Figure 5.

Hypothetical model to explain the reduction in telomere length during serial transplantation of HSCs. In adult mice, HSCs are predominantly in a nonstressed, resting state (indicated by the small arrows) where they function mainly to sustain homeostatic levels of hematopoietic cells. Since telomere shortening is primarily dependent on cell division (reference 41), there is no discernible telomere shortening over a time period of a few months in adult BA mice (data not shown). After transplantation into primary recipients, the cycling activity of the donor HSCs increases (thicker arrows), primarily to allow reconstitution of all hematopoietic lineages including the HSC pool. Consequently, a modest amount of telomere shortening occurs. The cycling activity of the donor HSCs is still elevated when they are once again isolated for a second round of transplantation. This results in a considerable drop in reconstitutive capacity because of poor engraftment in the secondary recipients and a further increase in the rate of HSC turnover (thickest arrows) so that regeneration of the HSC pool and hematopoietic reconstitution can be completed once again. It is also possible that, after transplantation, HSCs from primary recipients may be more prone to cell death or replicative exhaustion than HSCs taken directly from adult mice, which could also influence the rate of HSC division in secondary recipients. Thus, during hematopoietic reconstitution in the secondary recipients, telomeres in the HSCs undergo an even greater degree of shortening.