedGoogle Scholar
  146. Wright WE, Shay JW (2002) Historical claims and current interpretations of replicative aging. Nat Biotechnol 20:682–688PubMedGoogle Scholar
  147. Wynn RF, Cross MA, Hatton C, Will AM, Lashford LS, Dexter TM, Testa NG (1998) Accelerated telomere shortening in young recipients of allogeneic bone-marrow transplants. Lancet 351:178–181PubMedGoogle Scholar
  148. Yamada O, Akiyama M, Kawauchi K, Adachi T, Yamada H, Kanda N, Aikawa E (2003) Overexpression of telomerase confers a survival advantage through suppression of TRF1 gene expression while maintaining differentiation characteristics in K562 cells. Cell Transplant 12:365–377PubMedGoogle Scholar
  149. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med 352:1413–1424PubMedGoogle Scholar
  150. Yao CL, Feng YH, Lin XZ, Chu IM, Hsieh TB, Hwang SM (2006) Characterization of serum-free ex vivo-expanded hematopoietic stem cells derived from human umbilical cord blood CD133(+) cells. Stem Cells Dev 15:70–78PubMedGoogle Scholar
  151. Yasumoto S, Kunimura C, Kikuchi K, Tahara H, Ohji H, Yamamoto H, Ide T, Utakoji T (1996) Telomerase activity in normal human epithelial cells. Oncogene 13:433–439PubMedGoogle Scholar
  152. Yui J, Chiu CP, Lansdorp PM (1998) Telomerase activity in candidate stem cells from fetal liver and adult bone marrow. Blood 91:3255–3262PubMedGoogle Scholar
  153. Zhang X, Mar V, Zhou W, Harrington L, Robinson MO (1999) Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev 13:2388–2399PubMedGoogle Scholar
  154. Zhang R, Poustovoitov MV, Ye X, Santos HA, Chen W, Daganzo SM, Erzberger JP, Serebriiskii IG, Canutescu AA, Dunbrack RL, Pehrson JR, Berger JM, Kaufman PD, Adams PD (2005) Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA. Dev Cell 8:19–30PubMedGoogle Scholar
  155. Zhao JQ, Glasspool RM, Hoare SF, Bilsland A, Szatmari I, Keith WN (2000) Activation of telomerase RNA gene promoter activity by NF-Y, Sp1, and the retinoblastoma protein and repression by Sp3. Neoplasia 2:531–539PubMedGoogle Scholar
  156. Zhu X, Kumar R, Mandal M, Sharma N, Sharma HW, Dhingra U, Sokoloski JA, Hsiao R, Narayanan R (1996) Cell cycle-dependent modulation of telomerase activity in tumor cells. Proc Natl Acad Sci USA 93:6091–6095PubMedGoogle Scholar
  157. Zhu J, Zhang Y, Joe GJ, Pompetti R, Emerson SG (2005) NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal. Proc Natl Acad Sci USA 102:11728–11733PubMedGoogle Scholar
  158. Zimmermann S, Martens UM (2007) Telomeres and telomerase as targets for cancer therapy. Cell Mol Lif Sci 64:906–921Google Scholar
  159. Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM (2003) Lack of telomerase activity in human mesenchymal stem cells. Leukemia 17:1146–1149PubMedGoogle Scholar
  160. Zimmermann S, Glaser S, Ketteler R, Waller CF, Klingmüller U, Martens UM (2004) Effects of telomerase modulation in human hematopoietic progenitor cells. Stem Cells 22:741–749PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  1. 1.Department of Hematology/OncologyFreiburg University Medical CenterFreiburgGermany

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