Correlation between telomere length and proliferative capacity of hematopoietic stem cells

Abstract

Hematopoietic stem cells (HSCs), defined as cells capable of both self-renewal and differentiation into all blood lineages, sustain hematopoiesis throughout life of individuals. It has been considered that HSCs can infinitely regenerate cells with the same potential because telomere length is maintained upon their self-renewal division. However, it has reported that telomere shortening occurs in human HSCs with aging or after bone marrow transplantation. It is well known that serial bone marrow transplantation results poor reconstitution in mouse. These observations rather suggest that the decrease in stem cell activity is linked to telomere shortening. We therefore examined a relationship between level of repopulating activity and telomere length in HSCs isolated from TERT knockout mice which had null mutation in a catalytic subunit of telomerase and wild-type mice by using competitive repopulation assay and Flow-FISH on bone marrow cells after transplantation. Data clearly show a shortening of telomere length in bone marrow cells reconstituted with single HSCs as compared with those reconstituted with bone marrow competitor cells. There was no remarkable difference in reduction ratio of telomere length between wild-type and TERT KO mice. There however appeared no change in telomere length after transplantation with 100 HSCs. Long-term reconstitution was unsuccessful when 1 or 10 HSCs from third generation of the KO mice were transplantation. These results together indicate that the reconstitution capacity proportionally decreases with reduction in telomere length and that telomerase activity in HSCs is insufficient to prevent their telomere shortening though cell division.