Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.

TLDR

The lifespan of hematopoietic stem cells is uncertain, but telomere shortening with each division may eventually trigger senescence. Adult CD34⁺CD38lo stem cells have shorter telomeres than fetal counterparts, and telomere loss during cytokine‑driven proliferation indicates that their proliferative capacity is limited and declines with age, impacting models of hematopoiesis and gene therapy.

Abstract

The proliferative life-span of the stem cells that sustain hematopoiesis throughout life is not known. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes with each somatic cell division eventually reaches a critical point that triggers cellular senescence. We now show that candidate human stem cells with a CD34+CD38lo phenotype that were purified from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood. We also found that cells produced in cytokine-supplemented cultures of purified precursor cells show a proliferation-associated loss of telomeric DNA. These findings strongly suggest that the proliferative potential of most, if not all, hematopoietic stem cells is limited and decreases with age, a concept that has widespread implications for models of normal and abnormal hematopoiesis as well as gene therapy.