Telomeres in hematopoietic stem cells.

Hematopoietic stem cells have an impressive regenerative potential, strikingly illustrated in transplantation experiments using limited number of cells. In mice, serial transplantation experiments suggest that individual hematopoietic cells are capable of extensive self-renewal and that any possible limitations in the replicative potential of individual hematopoietic stem cells are not affecting normal blood cell formation. The situation with human hematopoietic stem cells is less clear. Unlike the situation in the mouse, the telomere length in nucleated human blood cells shows a remarkable decline with age. Furthermore, even partial telomerase deficiency in humans typically results in marrow failure, whereas complete lack of telomerase is tolerated up to several generations in the mouse. The decline in telomere length in human leukocytes with age follows a cubic function and is much higher in lymphocytes than in granulocytes. This finding suggests that, under normal circumstances, telomere loss is more likely to compromise the function of lymphocytes than the function of hematopoietic stem cells. To reconcile differences in telomere biology between man and mice, it has been proposed that telomere shortening evolved as a tumor suppressor mechanism in long-lived species that may not exist in shorter-lived mammals. According to this model, telomeres in human cells are intimately involved in signaling cell cycle progression and cell division. Most likely, a minimum number of telomere repeats is required at each telomere to prevent activation of a "telomere checkpoint" and allow cell cycle progression. Telomere length measurements appear useful to distinguish between depletion and exhaustion of hematopoietic stem cells as a cause of marrow failure.