Maintenance of the Hematopoietic Stem Cell Pool by CXCL12-CXCR4 Chemokine Signalling in Bone Marrow Stromal Cell Niches

Department of Medical Systems Control, Institute for Frontier Medical Sciences, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
Immunity (Impact Factor: 21.56). 01/2007; 25(6):977-88. DOI: 10.1016/j.immuni.2006.10.016
Source: PubMed


In the bone marrow, the special microenvironment niches nurture a pool of hematopoietic stem cells (HSCs). Many HSCs reside near the vasculature, but the molecular regulatory mechanism of niches for HSC maintenance remains unclear. Here we showed that the induced deletion of CXCR4, a receptor for CXC chemokine ligand (CXCL) 12 in adult mice, resulted in severe reduction of HSC numbers and increased sensitivity to myelotoxic injury, although it did not impair expansion of the more mature progenitors. Most HSCs were found in contact with the cells expressing high amounts of CXCL12, which we have called CXCL12-abundant reticular (CAR) cells. CAR cells surrounded sinusoidal endothelial cells or were located near the endosteum. CXCL12-CXCR4 signaling plays an essential role in maintaining the quiescent HSC pool, and CAR cells appear to be a key component of HSC niches, including both vascular and endosteal niches in adult bone marrow.

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    • "CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MPP, multipotent progenitor; BMPs, bone morphogenetic proteins; OPN, osteopontin; HA, hyaluronic acid. [16] [17]. Later, several studies confirmed the importance of Cxcl12 expressing cells in HSPC regulation but suggested different roles depending on their source and location. "
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    ABSTRACT: Recent discoveries have significantly expanded our previous knowledge about the role of bone marrow mesenchymal stem cells (BMSCs) in hematopoiesis. BMSCs and their derivatives modulate blood production and immunity at different levels but a prominent role has emerged for BMSCs in the regulation of hematopoietic stem and progenitor cells (HSPCs). Additionally, BMSC-like cells regulate B and T cell lymphopoiesis and also probably myelopoiesis. Furthermore, BMSCs might also exhibit key regulatory properties in non-physiological conditions. BMSCs in extramedullary sites might provide a permissive microenviroment to allow for transient hematopoiesis. BMSCs might be also involved in the manifestation and/or the development of hematopoietic diseases, as steming from their emerging roles in the progression of hematological malignancies. Here we review some key molecular pathways, adhesion molecules and ligand/receptor interactions that mediate the crosstalk between BMSCs and hematopoietic stem cells (HSCs) in health and disease. The development of novel markers to visualize and isolate individual cells will help to dissect the stromal-hematopoietic interplay. Copyright © 2015. Published by Elsevier B.V.
    Immunology letters 07/2015; DOI:10.1016/j.imlet.2015.06.020 · 2.51 Impact Factor
    • "The sum of the interactions with and soluble mediators released from these stromal cells influences hematopoiesis (Anthony and Link, 2014). Among these, one of the most studied examples of stromal cell-derived factors is the chemokine (C-X-C motif) ligand 12 (CXCL12) (also known as stromal cell-derived factor 1), which acts on hematopoietic stem and progenitor cells to regulate homing and survival, and to maintain quiescence (Greenbaum et al., 2013; Schajnovitz et al., 2011; Sugiyama et al., 2006). In addition to cell-cell interactions and the release of soluble mediators , BMSCs have a high capacity for enzymatic biotransformation of xenobiotics, especially polyaromatic hydrocarbons (Ganousis et al., 1992; Yamaguchi et al., 1997). "
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    ABSTRACT: Immunotoxicology assessments have historically focused on the effects that xenobiotics exhibit directly on immune cells. These studies are invaluable as they identify immune cell targets and help characterize mechanisms and/or adverse outcome pathways of xenobiotics within the immune system. However, leukocytes can receive environmental cues by cell-cell contact or via released mediators from cells of organs outside of the immune system. These organs include, but are not limited to, the mucosal areas such as the lung and the gut, the liver, and the central nervous system. Homeostatic perturbation in these organs induced directly by toxicants can initiate and alter the outcome of local and systemic immunity. This review will highlight some of the identified nonimmune influences on immune homeostasis and provide summaries of how immunotoxic mechanisms of selected xenobiotics involve nonimmune cells or mediators. Thus, this review will identify data gaps and provide possible alternative mechanisms by which xenobiotics alter immune function that could be considered during immunotoxicology safety assessment. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail:
    Toxicological Sciences 06/2015; 145(2):214-32. DOI:10.1093/toxsci/kfv060 · 3.85 Impact Factor
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    • "uld still be detected after 70 days (Sipkins et al., 2005 ). The labeled cells had increased in number , suggest - ing that HSPC persist and produce daughter cells in a perivascu - lar setting . Subsequently, in situ HSPC were also found to be in a perivascular position on bone sections ( Kiel et al . , 2005 ; Nom - bela - Arrieta et al . , 2013 ; Sugiyama et al . , 2006 ) . In live trans - planted animals , HSPCs were noted to accumulate closer to endosteal surfaces ( Lo Celso et al . , 2009 ; Xie et al . , 2009 ) . This was also the predominant position of human HSPC ( Guezguez et al . , 2013 ) . The arterioles penetrating bone are most prominent in the periendosteal region and are also the most radia"
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    ABSTRACT: Mesenchymal stromal cells (MSCs) are heterogeneous and primitive cells discovered first in the bone marrow (BM). They have putative roles in maintaining tissue homeostasis and are increasingly recognized as components of stem cell niches, which are best defined in the blood. The absence of in vivo MSC markers has limited our ability to track their behavior in vivo and draw comparisons with in vitro observations. Here we review the historical background of BM-MSCs, advances made in their prospective isolation, their developmental origin and contribution to maintaining subsets of hematopoietic cells, and how mesenchymal cells contribute to other stem cell niches. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Stem Cell 03/2015; 16(3):239-253. DOI:10.1016/j.stem.2015.02.019 · 22.27 Impact Factor
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