Overexpression of the Mesenchymal Stem Cell Cxcr4 Gene in Irradiated Mice Increases the Homing Capacity of These Cells
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The efficiency of the intravascular delivery of mesenchymal stem cells (MSCs) homing to bone marrow has been largely limited. This study aimed to evaluate the homing efficacy in irradiated mice of MSCs that have been engineered to overexpress the murine Cxcr4 gene. Mouse MSCs were infected by a lentivirus vector carrying Cxcr4. MSC migration was detected by an in vitro transwell migration assay. EGFP-positive MSCs were systemically injected into BALB/c mice and detected in bone marrow samples by flow cytometry. The concentration of mouse stromal-derived factor 1 was detected by ELISA. The plasma concentration of the inflammatory cytokines, interleukin (IL)-6, IL-10, MCP-1, IFN-γ, TNF-α, and IL-12p70, were determined by cytometric bead array. MSCs that overexpressed Cxcr4 displayed enhanced migration toward a stromal-derived factor 1 gradient. The transplantation of Cxcr4-overexpressing MSCs into irradiated mice leads to increased homing to the bone marrow. Moreover, the frequency of the EGFP-positive cells in a bone marrow infusion 24 h after total body irradiation was 2.2-fold more than at 4 h after irradiation. The concentration of both plasma and bone marrow stromal-derived factor 1 increased after irradiation, and this was positively correlated with the number of Cxcr4-overexpressing MSCs homing to the bone marrow. Moreover, compared with the control groups, the plasma levels of IL-6, IFN-γ, TNF-α, and MCP-1 and IL-12p70 in recipients infused with Cxcr4-overexpressing MSCs was significantly decreased. The level of IL-10 was increased, which correlated with changes in the Th1 and Th2 subset balance. MSCs that overexpressed Cxcr4 and were injected into irradiated mice had an enhanced homing capacity which was related to the bone marrow level of stromal-derived factor 1.
KeywordsChemokine receptor 4 Lentivirus Mesenchymal stem cell Mice Stromal cell-derived factor 1 Total body irradiation
The authors wish to acknowledge CuiPing Zhang and GuoLiang Song (Xuzhou medical College) for their technical assistance. The authors would like to thank Inder M. Verma (Salk Institute, San Diego, CA, USA) for kindly providing the LV-lacz and Shohei Hori for MIGR-1. This article was proofread by a native English professional with science background at Elixigen Corporation. This study was supported by Grants from the National Natural Science Foundation of China (No. 30971281 to K. Xu) and the Xuzhou Science and Technology Project, China (No. XZZD1138 to M. Li).
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