CXCR4-Transgene Expression Significantly Improves Marrow Engraftment of Cultured Hematopoietic Stem Cells

Authors

  • Sebastian Brenner M.D.,

    Corresponding author
    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    2. Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany
    • Department of Pediatrics, University Clinic Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany. Telephone: 49-351-458-6872; Fax: 49-351-458-6333
    Search for more papers by this author
  • Narda Whiting-Theobald,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Toshinao Kawai,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    2. Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan
    Search for more papers by this author
  • Gilda F. Linton,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Andrew G. Rudikoff,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Uimook Choi,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Martin F. Ryser,

    1. Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany
    Search for more papers by this author
  • Philip M. Murphy,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Joan M.G. Sechler,

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author
  • Harry L. Malech

    1. Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
    Search for more papers by this author

Abstract

Hematopoietic stem cells (HSCs) lose marrow reconstitution potential during ex vivo culture. HSC migration to stromal cell–derived factor (SDF)-1 (CXCL12) correlates with CXC chemokine receptor 4 (CXCR4) expression and marrow engraftment. We demonstrate that mobilized human CD34+ peripheral blood stem cells (CD34+ PBSCs) lose CXCR4 expression during prolonged culture. We transduced CD34+ PBSCs with retrovirus vector encoding human CXCR4 and achieved 18-fold more CXCR4 expression in over 87% of CD34+ cells. CXCR4-transduced cells yielded increased calcium flux and up to a 10-fold increase in migration to SDF-1. Six-day cultured CXCR4-transduced cells demonstrated significant engraftment in nonobese diabetic/severe combined immunodeficient mice under conditions in which control transduced cells resulted in low or no engraftment. We conclude that transduction-mediated overexpression of CXCR4 significantly improves marrow engraftment of cultured PBSCs.

Ancillary