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: 7.48). 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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    • "The aged pool of HSC is often characterized by a marked shift in lymphoid and myeloid lineage output. Such age-associated myeloid skewing of the differentiation potential, together with decreased homing efficiency , contributes to changes in the cellular composition of the HSC compartment and is believed to be an important contributor to the decline of immune competence in the elderly (Beerman et al., 2010; Gui et al., 2007; Müller and Pawelec, 2014). Studies on telomerase knockout mice have demonstrated that telomere dysfunction and accumulation of DNA damage induces alterations in the stem-cell environment, leading in turn to HSCintrinsic deficiencies in aged mice (Ju et al., 2007; Song et al., 2012). "
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    ABSTRACT: The vertebrate adaptive immune system is remarkable for its possession of a very broad range of antigen receptors imbuing the system with exquisite specificity, in addition to the phagocytic and inflammatory cells of the innate system shared with invertebrates. This system requires strict control both at the level of the generation the cells carrying these receptors and at the level of their activation and effector function mediation in order to avoid autoimmunity and mitigate immune pathology. Thus, quality control checkpoints are built into the system at multiple nodes in the response, relying on clonal selection and regulatory networks to maximize pathogen-directed effects and minimize collateral tissue damage. However, these checkpoints are compromised with age, resulting in poorer immune control manifesting as tissue-damaging autoimmune and inflammatory phenomena which can cause widespread systemic disease, paradoxically compounding the problems associated with increased susceptibility to infectious disease and possibly cancer in the elderly. Better understanding the reasons for slippage of immune control will pave the way for developing rational strategies for interventions to maintain appropriate immunity while reducing immunopathology. Copyright © 2015. Published by Elsevier B.V.
    Ageing Research Reviews 02/2015; 23(Pt A). DOI:10.1016/j.arr.2015.01.005 · 4.94 Impact Factor
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    • "During normal haematopoiesis, the peripheral blood is estimated to have contributions from ~1000 HSCs (Catlin et al., 2011), whereas at any given time the majority of adult HSCs are in a quiescent state (Arai et al., 2004; Li and Clevers, 2010). On average, human HSCs are thought to divide once every 40 weeks (Catlin et al., 2011); however, blood cell production is a continuous process throughout life, with an adult human producing an estimated 1011 cells daily (Beerman et al., 2010). These properties make HSCs, like other tissue stem cells, prime targets for malignant transformation. "
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    ABSTRACT: Acute myeloid leukaemia (AML) is an uncontrolled clonal proliferation of abnormal myeloid progenitor cells in the bone marrow and blood. Advances in cancer genomics have revealed the spectrum of somatic mutations that give rise to human AML and drawn our attention to its molecular evolution and clonal architecture. It is now evident that most AML genomes harbour small numbers of mutations, which are acquired in a stepwise manner. This characteristic, combined with our ability to identify mutations in individual leukaemic cells and our detailed understanding of normal human and murine haematopoiesis, makes AML an excellent model for understanding the principles of cancer evolution. Furthermore, a better understanding of how AML evolves can help us devise strategies to improve the therapy and prognosis of AML patients. Here, we draw from recent advances in genomics, clinical studies and experimental models to describe the current knowledge of the clonal evolution of AML and its implications for the biology and treatment of leukaemias and other cancers.
    Disease Models and Mechanisms 08/2014; 7(8):941-951. DOI:10.1242/dmm.015974 · 4.97 Impact Factor
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    • "Given that the thymus requires the continual input of bone marrow progenitors, any age-related alterations in hematopoietic stem cells (HSC) function could conceivably contribute toward thymic involution. Studies have demonstrated that aged HSC appear to exhibit an increased bias toward myeloid differentiation together with a reduced capacity toward lymphoid maturation; which has been observed in mice and human (31, 32). Such alterations in HSC function may manifest within early thymocyte progenitor (ETP) activity. "
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    ABSTRACT: Age-related regression of the thymus is associated with a decline in naïve T cell output. This is thought to contribute to the reduction in T cell diversity seen in older individuals and linked with increased susceptibility to infection, autoimmune disease, and cancer. Thymic involution is one of the most dramatic and ubiquitous changes seen in the aging immune system, but the mechanisms which underlying this process are poorly understood. However, a picture is emerging, implicating the involvement of both extrinsic and intrinsic factors. In this review we assess the role of the thymic microenvironment as a potential target that regulates thymic involution, question whether thymocyte development in the aged thymus is functionally impaired, and explore the kinetics of thymic involution.
    Frontiers in Immunology 10/2013; 4:316. DOI:10.3389/fimmu.2013.00316
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