Age-Associated Characteristics of Murine Hematopoietic Stem Cells

By K. Sudo, H. Ema, Yohei Morita, H. Nakauchi. Journal of Experimental Medicine, 2000

741 citations recorded by the source corpus.

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.

Subfields: Hematology, Immunology

View Paper: https://www.semanticscholar.org/paper/f08d613bbce914dee63d78669d4d799c003183f1

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Citations in the corpus

Causes, consequences, and reversal of immune system aging. (2013, positive): “From an immunologic perspective, the most profound effect of stem cell aging in both mice (11, 18) and humans (17) is a decreased capacity to produce lymphocytes and an increase in myeloid potential.”
Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells (2015, background): “This is consistent with a recently suggested link between aging and self-renewal (Sun et al. 2014).”
Variation in cancer risk among tissues can be explained by the number of stem cell divisions (2015, background): “Hematopoietic stem cells have been estimated to divide every ~15 (35), 17 (36), 30 (37, 38), 57 (39) days.”
Aging Hematopoietic Stem Cells Decline in Function and Exhibit Epigenetic Dysregulation (2007, background): “When limited numbers of aged hematopoietic progenitors are transplanted into young recipients under competitive conditions, they show an overall reduction in long-term repopulating potential [2]; in particular, lymphopoiesis is deficient, whereas myelopoiesis is enhanced [3,4].”
The aged niche disrupts muscle stem cell quiescence (2012, result): “In support of our data, aged hematopoietic stem cells are more active in the aged niche 40,41 .”
Hematopoiesis: an evolving paradigm for stem cell biology. (2008, background): “In addition, the differentiation potential of older HSCs is biased toward myeloid versus lymphoid lineages (Sudo et al., 2000).”
Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion (2010, background): “We and others have previously shown that aging of the primitive HSC compartment is accompaniedby an intrinsic skewing of lineage potential, withHSCs from old mice preferentially reconstituting myeloid rather than lymphoid lineages (11, 12, 16, 18, 19).”
Long-term propagation of distinct hematopoietic differentiation programs in vivo. (2007, background): “Several studies suggest that cells with a differentiation characteristics may increase as mice age (Sudo et al., 2000; Kim et al., 2003; Rossi et al., 2005; Liang et al., 2005).”
Stems cells and the pathways to aging and cancer. (2008, background): “…also at play with fetal HSCs having a greater capacity to give rise to lymphoid lineage cells than stem cells from young adult mice (Morrison et al., 1995), which in turn possess greater lymphoid lineage potential than do HSCs from old mice (Kim et al., 2003; Rossi et al., 2005; Sudo et al., 2000).”
Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age (2011, background): “In humans, age-associated hematopoietic changes include decreased bonemarrow cellularity (14), declines in lymphopoiesis (7, 15, 16), red cell abnormalities such as anemia (17), and increases in the incidence of myelodysplastic syndromes, myeloproliferative disorders, and myeloid malignancies (18).”