CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med

Department of Microbiology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 05/2008; 205(4):777-83. DOI: 10.1084/jem.20072513
Source: PubMed


The quiescence of hematopoietic stem cells (HSCs) is critical for preserving a lifelong steady pool of HSCs to sustain the highly regenerative hematopoietic system. It is thought that specialized niches in which HSCs reside control the balance between HSC quiescence and self-renewal, yet little is known about the extrinsic signals provided by the niche and how these niche signals regulate such a balance. We report that CXCL12 produced by bone marrow (BM) stromal cells is not only the major chemoattractant for HSCs but also a regulatory factor that controls the quiescence of primitive hematopoietic cells. Addition of CXCL12 into the culture inhibits entry of primitive hematopoietic cells into the cell cycle, and inactivation of its receptor CXCR4 in HSCs causes excessive HSC proliferation. Notably, the hyperproliferative Cxcr4(-/-) HSCs are able to maintain a stable stem cell compartment and sustain hematopoiesis. Thus, we propose that CXCR4/CXCL12 signaling is essential to confine HSCs in the proper niche and controls their proliferation.

Download full-text


Available from: Yong-Rui Zou,
  • Source
    • "CXCR4 is normally expressed by most leukocytes and has one ligand, CXCL12 (Bachelerie et al., 2014; Bleul et al., 1996), which is constitutively expressed at high levels by stromal cells in the bone marrow and normally mediates HSC retention in bone marrow niches (Broxmeyer et al., 2003b; Broxmeyer et al., 2005; Dar et al., 2006; Sugiyama et al., 2006; Zou et al., 1998). In addition, CXCR4 signaling promotes hematopoietic stem cell (HSC) quiescence, homing to bone marrow from blood and differentiation into committed myeloid progenitors (Broxmeyer et al., 2003a, 2003b; Kawai et al., 2007; Nie et al., 2008; Sugiyama et al., 2006). Chromothripsis refers to multiple clustered genetic rearrangements and deletions affecting one or a few chromosomes (Stephens et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chromothripsis is a catastrophic cellular event recently described in cancer in which chromosomes undergo massive deletion and rearrangement. Here, we report a case in which chromothripsis spontaneously cured a patient with WHIM syndrome, an autosomal dominant combined immunodeficiency disease caused by gain-of-function mutation of the chemokine receptor CXCR4. In this patient, deletion of the disease allele, CXCR4(R334X), as well as 163 other genes from one copy of chromosome 2 occurred in a hematopoietic stem cell (HSC) that repopulated the myeloid but not the lymphoid lineage. In competitive mouse bone marrow (BM) transplantation experiments, Cxcr4 haploinsufficiency was sufficient to confer a strong long-term engraftment advantage of donor BM over BM from either wild-type or WHIM syndrome model mice, suggesting a potential mechanism for the patient's cure. Our findings suggest that partial inactivation of CXCR4 may have general utility as a strategy to promote HSC engraftment in transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 02/2015; 160(4). DOI:10.1016/j.cell.2015.01.014 · 32.24 Impact Factor
  • Source
    • "Various substances can be chemoattractants: stem cell factor SCF, colonyystimm ulating factors, prostaglandins, chemokines, transs forming growth factors beta 1–3, etc. (Halova et al., 2012). Osteoclasts, endothelial cells, and the subpopulaa tion of bone marrow reticular cells secrete chemokine CXCL12 (CCXXCCmotif ligand 12), which serves as chemoattractant for hemopoietic SCs and prevents their switch to the cell cycle (Nie et al., 2008). In injured tissues, soluble EM proteins (collagen, fibronectin, and vitronectin) and products of their partial hydrolysis can also serve as attractants for MSCs (Thibault et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The role of the microenvironment in the regulation of the main stem cell functions is considered. Special attention is paid to the effects of mechanical interactions and mechanical properties of the substrate on self-renewal, maintenance of potency, and differentiation in stem cells in vivo and in vitro. Primary cilia, mechanosensitive channels, receptors coupled with G proteins, and the proteins of intercellular junctions can be mechanosensors. In turn, the major role in mechanotransduction belongs to integrins, a large family of extracellular matrix receptors. Integrins are part of focal adhesions. They form bridges to link the cell membrane to the cytoskeleton and nucleus. The study of the integration of the biochemical and mechanical factors of the microenvironment is essential for the introduction of stem cell technology into regenerative medicine.
    Biology Bulletin 07/2014; 4(4):263-275. DOI:10.1134/S2079086414040069 · 0.25 Impact Factor
  • Source
    • "There has been recent progress in our understanding of the formative role of selection driving population divergence , even in the face of on-going gene flow (Via & West, 2008; Wolf et al., 2010; Feder et al., 2012). Technological advances in data collection paired with the analytical framework of population genomics have sparked increasing refinement of our ability to detect adaptive population divergence in situ, even without prior knowledge of the phenotypes under selection or the availability of extensive genome maps (Luikart et al., 2003; Nielsen, 2005; Storz, 2005; Stinchcombe & Hoekstra, 2008). Yet, many questions remain unresolved regarding the number, arrangement and genome-wide influence of ecologically relevant loci under selection that are required to overcome the homogenizing effects of gene flow to establish the reproductive barriers ultimately required for speciation (Via, 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent progress in methods for detecting adaptive population divergence in situ shows promise for elucidating the conditions under which selection acts to generate intraspecific diversity. Rapid ecological diversification is common in fishes; however, the role of phenotypic plasticity and adaptation to local environments is poorly understood. It is now possible to investigate genetic patterns to make inferences regarding phenotypic traits under selection and possible mechanisms underlying ecotype divergence, particularly where similar novel phenotypes have arisen in multiple independent populations. Here, we employed a bottom-up approach to test for signatures of directional selection associated with divergence of beach- and stream-spawning kokanee, the obligate freshwater form of sockeye salmon (Oncorhynchus nerka). Beach- and stream-spawners co-exist in many post-glacial lakes and exhibit distinct reproductive behaviours, life-history traits and spawning habitat preferences. Replicate ecotype pairs across five lakes in British Columbia, Canada were genotyped at 57 expressed sequence tag-linked and anonymous microsatellite loci identified in a previous genome scan. Fifteen loci exhibited signatures of directional selection (high FST outliers), four of which were identified in multiple lakes. However, the lack of parallel genetic patterns across all lakes may be a result of: 1) an inability to detect loci truly under selection; 2) alternative genetic pathways underlying ecotype divergence in this system; and/or 3) phenotypic plasticity playing a formative role in driving kokanee spawning habitat differences. Gene annotations for detected outliers suggest pathogen resistance and energy metabolism as potential mechanisms contributing to the divergence of beach- and stream-spawning kokanee, but further study is required.
    Journal of Evolutionary Biology 10/2013; 26(12). DOI:10.1111/jeb.12250 · 3.23 Impact Factor
Show more