Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

[1]  H. Broxmeyer,et al.  In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. , 1998, Blood.

[2]  C. Civin,et al.  Sustained, retransplantable, multilineage engraftment of highly purified adult human bone marrow stem cells in vivo. , 1996, Blood.

[3]  D. Roopenian,et al.  Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice. , 1997, Journal of immunology.

[4]  C. Eaves,et al.  Quantitation, mobilization, and clinical use of long-term culture-initiating cells in blood cell autografts. , 1995, Journal of hematotherapy.

[5]  D. Kohn,et al.  Sustained human hematopoiesis in immunodeficient mice by cotransplantation of marrow stroma expressing human interleukin-3: analysis of gene transduction of long-lived progenitors. , 1994, Blood.

[6]  David A. Williams,et al.  Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: Implications for gene therapy , 1996, Nature Medicine.

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

[8]  J. Hoxie,et al.  Phorbol Esters and SDF-1 Induce Rapid Endocytosis and Down Modulation of the Chemokine Receptor CXCR4 , 1997, The Journal of cell biology.

[9]  J. Inazawa,et al.  Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. , 1995, Genomics.

[10]  I. Weissman,et al.  The biology of hematopoietic stem cells. , 1995, Annual review of cell and developmental biology.

[11]  R. Haas,et al.  Expression of the Human Immunodeficiency Virus Type-1 Coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ Hematopoietic Progenitor Cells , 1997 .

[12]  B. Premack,et al.  Chemokine receptors: Gateways to inflammation and infection , 1996, Nature Medicine.

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

[14]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[15]  G. Suzuki,et al.  Disturbed CD4+ T Cell Homeostasis and In Vitro HIV-1 Susceptibility in Transgenic Mice Expressing T Cell Line–tropic HIV-1 Receptors , 1998, The Journal of experimental medicine.

[16]  J. Dick,et al.  Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. , 1992, Science.

[17]  T. Springer,et al.  A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1) , 1996, The Journal of experimental medicine.

[18]  I. Weissman,et al.  The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. , 1988, Science.