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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.
 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)
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|
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|
|
|
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|
|
|
|
|
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|
|
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|
|
|
|
|
|
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|
|
|
|
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|
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|
|
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[Abstract]
[Full Text]
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
|
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|
|
|
|
|
|
|
R. Manfredini, R. Zini, S. Salati, M. Siena, E. Tenedini, E. Tagliafico, M. Montanari, T. Zanocco-Marani, C. Gemelli, T. Vignudelli, et al.
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496 - 506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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23(4):
561 - 574.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wysoczynski, R. Reca, J. Ratajczak, M. Kucia, N. Shirvaikar, M. Honczarenko, M. Mills, J. Wanzeck, A. Janowska-Wieczorek, and M. Z. Ratajczak
Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient
Blood,
January 1, 2005;
105(1):
40 - 48.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Brenner, N. Whiting-Theobald, T. Kawai, G. F. Linton, A. G. Rudikoff, U. Choi, M. F. Ryser, P. M. Murphy, J. M.G. Sechler, and H. L. Malech
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December 1, 2004;
22(7):
1128 - 1133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
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