Stem cells and the aging hematopoietic system

Department of Pathology, Harvard Medical School, Harvard Stem Cell Institute, Immune Disease Institute, Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA 02115, USA.
Current opinion in immunology (Impact Factor: 7.87). 08/2010; 22(4):500-6. DOI: 10.1016/j.coi.2010.06.007
Source: PubMed

ABSTRACT Advancing age is accompanied by a number of clinically significant conditions arising in the hematopoietic system that include: diminution and decreased competence of the adaptive immune system, elevated incidence of certain autoimmune diseases, increased hematological malignancies, and elevated incidence of age-associated anemia. As with most tissues, the aged hematopoietic system also exhibits a reduced capacity to regenerate and return to normal homeostasis after injury or stress. Evidence suggests age-dependent functional alterations within the hematopoietic stem cell compartment significantly contribute to many of these pathophysiologies. Recent developments have shed light on how aging of the hematopoietic stem cell compartment contributes to hematopoietic decline through diverse mechanisms.

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    • "Aged LNK ) ⁄ ) HSCs are far superior to aged WT HSCs in their abilities to repopulate both primary and secondary hosts. Additionally, aged WT HSCs displayed a lineage output profoundly skewed toward myelopoiesis , a phenomenon that has been attributed to the expansion of a specific subset of HSCs clones (Beerman et al., 2010), contrasting the balanced lineage program exhibited by aged LNK ) ⁄ ) HSCs (Fig. 2A, B). It remains to be seen whether knockdown of LNK in aged WT HSCs would lead to a similar repopulating potential upon transplantation as that of aged LNK ) ⁄ ) HSCs that have never 'seen' LNK throughout their ontogeny. "
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    ABSTRACT: Aging causes profound effects on the hematopoietic stem cell (HSC) pool, including an altered output of mature progeny and enhanced self-propagation of repopulating-defective HSCs. An important outstanding question is whether HSCs can be protected from aging. The signal adaptor protein LNK negatively regulates hematopoiesis at several cellular stages. It has remained unclear how the enhanced sensitivity to cytokine signaling caused by LNK deficiency affects hematopoiesis upon aging. Our findings demonstrate that aged LNK(-/-) HSCs displayed a robust overall reconstitution potential and gave rise to a hematopoietic system with a balanced lineage distribution. Although aged LNK(-/-) HSCs displayed a distinct molecular profile in which reduced proliferation was central, little or no difference in the proliferation of aged LNK(-/-) HSCs was observed after transplantation when compared to aged WT HSCs. This coincided with equal telomere maintenance in WT and LNK(-/-) HSCs. Collectively, our studies suggest that enhanced cytokine signaling can counteract functional age-related HSC decline.
    Aging cell 07/2012; 11(6). DOI:10.1111/j.1474-9726.2012.00863.x · 5.94 Impact Factor
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    • "The hematopoietic system declines with age, resulting in a diminished production of adaptive immune cells, termed immunosenescence , and an increased incidence of anemia and myeloid malignancies (Fig. 1; Beerman et al., 2010b). Although aged mice have increased numbers of phenotypic HSCs, the functional capacity of these cells is actually compromised, as evidenced by the decrease in long-term multilineage reconstitution potential of purified old HSCs transplanted into young recipient "
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    ABSTRACT: Hematopoietic stem cells (HSCs) give rise to all lineages of blood cells. Because HSCs must persist for a lifetime, the balance between their proliferation and quiescence is carefully regulated to ensure blood homeostasis while limiting cellular damage. Cell cycle regulation therefore plays a critical role in controlling HSC function during both fetal life and in the adult. The cell cycle activity of HSCs is carefully modulated by a complex interplay between cell-intrinsic mechanisms and cell-extrinsic factors produced by the microenvironment. This fine-tuned regulatory network may become altered with age, leading to aberrant HSC cell cycle regulation, degraded HSC function, and hematological malignancy.
    The Journal of Cell Biology 11/2011; 195(5):709-20. DOI:10.1083/jcb.201102131 · 9.69 Impact Factor
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    • "In humans, only fragmentary and contradictory information is available concerning age-related changes in HSC (Waterstrat et al., 2008; Taraldsrud et al., 2009; Beerman et al., 2010). One study (Chatta et al., 1993) suggested that the proportion of HSC and in particular myeloid progenitors in mononucleated cells was the same in young and elderly adults but the generation of mixed granulocyte–macrophage colonies decreased with age (Marley et al., 1999). "
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    ABSTRACT: Adult stem cells are critical for maintaining cellular homeostasis throughout life, yet the effects of age on their regenerative capacity are poorly understood. All lymphoid and myeloid blood cell lineages are continuously generated from hematopoietic stem cells present in human bone marrow. With age, significant changes in the function and composition of mature blood cells are observed. In this study, we report that age-related changes also occur in the human hematopoietic stem cell compartment. We find that the proportion of multipotent CD34(+) CD38(-) cells increases in the bone marrow of elderly (>70 years) individuals. CD34(+) CD38(+) CD90(-) CD45RA(+/-) CD10(-) and CD34(+) CD33(+) myeloid progenitors persist at the same level in the bone marrow, while the frequency of early CD34(+) CD38(+) CD90(-) CD45RA(+) CD10(+) and committed CD34(+) CD19(+) B-lymphoid progenitors decreases with age. In contrast to mice models of aging, transplantation experiments with immunodeficient NOD/SCID/IL-2Rγ null (NSG) mice showed that the frequency of NSG repopulating cells does not change significantly with age, and there is a decrease in myeloid lineage reconstitution. An age-related decrease in the capacity of CD34(+) cells to generate myeloid cells was also seen in colony-forming assays in vitro. Thus, with increasing age, human hematopoietic stem/progenitor cells undergo quantitative changes as well as functional modifications.
    Aging cell 06/2011; 10(3):542-6. DOI:10.1111/j.1474-9726.2011.00675.x · 5.94 Impact Factor
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