Conclusions and Outlook

Hematopoietic stem cells maintain hematopoiesis through tightly regulated layers of self-renewal, differentiation, and cell death during the entire life span of vertebrates. Nevertheless, programmed telomere shortening as a hallmark of replicative senescence occurs in HSCs, which is not completely understood, since conventional correlations between telomere maintenance and telomerase activity appear to be only partially valid in these cells. Importantly, telomerase activity and telomere dynamics seem to play a different role in embryonic stem cells compared to adult stem cells. Although stem cell proliferation generally allows for tissue repair and regeneration, it also bears the risk of cancer, which is impaired by tumor suppressor mechanisms, either eliminating potential cancer cells by apoptosis or limiting their proliferation by senescence. Apparently, factors ensuring stem cell proliferation as a prerequisite of relative longevity must be well balanced with mechanisms that prevent cancer (reviewed in Beausejour and Campisi 2006). In this context, coexistence of telomerase expression - maybe here rather as an antiapoptotic factor - and telomere shortening might appear less contradictory in the hematopoietic stem cell compartment.

The paucity of markers for cellular senescence makes it difficult to evaluate the relevance of this phenomenon for in vivo aging - not only in stem cells. Most recently the combinatory use of three biomarkers (telomere dysfunction, activation of the ATM DNA-damage response, and heterochromatinization of the nuclear genome) in aging baboons provided evidence that senescent cells exist in vivo and can account for more than 15% of skin fibroblasts in aged animals (Herbig et al. 2006). Whether the stem cell compartment is affected to the same extent remains elusive. Hence, the identification of further senescence markers could facilitate a better monitoring of senescence phenotypes in vivo, not least in hematopoietic stem cells. Furthermore, elucidating the particular mechanisms of telomerase expression and telomere maintenance in HSCs might contribute to strategies which focus on rejuvenation of stem cell populations for gene therapy and transplantation and the repopulation capacity of HSC after myelo-ablative therapies.

Acknowledgements This work was supported by a European Community Grant LSHC-CT-2004-502943 (MOL CANCER MED).

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