Changes in frequency and proliferation of hemopoietic stem cells during aging are strain dependent: Correlation between mouse lifespan and cycling activity

Abstract

Recently it has been suggested that telomere shortening in hemopoietic stem cells during aging results in a reduced proliferation potential, hi addition it has been demonstrated that marked differences in the size and cycling activity of the murine stem cell pool exist between mice of different inbred strains. To address these issues we have quantified the frequency and proliferation of five subsets of primitive hemopoietic cells, using the cobblestone area forming cell (CAFC) assay, in marrow of 5 strains of mice with lifespans ranging from about 500 to 800 days. Stem cell characteristics were determined in young (6 weeks) and old (12 months) mice. We report striking effects of both intrinsic strain iifespan and individual mouse age on stem cell populations. First, the relative and absolute numbers of the most primitive stem cell subsets was 4-5 fold higher in old than in young mice. Second, a considerable strain to strain variation in the number of primitive cells was observed: when absolute frequencies were calculated, a strong trend existed towards higher stem cell numbers in strains with a longer Iifespan. Third, stem cells from old mice had a lower cycling activity than cells from young mice. Moreover this was highly strain-dependent: short-lived CBA/J mice showed much more pronounced effects than long-lived C57BL/6 mice. Finally, a significant negative correlation was demonstrated in young mice between Iifespan and proliferative activity. These data demonstrate that aging has a major impact on the frequency and cell cycle kinetics of the primitive hemopoietic cell compartments, In addition, the observation that cycling activity of stem cells is related to the maximal Iifespan of the mouse strain may open ways to identify the genetic mechanisms of both strain- and age-dependent variation in the structure of primitive hemopoietic cell compartments.