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Blood, 15 April 2004, Vol. 103, No. 8, pp. 2942-2949. Prepublished online as a Blood First Edition Paper on December 24, 2003; DOI 10.1182/blood-2003-07-2607. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2607v1 103/8/2942    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kahn, J. Articles by Lapidot, T. Search for Related Content PubMed PubMed Citation Articles by Kahn, J. Articles by Lapidot, T. Related Collections Hematopoiesis and Stem Cells Signal Transduction Chemokines, Cytokines, and Interleukins Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  GENE THERAPY Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation Joy Kahn, Tamara Byk, Lottie Jansson-Sjostrand, Isabelle Petit, Shoham Shivtiel, Arnon Nagler, Izhar Hardan, Varda Deutsch, Zulma Gazit, Dan Gazit, Stefan Karlsson, and Tsvee Lapidot From the Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Medicine and Gene Therapy, Lund University, Sweden; Hematology and Bone Marrow Transplantation Department, Chaim Sheba Medical Center, Tel Hashomer, Israel; Hematology Institute, Tel Aviv Sourasky Medical Center, Israel; and Skeletal Biotechnology Laboratory, Hebrew University-Hadassah Medical Center, Jerusalem, Israel. A major limitation to clinical stem cell–mediated gene therapy protocols is the low levels of engraftment by transduced progenitors. We report that CXCR4 overexpression on human CD34+ progenitors using a lentiviral gene transfer technique helped navigate these cells to the murine bone marrow and spleen in response to stromal-derived factor 1 (SDF-1) signaling. Cells overexpressing CXCR4 exhibited significant increases in SDF-1–mediated chemotaxis and actin polymerization compared with control cells. A major advantage of CXCR4 overexpression was demonstrated by the ability of transduced CD34+ cells to respond to lower, physiologic levels of SDF-1 when compared to control cells, leading to improved SDF-1–induced migration and proliferation/survival, and finally resulting in significantly higher levels of in vivo repopulation of nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice including primitive CD34+/CD38-/low cells. Importantly, no cellular transformation was observed following transduction with the CXCR4 vector. Unexpectedly, we documented lack of receptor internalization in response to high levels of SDF-1, which can also contribute to increased migration and proliferation by the transduced CD34+ cells. Our results suggest CXCR4 overexpression for improved definitive human stem cell motility, retention, and multilineage repopulation, which could be beneficial for in vivo navigation and expansion of hematopoietic progenitors. (Blood. 2004;103:2942-2949) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. H. Seeger, T. Rasper, M. Koyanagi, H. Fox, A. M. Zeiher, and S. Dimmeler CXCR4 Expression Determines Functional Activity of Bone Marrow-Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1802 - 1809. 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