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Hematopoietic stem cell development, aging and functional failure

  • Progress in Hematology
  • Hematopoietic stem cell aging
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

Hematopoietic stem cells (HSCs) are found in yolk sac, fetal liver, umbilical cord blood, placenta, and amniotic fluid during mammalian embryonic development. In adults, HSCs reside in marrow cavity of long bones where they self-renew and differentiate to replenish short-lived mature blood cells. HSCs exist in very low frequencies within specific “niches” where they interact with the surrounding environment through molecular associations. Overall HSC function can last much longer than a normal lifetime, but HSCs do show functional senescence with characteristic features of decreased self-renewal, reduced clonal stability, reduced homing and engraftment, and biased lineage commitment. The progressive shortening of telomeres with increasing age, especially under conditions with specific mutations in the telomerase gene complex, could predispose patients to HSC dysfunction and bone marrow failure diseases. Continuous investigation into HSC biology should facilitate the utilization of HSCs as a therapeutic modality and helps to prevent HSC malfunction.

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References

  1. Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy. N Engl J Med. 1957;257:491–6.

    Article  PubMed  CAS  Google Scholar 

  2. Thomas ED, Ashley CA, Lochte HL Jr, Jaretzki A III, Sahler OD, Ferrebee JW. Homografts of bone marrow in dogs after lethal total-body radiation. Blood. 1959;14:720–36.

    PubMed  CAS  Google Scholar 

  3. Thomas ED, Lochte HL Jr, Cannon JH, Sahler OD, Ferrebee JW. Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest. 1959;38:1709–16.

    Article  PubMed  CAS  Google Scholar 

  4. Ferrebee JW, Atkins L, Lochte HL Jr, McFarland RB, Jones AR, Dammin GJ, Thomas ED. The collection, storage and preparation of viable cadaver marrow for intravenous use. Blood. 1959;14:140–7.

    PubMed  CAS  Google Scholar 

  5. Thomas ED, Ferrebee JW. Prolonged storage of marrow and its use in the treatment of radiation injury. Transfusion. 1962;2:115–7.

    Article  PubMed  CAS  Google Scholar 

  6. Chen J. Senescence and functional failure in hematopoietic stem cells. Exp Hematol. 2004;32:1025–32.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Moore MA, McNeill TA, Haskill JS. Density distribution analysis of in vivo and in vitro colony forming cells in developing fetal liver. J Cell Physiol. 1970;75:181–92.

    Article  PubMed  CAS  Google Scholar 

  9. Ferkowicz MJ, Yoder MC. Blood island formation: longstanding observations and modern interpretations. Exp Hematol. 2005;33:1041–7.

    Article  PubMed  Google Scholar 

  10. Yoshimoto M, Yoder MC. Developmental biology: birth of the blood cell. Nature. 2009;457:801–3.

    Article  PubMed  CAS  Google Scholar 

  11. Yoshimoto M, Porayette P, Yoder MC. Overcoming obstacles in the search for the site of hematopoietic stem cell emergence. Cell Stem Cell. 2008;3:583–6.

    Article  PubMed  CAS  Google Scholar 

  12. Eilken HM, Nishikawa S, Schroeder T. Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature. 2009;457:896–900.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  16. Samokhvalov IM, Samokhvalova NI, Nishikawa S. Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature. 2007;446:1056–61.

    Article  PubMed  CAS  Google Scholar 

  17. Lux CT, Yoshimoto M, McGrath K, Conway SJ, Palis J, Yoder MC. All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood. 2008;111:3435–8.

    Article  PubMed  CAS  Google Scholar 

  18. Harrison DE, Russell ES. Fetal liver erythropoiesis and yolk sac cells. Science. 1972;177:187.

    Article  PubMed  CAS  Google Scholar 

  19. Jordan CT, Astle CM, Zawadzki J, Mackarehtschian K, Lemischka IR, Harrison DE. Long-term repopulating abilities of enriched fetal liver stem cells measured by competitive repopulation. Exp Hematol. 1995;23:1011–5.

    PubMed  CAS  Google Scholar 

  20. Chen J, Astle CM, Harrison DE. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp Hematol. 1999;27:928–35.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  23. Kim I, He S, Yilmaz OH, Kiel MJ, Morrison SJ. Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood. 2006;108:737–44.

    Article  PubMed  CAS  Google Scholar 

  24. Rhodes KE, Gekas C, Wang Y, Lux CT, Francis CS, Chan DN, Conway S, Orkin SH, Yoder MC, Mikkola HK. The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell. 2008;2:252–63.

    Article  PubMed  CAS  Google Scholar 

  25. Robin C, Bollerot K, Mendes S, Haak E, Crisan M, Cerisoli F, Lauw I, Kaimakis P, Jorna R, Vermeulen M, Kayser M, van der Linden R, Imanirad P, Verstegen M, Nawaz-Yousaf H, Papazian N, Steegers E, Cupedo T, Dzierzak E. Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell. 2009;5:385–95.

    Article  PubMed  CAS  Google Scholar 

  26. Broxmeyer HE, Douglas GW, Hangoc G, Cooper S, Bard J, English D, Arny M, Thomas L, Boyse EA. Human umbilical cord blood as a potential source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA. 1989;86:3828–32.

    Article  PubMed  CAS  Google Scholar 

  27. Auerbach AD, Liu Q, Ghosh R, Pollack MS, Douglas GW, Broxmeyer HE. Prenatal identification of potential donors for umbilical cord blood transplantation for Fanconi anemia. Transfusion. 1990;30:682–7.

    Article  PubMed  CAS  Google Scholar 

  28. Wagner JE, Broxmeyer HE, Byrd RL, Zehnbauer B, Schmeckpeper B, Shah N, Griffin C, Emanuel PD, Zuckerman KS, Cooper S. Transplantation of umbilical cord blood after myeloablative therapy: analysis of engraftment. Blood. 1992;79:1874–81.

    PubMed  CAS  Google Scholar 

  29. Gluckman E, Wagner J, Hows J, Kernan N, Bradley B, Broxmeyer HE. Cord blood banking for hematopoietic stem cell transplantation: an international cord blood transplant registry. Bone Marrow Transplant. 1993;11:199–200.

    PubMed  CAS  Google Scholar 

  30. Ditadi A, de Coppi P, Picone O, Gautreau L, Smati R, Six E, Bonhomme D, Ezine S, Frydman R, Cavazzana-Calvo M, Andre-Schmutz I. Human and murine amniotic fluid c-Kit+Lin− cells display hematopoietic activity. Blood. 2009;113:3953–60.

    Article  PubMed  CAS  Google Scholar 

  31. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science. 1988;241:58–62.

    Article  PubMed  CAS  Google Scholar 

  32. Abkowitz JL, Linenberger ML, Newton MA, Shelton GH, Ott RL, Guttorp P. Evidence for the maintenance of hematopoiesis in a large animal by the sequential activation of stem-cell clones. Proc Natl Acad Sci USA. 1990;87:9062–6.

    Article  PubMed  CAS  Google Scholar 

  33. Abkowitz JL, Catlin SN, Guttorp P. Evidence that hematopoiesis may be a stochastic process in vivo. Nat Med. 1996;2:190–7.

    Article  PubMed  CAS  Google Scholar 

  34. Abkowitz JL, Catlin SN, McCallie MT, Guttorp P. Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood. 2002;100:2665–7.

    Article  PubMed  CAS  Google Scholar 

  35. Shepherd BE, Kiem HP, Lansdorp PM, Dunbar CE, Aubert G, LaRochelle A, Seggewiss R, Guttorp P, Abkowitz JL. Hematopoietic stem-cell behavior in nonhuman primates. Blood. 2007;110:1806–13.

    Article  PubMed  CAS  Google Scholar 

  36. Chen J, Ellison FM, Keyvanfar K, Omokaro SO, Desierto MJ, Eckhaus MA, Young NS. Enrichment of hematopoietic stem cells with SLAM and LSK markers for the detection of hematopoietic stem cell function in normal and Trp53 null mice. Exp Hematol. 2008;36:1236–43.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  38. Stewart FM, Crittenden RB, Lowry PA, Pearson-White S, Quesenberry PJ. Long-term engraftment of normal and post-5-fluorouracil murine marrow into normal nonmyeloablated mice. Blood. 1993;81:2566–71.

    PubMed  CAS  Google Scholar 

  39. Quesenberry PJ, Ramshaw H, Crittenden RB, Stewart FM, Rao S, Peters S, Becker P, Lowry P, Blomberg M, Reilly J. Engraftment of normal murine marrow into nonmyeloablated host mice. Blood Cells. 1994;20:348–50.

    PubMed  CAS  Google Scholar 

  40. Ramshaw HS, Crittenden RB, Dooner M, Peters SO, Rao SS, Quesenberry PJ. High levels of engraftment with a single infusion of bone marrow cells into normal unprepared mice. Biol Blood Marrow Transplant. 1995;1:74–80.

    PubMed  CAS  Google Scholar 

  41. Rao SS, Peters SO, Crittenden RB, Stewart FM, Ramshaw HS, Quesenberry PJ. Stem cell transplantation in the normal nonmyeloablated host: relationship between cell dose, schedule, and engraftment. Exp Hematol. 1997;25:114–21.

    PubMed  CAS  Google Scholar 

  42. Nilsson SK, Dooner MS, Tiarks CY, Weier HU, Quesenberry PJ. Potential and distribution of transplanted hematopoietic stem cells in a nonablated mouse model. Blood. 1997;89:4013–20.

    PubMed  CAS  Google Scholar 

  43. Nilsson SK, Dooner MS, Weier HU, Frenkel B, Lian JB, Stein GS, Quesenberry PJ. Cells capable of bone production engraft from whole bone marrow transplants in nonablated mice. J Exp Med. 1999;189:729–34.

    Article  PubMed  CAS  Google Scholar 

  44. Zhong JF, Zhan Y, Anderson WF, Zhao Y. Murine hematopoietic stem cell distribution and proliferation in ablated and nonablated bone marrow transplantation. Blood. 2002;100:3521–6.

    Article  PubMed  CAS  Google Scholar 

  45. Gong JK. Endosteal marrow: a rich source of hematopoietic stem cells. Science. 1978;199:1443–5.

    Article  PubMed  CAS  Google Scholar 

  46. Lowry PA, Shultz LD, Greiner DL, Hesselton RM, Kittler EL, Tiarks CY, Rao SS, Reilly J, Leif JH, Ramshaw H, Stewart FM, Quesenberry PJ. Improved engraftment of human cord blood stem cells in NOD/LtSz-scid/scid mice after irradiation or multiple-day injections into unirradiated recipients. Biol Blood Marrow Transplant. 1996;2:15–23.

    PubMed  CAS  Google Scholar 

  47. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425:841–6.

    Article  PubMed  CAS  Google Scholar 

  48. Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L. Identification of the haematopoietic stem cell niche and control of the niche size. Nature. 2003;425:836–41.

    Article  PubMed  CAS  Google Scholar 

  49. Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K, Miyazaki H, Takahashi T, Suda T. Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell. 2007;1:685–97.

    Article  PubMed  CAS  Google Scholar 

  50. Lo CC, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Cote D, Rowe DW, Lin CP, Scadden DT. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature. 2009;457:92–6.

    Article  CAS  Google Scholar 

  51. Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D, Perko K, Alexander R, Schwartz J, Grindley JC, Park J, Haug JS, Wunderlich JP, Li H, Zhang S, Johnson T, Feldman RA, Li L. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457:97–101.

    Article  PubMed  CAS  Google Scholar 

  52. Chitteti BR, Cheng YH, Poteat B, Rodriguez-Rodriguez S, Goebel WS, Carlesso N, Kacena MA, Srour EF. Impact of interactions of cellular components of the bone marrow microenvironment on hematopoietic stem and progenitor cell function. Blood. 2010;115(16):3239–48.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  54. Kiel MJ, Morrison SJ. Maintaining hematopoietic stem cells in the vascular niche. Immunity. 2006;25:862–4.

    Article  PubMed  CAS  Google Scholar 

  55. 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;25:977–88.

    Article  PubMed  CAS  Google Scholar 

  56. Kiel MJ, Acar M, Radice GL, Morrison SJ. Hematopoietic stem cells do not depend on N-cadherin to regulate their maintenance. Cell Stem Cell. 2009;4:170–9.

    Article  PubMed  CAS  Google Scholar 

  57. Arai F, Suda T. Maintenance of quiescent hematopoietic stem cells in the osteoblastic niche. Ann N Y Acad Sci. 2007;1106:41–53.

    Article  PubMed  CAS  Google Scholar 

  58. Bhattacharya D, Czechowicz A, Ooi AG, Rossi DJ, Bryder D, Weissman IL. Niche recycling through division-independent egress of hematopoietic stem cells. J Exp Med. 2009;206:2837–50.

    Article  PubMed  CAS  Google Scholar 

  59. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.

    Article  Google Scholar 

  60. Haylick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.

    Article  Google Scholar 

  61. Harrison DE. Normal function of transplanted marrow cell lines from aged mice. J Gerontol. 1975;30:279–85.

    PubMed  CAS  Google Scholar 

  62. Harrison DE, Doubleday JW. Normal function of immunologic stem cells from aged mice. J Immunol. 1975;114:1314–7.

    PubMed  CAS  Google Scholar 

  63. Harrison DE. Mouse erythropoietic stem cell lines function normally 100 months: loss related to number of transplantations. Mech Ageing Dev. 1979;9:427–33.

    Article  PubMed  CAS  Google Scholar 

  64. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M, Scadden DT. Hematopoietic stem cell quiescence maintained by p21cip1/waf1. Science. 2000;287:1804–8.

    Article  PubMed  CAS  Google Scholar 

  65. Yu H, Yuan Y, Shen H, Cheng T. Hematopoietic stem cell exhaustion impacted by p18 INK4C and p21 Cip1/Waf1 in opposite manners. Blood. 2006;107:1200–6.

    Article  PubMed  CAS  Google Scholar 

  66. Van Zant G, Holland BP, Eldridge PW, Chen JJ. Genotype-restricted growth and aging patterns in hematopoietic stem cell populations of allophenic mice. J Exp Med. 1990;171:1547–65.

    Article  PubMed  Google Scholar 

  67. Chen J, Astle CM, Harrison DE. Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol. 2000;28:442–50.

    Article  PubMed  CAS  Google Scholar 

  68. de Haan G, Nijhof W, Van ZG. Mouse strain-dependent changes in frequency and proliferation of hematopoietic stem cells during aging: correlation between lifespan and cycling activity. Blood. 1997;89:1543–50.

    PubMed  Google Scholar 

  69. de Haan G, Van ZG. Dynamic changes in mouse hematopoietic stem cell numbers during aging. Blood. 1999;93:3294–301.

    PubMed  Google Scholar 

  70. Morrison SJ, Wandycz AM, Akashi K, Globerson A, Weissman IL. The aging of hematopoietic stem cells. Nat Med. 1996;2:1011–6.

    Article  PubMed  CAS  Google Scholar 

  71. Liang Y, Van ZG, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005;106:1479–87.

    Article  PubMed  CAS  Google Scholar 

  72. Sudo K, Ema H, Morita Y, Nakauchi H. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000;192:1273–80.

    Article  PubMed  CAS  Google Scholar 

  73. Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci USA. 2005;102:9194–9.

    Article  PubMed  CAS  Google Scholar 

  74. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van ZG, Wang L, Zheng Y, Geiger H. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108:2190–7.

    Article  PubMed  CAS  Google Scholar 

  75. Janzen V, Forkert R, Fleming HE, Saito Y, Waring MT, Dombkowski DM, Cheng T, DePinho RA, Sharpless NE, Scadden DT. Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a. Nature. 2006;443:421–6.

    PubMed  CAS  Google Scholar 

  76. Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, Suda T. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12:446–51.

    Article  PubMed  CAS  Google Scholar 

  77. Yao YG, Ellison FM, McCoy JP, Chen J, Young NS. Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background. Hum Mol Genet. 2007;16:286–94.

    Article  PubMed  CAS  Google Scholar 

  78. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–19.

    Article  PubMed  CAS  Google Scholar 

  79. Young NS, Bacigalupo A, Marsh JC. Aplastic anemia: pathophysiology and treatment. Biol Blood Marrow Transplant. 2010;16:S119–25.

    Article  PubMed  Google Scholar 

  80. Bloom ML, Wolk AG, Simon-Stoos KL, Bard JS, Chen J, Young NS. A mouse model of lymphocyte infusion-induced bone marrow failure. Exp Hematol. 2004;32:1163–72.

    Article  PubMed  CAS  Google Scholar 

  81. Chen J, Lipovsky K, Ellison FM, Calado RT, Young NS. Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure. Blood. 2004;104:1671–8.

    Article  PubMed  CAS  Google Scholar 

  82. Chen J. Animal models for acquired bone marrow failure syndromes. Clin Med Res. 2005;3:102–8.

    Article  PubMed  Google Scholar 

  83. Chen J, Ellison FM, Eckhaus MA, Smith AL, Keyvanfar K, Calado RT, Young NS. Minor antigen h60-mediated aplastic anemia is ameliorated by immunosuppression and the infusion of regulatory T cells. J Immunol. 2007;178:4159–68.

    PubMed  CAS  Google Scholar 

  84. Tang Y, Desierto MJ, Chen J, Young NS. The role of the Th1 transcription factor T-bet in a mouse model of immune-mediated bone-marrow failure. Blood. 2010;115:541–8.

    Article  PubMed  CAS  Google Scholar 

  85. Omokaro SO, Desierto MJ, Eckhaus MA, Ellison FM, Chen J, Young NS. Lymphocytes with aberrant expression of Fas or Fas ligand attenuate immune bone marrow failure in a mouse model. J Immunol. 2009;182:3414–22.

    Article  PubMed  CAS  Google Scholar 

  86. de Latour RP, Visconte V, Takaku T, Wu C, Erie AJ, Sarcon AK, Desierto MJ, Scheinberg P, Keyvanfar K, Nunez O, Chen J, Young NS. Th17 immune responses contribute to the pathophysiology of aplastic anemia. Blood. 2010;116:4175–84.

    Article  PubMed  CAS  Google Scholar 

  87. Sarcon AK, Desierto MJ, Zhou W, Visconte V, Gibellini F, Chen J, Young NS. Role of perforin-mediated cell apoptosis in murine models of infusion-induced bone marrow failure. Exp Hematol. 2009;37:477–86.

    Article  PubMed  CAS  Google Scholar 

  88. Vulliamy TJ, Knight SW, Mason PJ, Dokal I. Very short telomeres in the peripheral blood of patients with X-linked and autosomal dyskeratosis congenita. Blood Cells Mol Dis. 2001;27:353–7.

    Article  PubMed  CAS  Google Scholar 

  89. Fogarty PF, Yamaguchi H, Wiestner A, Baerlocher GM, Sloand E, Zeng WS, Read EJ, Lansdorp PM, Young NS. Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362:1628–30.

    Article  PubMed  CAS  Google Scholar 

  90. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci USA. 2005;102:15960–4.

    Article  PubMed  CAS  Google Scholar 

  91. Marrone A, Walne A, Tamary H, Masunari Y, Kirwan M, Beswick R, Vulliamy T, Dokal I. Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. Blood. 2007;110:4198–205.

    Article  PubMed  CAS  Google Scholar 

  92. Xin ZT, Beauchamp AD, Calado RT, Bradford JW, Regal JA, Shenoy A, Liang Y, Lansdorp PM, Young NS, Ly H. Functional characterization of natural telomerase mutations found in patients with hematologic disorders. Blood. 2007;109:524–32.

    Article  PubMed  CAS  Google Scholar 

  93. Aspesi A, Vallero S, Rocci A, Pavesi E, Lanciotti M, Ramenghi U, Dianzani I. Compound heterozygosity for two new TERT mutations in a patient with aplastic anemia. Pediatr Blood Cancer. 2010;55:550–3.

    Article  PubMed  Google Scholar 

  94. Calado RT, Graf SA, Wilkerson KL, Kajigaya S, Ancliff PJ, Dror Y, Chanock SJ, Lansdorp PM, Young NS. Mutations in the SBDS gene in acquired aplastic anemia. Blood. 2007;110:1141–6.

    Article  PubMed  CAS  Google Scholar 

  95. Vulliamy T, Marrone A, Dokal I, Mason PJ. Association between aplastic anaemia and mutations in telomerase RNA. Lancet. 2002;359:2168–70.

    Article  PubMed  CAS  Google Scholar 

  96. Yamaguchi H, Baerlocher GM, Lansdorp PM, Chanock SJ, Nunez O, Sloand E, Young NS. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102:916–8.

    Article  PubMed  CAS  Google Scholar 

  97. Marrone A, Stevens D, Vulliamy T, Dokal I, Mason PJ. Heterozygous telomerase RNA mutations found in dyskeratosis congenita and aplastic anemia reduce telomerase activity via haploinsufficiency. Blood. 2004;104:3936–42.

    Article  PubMed  CAS  Google Scholar 

  98. Ly H, Calado RT, Allard P, Baerlocher GM, Lansdorp PM, Young NS, Parslow TG. Functional characterization of telomerase RNA variants found in patients with hematologic disorders. Blood. 2005;105:2332–9.

    Article  PubMed  CAS  Google Scholar 

  99. Han B, Liu B, Cui W, Wang X, Lin J, Zhao Y. Telomerase gene mutation screening in Chinese patients with aplastic anemia. Leuk Res. 2010;34:258–60.

    Article  PubMed  CAS  Google Scholar 

  100. Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352:1413–24.

    Article  PubMed  CAS  Google Scholar 

  101. Sanchez-Medal L, Gomez-Leal A, Duarte L, Guadalupe RM. Anabolic androgenic steroids in the treatment of acquired aplastic anemia. Blood. 1969;34:283–300.

    PubMed  CAS  Google Scholar 

  102. Calado RT, Yewdell WT, Wilkerson KL, Regal JA, Kajigaya S, Stratakis CA, Young NS. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood. 2009;114:2236–43.

    Article  PubMed  CAS  Google Scholar 

  103. Blasco MA, Lee HW, Hande MP, Samper E, Lansdorp PM, DePinho RA, Greider CW. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997;91:25–34.

    Article  PubMed  CAS  Google Scholar 

  104. Lee HW, Blasco MA, Gottlieb GJ, Horner JW, Greider CW, DePinho RA. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392:569–74.

    Article  PubMed  CAS  Google Scholar 

  105. Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999;96:701–12.

    Article  PubMed  CAS  Google Scholar 

  106. Ju Z, Jiang H, Jaworski M, Rathinam C, Gompf A, Klein C, Trumpp A, Rudolph KL. Telomere dysfunction induces environmental alterations limiting hematopoietic stem cell function and engraftment. Nat Med. 2007;13:742–7.

    Article  PubMed  CAS  Google Scholar 

  107. Samper E, Fernandez P, Eguia R, Martin-Rivera L, Bernad A, Blasco MA, Aracil M. Long-term repopulating ability of telomerase-deficient murine hematopoietic stem cells. Blood. 2002;99:2767–75.

    Article  PubMed  CAS  Google Scholar 

  108. Allsopp RC, Cheshier S, Weissman IL. Telomere shortening accompanies increased cell cycle activity during serial transplantation of hematopoietic stem cells. J Exp Med. 2001;193:917–24.

    Article  PubMed  CAS  Google Scholar 

  109. Allsopp RC, Morin GB, DePinho R, Harley CB, Weissman IL. Telomerase is required to slow telomere shortening and extend replicative lifespan of HSCs during serial transplantation. Blood. 2003;102:517–20.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This work was supported by NIH intramural research funds.

Author information

Authors and Affiliations

  1. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Clinical Research Center Room 3E-5132, 10 Center Drive, Bethesda, MD, 20892-1202, USA

    Jichun Chen

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  1. Jichun Chen
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Correspondence to Jichun Chen.

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Chen, J. Hematopoietic stem cell development, aging and functional failure. Int J Hematol 94, 3–10 (2011). https://doi.org/10.1007/s12185-011-0856-1

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  • DOI: https://doi.org/10.1007/s12185-011-0856-1

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