Decreased homing of retrovirally transduced human bone marrow CD34+ cells in the NOD/SCID mouse model.

Abstract:

OBJECTIVE:Many clinical gene therapy trials have described poor engraftment of retrovirally transduced CD34(+) cells. Because engraftment is dependent upon successful homing of graft cells to the bone marrow (BM), we examined whether retroviral-mediated gene transfer (RMGT) induces a homing defect in CD34(+) cells. METHODS:Homing of fluorescently labeled human BM CD34(+) cells transduced with three separate retroviral vectors (MFG-eGFP, LNC-eGFP, and LXSN) was assessed in nonobese diabetic/severe combined immunodeficient mice. RESULTS:Homing of transduced CD34(+) cells was significantly decreased 20 hours after transplantation compared with freshly isolated control and cultured untransduced control cells. Specifically, homing of GFP(+) cells in the graft was preferentially decreased thus skewing the contribution of transduced cells to engraftment. Transduced cells were not selectively trapped in other organs and BM-homed transduced cells did not undergo apoptosis at a higher rate than untransduced cells. Adhesion molecule expression and binding activity was not altered by RMGT. This homing defect was reversed when transduced cells were cultured over CH-296 for 2 additional days with SCF only. CONCLUSION:These data suggest that RMGT of hematopoietic cells may compromise their homing potential and implicate transduction-induced reduced homing in the observed low engraftment of retrovirally transduced CD34(+) cells. These results may have a direct clinical application in gene therapy protocols.

journal_name

Exp Hematol

journal_title

Experimental hematology

authors

Hall KM,Horvath TL,Abonour R,Cornetta K,Srour EF

doi

10.1016/j.exphem.2005.12.014

keywords:

subject

Has Abstract

pub_date

2006-04-01 00:00:00

pages

433-42

issue

4

eissn

0301-472X

issn

1873-2399

pii

S0301-472X(05)00582-5

journal_volume

34

pub_type

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