Awaking dormant hematopoietic stem cells

Heidelberg Institute for Stem Cell Technology and Experimental Medicine, German Cancer Research Center, Germany.
Nature Reviews Immunology (Impact Factor: 34.99). 03/2010; 10(3):201-9. DOI: 10.1038/nri2726
Source: PubMed


Haematopoietic stem cells (HSCs) in mouse bone marrow are located in specialized niches as single cells. During homeostasis, signals from this environment keep some HSCs dormant, which preserves long-term self-renewal potential, while other HSCs actively self renew to maintain haematopoiesis. In response to haematopoietic stress, dormant HSCs become activated and rapidly replenish the haematopoietic system. Interestingly, three factors - granulocyte colony-stimulating factor, interferon-alpha and arsenic trioxide - have been shown to efficiently activate dormant stem cells and thereby could break their resistance to anti-proliferative chemotherapeutics. Thus, we propose that two-step strategies could target resistant leukaemic stem cells by priming tumours with activators of dormancy followed by chemotherapy or targeted therapies.

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    • "This suggests that homeostatic HSCs have an array of mechanisms in place to protect their cellular integrity, extending an observation that we have made previously in hematopoietic progenitors (Klimmeck et al., 2012). Along these lines, two interferon-inducible proteins involved in host defense (Ifitm1 and Irgm2) were expressed at higher levels in HSCs compared with MPP1 (Figure 2C), suggesting that the type I interferon pathway is not only critical for the response to stress but also during homeostasis (Essers et al., 2009; Trumpp et al., 2010). Moreover, HSCs and MPP1 employ different intracellular serpins for protection against death during stress because Serpinb6a and Serpinb1a were expressed at higher levels in either HSC or MPP1, respectively (Figure 2C). "
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    ABSTRACT: In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy.
    Cell Stem Cell 10/2014; 15(4):507-522. DOI:10.1016/j.stem.2014.07.005 · 22.27 Impact Factor
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    • "These cytokines are therefore best viewed as non-specific stimulants that recruit and activate progenitors residing in the quiescent niches rendering them responsive to other growth signals. In this capacity, IFN and TNF participate in awakening of dormant progenitors within the marrow niche [2] and serve as coupling mechanisms between inflammation and injury, and stimulation of hematopoiesis. Activation of hematopoietic progenitors is associated with wide variations in patterns of expression of intracellular molecules and cell surface receptors. "
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    ABSTRACT: Enhanced hematopoiesis accompanies systemic responses to injury and infection. Tumor necrosis factor (TNF) produced by injured cells and interferons (IFN) secreted by inflammatory cells are co-products of the process of clearance of debris and removal of still viable but dysfunctional cells. Concomitantly, these cytokines induce hematopoietic stem and progenitor cell (HSPC) activity as an intrinsic component of the systemic response. The proposed scenario includes induction of HSPC activity by type I (IFNα/β) and II (IFNγ) receptors within the quiescent bone marrow niches rendering progenitors responsive to additional signals. TNFα converges as a non-selective stimulant of HSPC activity and both cytokines synergize with other growth factors in promoting differentiation. These physiological signaling pathways of stress hematopoiesis occur quite frequent and do not cause HSPC extinction. The proposed role of INFs and TNFs in stress hematopoiesis commends revision of their alleged involvement in bone marrow failure syndromes.
    Blood Reviews 09/2014; 29(1). DOI:10.1016/j.blre.2014.09.002 · 5.57 Impact Factor
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    • "In recent years, there has been rapid expansion of the clinical use of hematopoietic stem cells as well as its concomitant understanding of its basic biology. These stem cells, which are a critical component of transplantation, are progenitors to the blood cells of the body that constitutes the myeloid and erythroid lineage [2]. They continuously provide mature blood cells during the lifespan of the individual. "
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    ABSTRACT: Stem cells have the capability to proliferate and differentiate into various cells of the body. Few stem cell sources have been approved for transplantation, among them are the hematopoietic progenitor cells which are progenitors of the myeloid and erythroid lineage in the hematopoietic system, that continually provides mature blood cells during the lifespan of the individual. These well-characterized stem cells are clinically relevant in the treatment of diseases such as breast cancer, leukemias, and congenital immunodeficiencies. Peripheral blood stem transplantation is a standard procedure after its first successful transplantation more than 35 years ago. The minimum intended dose of stem cells given to the patient is 2.5 × 10(6) -5 × 10(6) cells. In this study, we are establishing a correlation between the number of stem cells enumerated and the weight of the patient as a determinant for suitable transplantation. We have established a conversion factor to deliver the required dose of approximately 3 × 10(6) stem cells/kg body weight. This will ensure a uniform collection strategy that is sufficient for transplantation irrespective of the weight of the patient. This approach, if incorporated, will lead to a significantly lesser rate of bone marrow transplantation failures as sufficient number of stem cells will ensure engraftment of stem cells.
    Journal of Transplantation 08/2014; 2014:473503. DOI:10.1155/2014/473503
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