Evidence for a Mitotic Clock in Human Hematopoietic Stem Cells: Loss of Telomeric DNA with Age

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1994 Oct 11

PMID 7937905

Citations 255

Authors

H Vaziri

W Dragowska

R C Allsopp

T E Thomas

C B Harley

P M Lansdorp

Affiliations

Soon will be listed here.

Abstract

The proliferative life-span of the stem cells that sustain hematopoiesis throughout life is not known. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes with each somatic cell division eventually reaches a critical point that triggers cellular senescence. We now show that candidate human stem cells with a CD34+CD38lo phenotype that were purified from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood. We also found that cells produced in cytokine-supplemented cultures of purified precursor cells show a proliferation-associated loss of telomeric DNA. These findings strongly suggest that the proliferative potential of most, if not all, hematopoietic stem cells is limited and decreases with age, a concept that has widespread implications for models of normal and abnormal hematopoiesis as well as gene therapy.

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References

Lemischka I, Raulet D, Mulligan R . Developmental potential and dynamic behavior of hematopoietic stem cells. Cell. 1986; 45(6):917-27. DOI: 10.1016/0092-8674(86)90566-0. View

Greider C, Blackburn E . Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell. 1985; 43(2 Pt 1):405-13. DOI: 10.1016/0092-8674(85)90170-9. View

Mauch P, Down J, Warhol M, Hellman S . Recipient preparation for bone marrow transplantation. I. Efficacy of total-body irradiation and busulfan. Transplantation. 1988; 46(2):205-10. DOI: 10.1097/00007890-198808000-00004. View

Moyzis R, Buckingham J, Cram L, Dani M, Deaven L, Jones M . A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci U S A. 1988; 85(18):6622-6. PMC: 282029. DOI: 10.1073/pnas.85.18.6622. View

Lundblad V, Szostak J . A mutant with a defect in telomere elongation leads to senescence in yeast. Cell. 1989; 57(4):633-43. DOI: 10.1016/0092-8674(89)90132-3. View

Capel B, Hawley R, Covarrubias L, Hawley T, Mintz B . Clonal contributions of small numbers of retrovirally marked hematopoietic stem cells engrafted in unirradiated neonatal W/Wv mice. Proc Natl Acad Sci U S A. 1989; 86(12):4564-8. PMC: 287311. DOI: 10.1073/pnas.86.12.4564. View

Morin G . The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989; 59(3):521-9. DOI: 10.1016/0092-8674(89)90035-4. View

Keller G, Snodgrass R . Life span of multipotential hematopoietic stem cells in vivo. J Exp Med. 1990; 171(5):1407-18. PMC: 2187902. DOI: 10.1084/jem.171.5.1407. View

Harley C, Futcher A, Greider C . Telomeres shorten during ageing of human fibroblasts. Nature. 1990; 345(6274):458-60. DOI: 10.1038/345458a0. View

10.

Hastie N, Dempster M, Dunlop M, Thompson A, Green D, Allshire R . Telomere reduction in human colorectal carcinoma and with ageing. Nature. 1990; 346(6287):866-8. DOI: 10.1038/346866a0. View

11.

Fraser C, Eaves C, Szilvassy S, Humphries R . Expansion in vitro of retrovirally marked totipotent hematopoietic stem cells. Blood. 1990; 76(6):1071-6. View

12.

Terstappen L, Huang S, Safford M, Lansdorp P, Loken M . Sequential generations of hematopoietic colonies derived from single nonlineage-committed CD34+CD38- progenitor cells. Blood. 1991; 77(6):1218-27. View

13.

Blackburn E . Structure and function of telomeres. Nature. 1991; 350(6319):569-73. DOI: 10.1038/350569a0. View

14.

Lindsey J, McGill N, Lindsey L, Green D, Cooke H . In vivo loss of telomeric repeats with age in humans. Mutat Res. 1991; 256(1):45-8. DOI: 10.1016/0921-8734(91)90032-7. View

15.

Harley C . Telomere loss: mitotic clock or genetic time bomb?. Mutat Res. 1991; 256(2-6):271-82. DOI: 10.1016/0921-8734(91)90018-7. View

16.

Baum C, Weissman I, Tsukamoto A, Buckle A, Peault B . Isolation of a candidate human hematopoietic stem-cell population. Proc Natl Acad Sci U S A. 1992; 89(7):2804-8. PMC: 48751. DOI: 10.1073/pnas.89.7.2804. View

17.

Broxmeyer H, Hangoc G, Cooper S, Ribeiro R, Graves V, Yoder M . Growth characteristics and expansion of human umbilical cord blood and estimation of its potential for transplantation in adults. Proc Natl Acad Sci U S A. 1992; 89(9):4109-13. PMC: 525642. DOI: 10.1073/pnas.89.9.4109. View

18.

Counter C, Avilion A, LeFeuvre C, Stewart N, Greider C, Harley C . Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 1992; 11(5):1921-9. PMC: 556651. DOI: 10.1002/j.1460-2075.1992.tb05245.x. View

19.

Lansdorp P, Dragowska W . Long-term erythropoiesis from constant numbers of CD34+ cells in serum-free cultures initiated with highly purified progenitor cells from human bone marrow. J Exp Med. 1992; 175(6):1501-9. PMC: 2119250. DOI: 10.1084/jem.175.6.1501. View

20.

Hornung R, Longo D . Hematopoietic stem cell depletion by restorative growth factor regimens during repeated high-dose cyclophosphamide therapy. Blood. 1992; 80(1):77-83. View