Age-Associated Characteristics of Murine Hematopoietic Stem Cells

Abstract

Little is known of age-associated functional changes in hematopoietic stem cells (HSCs). We studied aging HSCs at the clonal level by isolating CD34−/lowc-Kit+Sca-1+ lineage marker–negative (CD34−KSL) cells from the bone marrow of C57BL/6 mice. A population of CD34−KSL cells gradually expanded as age increased. Regardless of age, these cells formed in vitro colonies with stem cell factor and interleukin (IL)-3 but not with IL-3 alone. They did not form day 12 colony-forming unit (CFU)-S, indicating that they are primitive cells with myeloid differentiation potential. An in vivo limiting dilution assay revealed that numbers of multilineage repopulating cells increased twofold from 2 to 18 mo of age within a population of CD34−KSL cells as well as among unseparated bone marrow cells. In addition, we detected another compartment of repopulating cells, which differed from HSCs, among CD34−KSL cells of 18-mo-old mice. These repopulating cells showed less differentiation potential toward lymphoid cells but retained self-renewal potential, as suggested by secondary transplantation. We propose that HSCs gradually accumulate with age, accompanied by cells with less lymphoid differentiation potential, as a result of repeated self-renewal of HSCs.

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

“…In the bone marrow hematopoietic stem cell LSK (Lineage − , Sca1 + , cKit + ) population, aging is associated with increased cellularity, which is believed to compensate for the lack of regenerative potential as these cells age (Sudo et al , 2000). The fraction of LSK‐positive cells was increased in young (4‐month‐old) SirT7 −/− bone marrow compared with WT littermates (Fig 2E and F).…”

Epigenetic regulation of aging stem cells

“…Early studies comparing HSC number in short-and long-lived mouse strains using in vitro cobblestone-forming assays reported an age-dependent decrease in HSC number in short-lived mouse strains (CH3/He, CBA/J and DBA/2), but an increase in HSC number in the longlived C57BL/6 mouse strain (de Haan et al, 1997;de Haan and Van Zant, 1999). Likewise, quantification of HSCs by fluorescence-activated cell sorting (FACS) using cell surface markers indicate that the frequency of cells expressing stem and progenitor markers (KLS; c-Kit þ , Lin À , Sca1 þ ) increases with age in C57BL/6 mice (Sudo et al, 2000;Kim et al, 2003;Rossi et al, 2005;Pearce et al, 2007). The observed increase in HSCs with age is due to specific expansion of the HSC compartment capable of long-term reconstitution of the hematopoietic system in a recipient mouse, termed LT-HSCs (Rossi et al, 2005;Chambers et al, 2007;Pearce et al, 2007).…”

“…The observed increase in HSCs with age is due to specific expansion of the HSC compartment capable of long-term reconstitution of the hematopoietic system in a recipient mouse, termed LT-HSCs (Rossi et al, 2005;Chambers et al, 2007;Pearce et al, 2007). Notably, the majority of LT-HSCs are relatively quiescent and do not undergo major changes in cell cycle status with age, suggesting that HSC expansion is not caused by substantial changes in HSC cycling (Cheshier et al, 1999;Sudo et al, 2000;Chambers et al, 2007;Rossi et al, 2007b). Although FACS-based analysis and in vitro assays might characterize different populations of stem cells-perhaps more committed progenitors in the case of in vitro assays-these data raise the possibility that the genetic background of mouse strains influences the proliferative control of HSCs and their progeny during aging (de Haan et al, 1997;de Haan and Van Zant, 1999).…”

“…HSCs isolated from older mice show defects in mobilization and homing to bone marrow (Morrison et al, 1996;Kim et al, 2003;Liang et al, 2005;Xing et al, 2006). In competitive transplantation assays, a rigorous test for both self-renewal and multipotency during which donor HSCs are co-injected with wild-type bone marrow and assessed for their ability to regenerate all blood lineages, aged HSCs shows defect in long-term reconstitution of the immune system (Sudo et al, 2000;Kamminga et al, 2005;Rossi et al, 2005;Chambers et al, 2007). Aged HSCs also give rise to more cells of myeloid lineage at the expense of lymphoid fates (Sudo et al, 2000;Kim et al, 2003;Rossi et al, 2005;Cho et al, 2008;Guerrettaz et al, 2008).…”

“…In competitive transplantation assays, a rigorous test for both self-renewal and multipotency during which donor HSCs are co-injected with wild-type bone marrow and assessed for their ability to regenerate all blood lineages, aged HSCs shows defect in long-term reconstitution of the immune system (Sudo et al, 2000;Kamminga et al, 2005;Rossi et al, 2005;Chambers et al, 2007). Aged HSCs also give rise to more cells of myeloid lineage at the expense of lymphoid fates (Sudo et al, 2000;Kim et al, 2003;Rossi et al, 2005;Cho et al, 2008;Guerrettaz et al, 2008). This myeloid bias in aging HSC populations has been explained by alterations in the subcomposition of the HSC pool, which is thought to contain clones with pre-determined differentiation bias (Dykstra et al, 2007;Cho et al, 2008;Beerman et al, 2010a;Morita et al, 2010).…”