Cho RH, Sieburg HB, Muller-Sieburg CE.. A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood 111: 5553-5561

Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
Blood (Impact Factor: 10.45). 07/2008; 111(12):5553-61. DOI: 10.1182/blood-2007-11-123547
Source: PubMed


Whether hematopoietic stem cells (HSCs) change with aging has been controversial. Previously, we showed that the HSC compartment in young mice consists of distinct subsets, each with predetermined self-renewal and differentiation behavior. Three classes of HSCs can be distinguished based on their differentiation programs: lymphoid biased, balanced, and myeloid biased. We now show that aging causes a marked shift in the representation of these HSC subsets. A clonal analysis of repopulating HSCs demonstrates that lymphoid-biased HSCs are lost and long-lived myeloid-biased HSCs accumulate in the aged. Myeloid-biased HSCs from young and aged sources behave similarly in all aspects tested. This indicates that aging does not change individual HSCs. Rather, aging changes the clonal composition of the HSC compartment. We show further that genetic factors contribute to the age-related changes of the HSC subsets. In comparison with B6 mice, aged D2 mice show a more pronounced shift toward myeloid-biased HSCs with a corresponding reduction in the number of both T- and B-cell precursors. This suggests that low levels of lymphocytes in the blood can be a marker for HSC aging. The loss of lymphoid-biased HSCs may contribute to the impaired immune response to infectious diseases and cancers in the aged.

Download full-text


Available from: Hans Sieburg
  • Source
    • "Single cell based analysis shows DNA damage accumulation and myeloid lineage bias in aged HSCs (Walter et al., 2015). Nevertheless, counter opinion maintains that these observations could be the result of selective expansion of myeloid biased HSCs and loss of HSCs with lymphoid potential (Cho et al., 2008). No apparent differences between the myeloid biased HSCs from young and old mice were reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In most of the mammalian tissues, homeostasis as well as injury repair depends upon a small number of resident adult stem cells. The decline in tissue/organ function in aged organisms has been directly linked with poorly functioning stem cells. Altered function of hematopoietic stem cells (HSCs) is at the center of an ageing hematopoietic system, a tissue with high cellular turnover. Poorly engrafting, myeloid biased HSCs with higher levels of DNA damage accumulation are the hallmark features of an aged hematopoietic system. These cells show higher proliferation rate than their younger counterparts. It was proposed that quiescence of these cells over long period of time leads to accumulation of DNA damage, eventually resulting in poor function/pathological conditions in hematopoietic system. However, various mouse models with pre-mature ageing phenotype also show highly proliferative HSCs. This review examines the evidence that links proliferation of HSCs with ageing, which leads to functional changes in the hematopoietic system. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2016 · Developmental Dynamics
  • Source
    • "Fasting Inhibits IGF-1/PKA to Promote Regeneration myeloid-biased, and balanced-HSCs ratio (Figures 2F, S2D, and S2E). Whereas most HSCs from young mice are balanced in lymphopoiesis and myelopoiesis, the majority of HSCs from elderly mice are myeloid biased (Beerman et al., 2010; Challen et al., 2010; Cho et al., 2008; Dykstra et al., 2007; Morita et al., 2010; Muller-Sieburg et al., 2004; Pang et al., 2011). We therefore investigated if PF cycles can correct this bias in aged mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration.
    Full-text · Article · Jun 2014 · Cell Stem Cell
  • Source
    • "However, our data cannot disentangle cell-type effects. Other contributing factors may include developmental processes such as age-related changes to the progenitor cell pool [75-77], as suggested previously [28], or age-related shifts in blood cell signaling and metabolism [78]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Preterm birth confers a high risk of adverse long-term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18 years comparing survivors of extremely preterm birth with infants born at term. Using 12 extreme preterm birth cases and 12 matched, term controls, we extracted DNA from archived neonatal blood spots and blood collected in a similar way at 18 years of age. DNA methylation was measured at 347,789 autosomal locations throughout the genome using Infinium HM450 arrays. Representative methylation differences were confirmed by Sequenom MassArray EpiTYPER. At birth we found 1,555 sites with significant differences in methylation between term and preterm babies. At 18 years of age, these differences had largely resolved, suggesting that DNA methylation differences at birth are mainly driven by factors relating to gestational age, such as cell composition and/or maturity. Using matched longitudinal samples, we found evidence for an epigenetic legacy associated with preterm birth, identifying persistent methylation differences at ten genomic loci. Longitudinal comparisons of DNA methylation at birth and 18-years uncovered a significant overlap between sites that were differentially-methylated at birth and those that changed with age. However, we note that overlapping sites may either differ in the same (300/1,555) or opposite (431/1,555) direction during gestation and aging respectively. We present evidence for widespread methylation differences between extreme preterm and term infants at birth that are largely resolved by 18 years of age. These results are consistent with methylation changes associated with blood cell development, cellular composition, immune induction and age at these time points. Finally, we identified ten probes significantly associated with preterm individuals and with greater than 5% methylation discordance at birth and 18 years that may reflect a long term epigenetic legacy of preterm birth.
    Full-text · Article · Oct 2013 · Genome Medicine
Show more