Telomere Dynamics in Mature Hematopoietic Cells

Certain mature hematopoietic cells like T lymphocytes also have low levels of telomerase activity rising transiently in response to antigen stimulation similar to HSCs (Liu et al. 1999, Weng et al. 1998, Weng et al. 1996). Since extensive cell division and clonal expansion are critical for effective immune function, telomere dynamics are of particular interest in these cells. Again, limited telomerase levels are not sufficient to prevent telomere shortening and replicative senescence. However, overexpression of hTERT is able to reconstitute a constant high level of telomerase activity and extend the life span of T cells (Hooijberg et al. 2000, Rufer et al. 2001b). Although the rate of telomere shortening is lower in hTERT-transduced T cells, long-term studies indicate here a progressive telomere loss eventually resulting in even shorter telomeres at senescence than in controls (Roth et al. 2005). Interestingly, elimination of endogenous hTERT in human T lymphocytes using a dominant-negative mutant (DN-hTERT) leads to a decreased life span and cytogenetic abnormalities, which indicates the major influence of hTERT on the longevity of these cells-without preventing overall telomere shortening but maybe playing a role in the repair of sporadic telomere attrition (Roth et al. 2003).

Telomere shortening featured by mature hematopoietic cells in vivo follows a cubic function over time, which is marked by a significant drop within the first year of life and a slower, steady decline thereafter (Rufer et al. 1999) (reviewed in (Ohyashiki et al. 2002) ). A recent longitudinal study of telomere length from newborn baboons confirmed the rapid decline in telomere length in granulocytes and lymphocytes in the first year after birth. After around one year the telomere length appeared to stabilize in all cell types, suggesting that HSCs switch to a different functional mode characterized by a decreased turnover rate after an initial phase of rapid expansion (Baerlocher et al. 2007). Individual replicative histories of lymphocytes are represented by heterogeneous telomere length distributions in different subpopulations, namely a shorter mean telomere length in T cells compared with B cells within which memory cells have longer telomeres than naive cells (Baerlocher and Lansdorp 2003, Martens et al. 2002, Rufer et al. 1999). A later study indicates that B cells are capable of inducing telomerase after stimulation, resulting in telomere maintenance during differentiation from naive to memory B cells (Son et al. 2003). Since granulocytes have a short life span and do not replicate, their age-related telomere loss is much less pronounced than in lymphocytes. Therefore, the rather homogeneous telomere length of granulocytes seems to be a good surrogate marker for HSC proliferation kinetics under the assumption that the HSCs exhibit a constant telomere shortening during replication and differentiation from the HSC to granulocytes (Rufer et al. 1999) (reviewed in Verfaillie et al. 2002). A stochastic simulation method based upon granulocyte telomere lengths was used to estimate HSC replication rates in vivo and found human HSCs replicating only once per 45 weeks (Shepherd et al. 2004), which is substantially slower than the estimates for murine HSCs (1 per 2.5 weeks) (Abkowitz et al. 2000). Such infrequent cell divisions in human HSCs would put their above mentioned calculated telomere loss into perspective. Understanding these HSC dynamics in vivo could be important to assess the consequences of allogeneic stem cell transplantation discussed above. Besides an overall trend in age-related telomere shortening, the telomere length of hematopoietic cells at any given age shows significant differences (Frenck et al. 1998, Rufer et al. 1998), which are primarily determined genetically as twin studies revealed (Rufer et al. 1999, Slagboom et al. 1994).

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