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Stem Cells 2004;22:1128-1133 www.StemCells.com
© 2004 AlphaMed Press

RAPID COMMUNICATION

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

Sebastian Brennera,b, Narda Whiting-Theobalda, Toshinao Kawaia,c, Gilda F. Lintona, Andrew G. Rudikoffa, Uimook Choia, Martin F. Ryserb, Philip M. Murphya, Joan M.G. Sechlera, Harry L. Malecha

a Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA;
b Department of Pediatrics, University Clinic Carl Gustav Carus, Dresden, Germany;
c Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan

Key Words. Engraftment • CXCR4 • Ex vivo gene transfer • Hematopoietic stem cells (HSCs)

Correspondence: Sebastian Brenner, M.D., Department of Pediatrics, University Clinic Carl Gustav Carus, Fetscherstr. 74, 01307 Dresden, Germany. Telephone: 49-351-458-6872; Fax: 49-351-458-6333; e-mail: Sebastian.Brenner{at}uniklinikum-dresden.de

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.




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