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Overexpression of CXCR4 on human CD34(+) progenitors increases their proliferation, migration, and NOD/SCID repopulation

Kahn, J; Byk, T; Jansson Sjöstrand, Lottie LU ; Petit, I; Shivtiel, S; Nagler, A; Hardan, I; Deutsch, V; Gazit, Z and Gazit, D, et al. (2004) In Blood 103(8). p.2942-2949
Abstract
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 SDIF-1-induced migration and... (More)
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 SDIF-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. (Less)
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publishing date
type
Contribution to journal
publication status
published
subject
in
Blood
volume
103
issue
8
pages
2942 - 2949
publisher
American Society of Hematology
external identifiers
  • wos:000222163500023
  • pmid:15070669
  • scopus:11144356195
ISSN
1528-0020
DOI
10.1182/blood-2003-07-2607
language
English
LU publication?
yes
id
ec5ac67e-2ca5-48bc-8ca7-2e61ccdcff9a (old id 274958)
date added to LUP
2007-10-23 15:23:50
date last changed
2017-09-24 03:37:45
@article{ec5ac67e-2ca5-48bc-8ca7-2e61ccdcff9a,
  abstract     = {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 SDIF-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.},
  author       = {Kahn, J and Byk, T and Jansson Sjöstrand, Lottie and Petit, I and Shivtiel, S and Nagler, A and Hardan, I and Deutsch, V and Gazit, Z and Gazit, D and Karlsson, Stefan and Lapidot, T},
  issn         = {1528-0020},
  language     = {eng},
  number       = {8},
  pages        = {2942--2949},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Overexpression of CXCR4 on human CD34(+) progenitors increases their proliferation, migration, and NOD/SCID repopulation},
  url          = {http://dx.doi.org/10.1182/blood-2003-07-2607},
  volume       = {103},
  year         = {2004},
}