CXCR4 is required for the quiescence of primitive hematopoietic cells

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.

[1]  M. Kaul,et al.  HIV/gp120 decreases adult neural progenitor cell proliferation via checkpoint kinase-mediated cell-cycle withdrawal and G1 arrest. , 2007, Cell stem cell.

[2]  T. Nagasawa,et al.  Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. , 2006, Immunity.

[3]  Kevin Wei,et al.  A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development , 2006, The Journal of experimental medicine.

[4]  W. Vainchenker,et al.  Reduced retention of radioprotective hematopoietic cells within the bone marrow microenvironment in CXCR4-/- chimeric mice. , 2006, Blood.

[5]  A. Trumpp,et al.  Bone-marrow haematopoietic-stem-cell niches , 2006, Nature Reviews Immunology.

[6]  Thomas Ludwig,et al.  Complete rescue of obesity, diabetes, and infertility in db/db mice by neuron-specific LEPR-B transgenes. , 2005, The Journal of clinical investigation.

[7]  T. Okano,et al.  p57Kip2 is expressed in quiescent mouse bone marrow side population cells. , 2005, Biochemical and biophysical research communications.

[8]  Christie M. Orschell,et al.  Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist , 2005, The Journal of experimental medicine.

[9]  C. Eaves.  SDF-1 tells stem cells to mind their P's and Z's. , 2005, The Journal of clinical investigation.

[10]  Dan R. Littman,et al.  The Role of CXCR4 in Maintaining Peripheral B Cell Compartments and Humoral Immunity , 2004, The Journal of experimental medicine.

[11]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[12]  Lina M. Nilsson,et al.  PTX-sensitive signals in bone marrow homing of fetal and adult hematopoietic progenitor cells. , 2004, Blood.

[13]  H. Broxmeyer,et al.  Stromal cell‐derived factor‐1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and Gαi proteins and enhances engraftment of competitive, repopulating stem cells , 2003, Journal of leukocyte biology.

[14]  H. Broxmeyer,et al.  Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo , 2003, The Journal of Immunology.

[15]  S. Rafii,et al.  Recruitment of Stem and Progenitor Cells from the Bone Marrow Niche Requires MMP-9 Mediated Release of Kit-Ligand , 2002, Cell.

[16]  Irving L. Weissman,et al.  Hematopoietic Stem Cells Are Uniquely Selective in Their Migratory Response to Chemokines , 2002, The Journal of experimental medicine.

[17]  M. Le Bousse-Kerdilès,et al.  Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. , 2002, Blood.

[18]  R. Taichman,et al.  Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. , 2000, The Journal of clinical investigation.

[19]  D. Scadden,et al.  Hematopoietic stem cell quiescence maintained by p21cip1/waf1. , 2000, Science.

[20]  T. Kishimoto,et al.  A cell-autonomous requirement for CXCR4 in long-term lymphoid and myeloid reconstitution. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.

[22]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Kouji Matsushima,et al.  The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract , 1998, Nature.

[24]  Masahiko Kuroda,et al.  Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development , 1998, Nature.

[25]  S. Nishikawa,et al.  Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1 , 1996, Nature.

[26]  M. Tavassoli,et al.  Alterations of bone marrow sinus endothelium induced by ionizing irradiation: implications in the homing of intravenously transplanted marrow cells. , 1992, Blood cells.