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.

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Available from: Yong-Rui Zou
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    • "SDF-1 is highly expressed in the bone marrow by various stromal cells including osteoblasts, endothelial cells, and perivascular reticular cells (Lapidot et al., 2005; Sugiyama et al., 2006). Notably, SDF-1 is also involved in other stem cell functions including regulation of cell quiescence and survival (Nie et al., 2008; Sugiyama et al., 2006). Our data suggest that extremely high levels of SDF-1 in the dermis might be required for skin homeostasis, including epidermal turnover and morphogenesis. "
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    ABSTRACT: Stromal cells provide a crucial microenvironment for overlying epithelium. Here we investigated the expression and function of a stromal cell-specific protein, stromal cell-derived factor-1 (SDF-1), in normal human skin and in the tissues of diseased skin. Immunohistology and laser capture microdissection (LCM)-coupled quantitative real-time RT-PCR revealed that SDF-1 is constitutively and predominantly expressed in dermal stromal cells in normal human skin in vivo. To our surprise, an extremely high level of SDF-1 transcription was observed in the dermis of normal human skin in vivo, evidenced by much higher mRNA expression level than type I collagen, the most abundant and highly expressed protein in human skin. SDF-1 was also upregulated in the tissues of many human skin disorders including psoriasis, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Double immunostaining for SDF-1 and HSP47 (heat shock protein 47), a marker of fibroblasts, revealed that fibroblasts were the major source of stroma-cell-derived SDF-1 in both normal and diseased skin. Functionally, SDF-1 activates the ERK (extracellular-signal-regulated kinases) pathway and functions as a mitogen to stimulate epidermal keratinocyte proliferation. Both overexpression of SDF-1 in dermal fibroblasts and treatment with rhSDF-1 to the skin equivalent cultures significantly increased the number of keratinocyte layers and epidermal thickness. Conversely, the stimulative function of SDF-1 on keratinocyte proliferation was nearly completely eliminated by interfering with CXCR4, a specific receptor of SDF-1, or by knock-down of SDF-1 in fibroblasts. Our data reveal that extremely high levels of SDF-1 provide a crucial microenvironment for epidermal keratinocyte proliferation in both physiologic and pathologic skin conditions.
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    • "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). "
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    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.
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    • "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). "
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    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.
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