Mouse Strain-Dependent Changes in Frequency and Proliferation of Hematopoietic Stem Cells During Aging: Correlation Between Lifespan and Cycling Activity

Abstract

We have quantified the frequency and proliferation of five subsets of primitive hematopoietic cells, using the cobblestone area forming cell (CAFC) assay, in marrow of five 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 lifespan and individual mouse age on stem cell populations. First, the relative and absolute numbers of the most primitive stem cell subsets was threefold to fourfold 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, there was a trend for longer lifespan to be correlated with a larger stem cell pool. Third, stem cells from old mice had a far lower cycling activity than cells from young mice. However, this was highly strain dependent: short-lived C3H/He and CBA/J mice showed a stronger reduction in cycling activity during aging than long-lived C57BL/6 mice. Finally, a significant negative correlation was demonstrated in young mice between maximal lifespan and proliferative activity. These data show that aging has a major impact on the frequency and cell-cycle kinetics of primitive hematopoietic cell compartments. In addition, the observation that cycling activity of stem cells is related to the maximal lifespan of the mouse strain may open ways to identify the genetic mechanisms of both strain- and age-dependent variation in the structure of primitive hematopoietic cell compartments.

Evidence for a continuous decline in haemopoietic cell function from birth: application to evaluating bone marrow failure in children

“…The increase in the frequency of CFU-GM in the bone marrow as a function of age may seem surprising at ®rst sight. However, a similar age-related increase in the frequency of clonogenic cells has also been found in mice (Morrison et al, 1996;de Haan et al, 1997). This increase could be accounted for by a reduced level of mature cell production which, in turn, might indicate a progressive functional de®ciency of the progenitor cells themselves.…”

Cellular aging leads to functional heterogeneity of hematopoietic stem cells: a modeling perspective

“…Additionally, experimental data indicate, e.g., that the age‐dependent development of HSC activity is highly strain specific. Whereas in some mouse strains the cycling activity of HSC has been reported to decrease with age (e.g., DBA mice), in others strains this effect is not detectable (e.g., B6 mice) (De Haan et al. , 1997; De Haan & Zant, 1999).…”

Genetic fingerprint defines hematopoietic stem cell pool size and function

“…Significant progress has been made during the last decade in developing culture systems to study the differentiation of human CD34 cells intto enucleate reticulocytes and using various cell surface markers to monitor the progression through all stages of erythroid differentiation. [4][5][6][7] These developments are enabling detailed characterization of normal and disordered human erythropoiesis. [8][9][10][11][12][13] Importantly, as a result of this progress it is now possible to obtain insights into at what stage of the complex process of erythroid differentiation various genes contribute to ineffective erythropoiesis.…”

“…Phenotypic diversity is frequently caused by genetic variations such as single nucleotide polymorphism (SNP). It was reported that the size and function of the HSC pool vary between mice strains, [5][6][7][8][9] which suggests genetic background, such as SNP and copy number variations, define HSC homeostasis. In 2007, Liang et al identified latexin (Lxn) as an HSC regulatory gene whose expression level is inversely correlated with HSC number.…”