The Effect of CXCR4 Overexpression on Mesenchymal Stem Cell Transplantation in Ischemic Stroke.

Abstract

There is no doubt that the therapeutic efficacy of mesenchymal stem cells (MSCs) needs improvement. SDF-1 (chemokine for MSC homing) and its receptor CXCR4 play a critical role in the migration of MSCs in ischemia. We investigated the effects of the therapeutic application of MSCs transfected to overexpress CXCR4 using an adenoviral construct in the rat stroke model. Both flow cytometry and Western blot analysis indicated that the level of CXCR4 expression was low in naive hMSCs but was consistently high in CXCR4-hMSCs. In vivo migration test using the transwell system showed that the degree of migration was increased in CXCR4-hMSCs compared with the naive hMSCs and was completely blocked by treatment with AMD3100, an antagonist of the CXCR4 receptor. Compared with rats that received naive MSCs, behavioral recovery was more pronounced in rats that received CXCR4-hMSCs (p = 0.023). An immunohistochemistry study using human nuclear antibody (NuMA) showed that the migration of hMSCs in the ischemic boundary zone was increased after 3 days of injection of CXCR4-hMSCs compared with after injection of naive hMSCs. In addition, polymerase chain reaction was performed to assess the biodistribution of human-specific DNA outside the brain after intravenous injection of hMSCs. The expression of human-specific DNA was increased in the lungs of rats receiving naive MSCs, whereas the human-specific DNA expression was increased in the brain of rats receiving CXCR4-hMSCs. Our results indicate that MSCs transfected with the CXCR4 gene expression cassette may be useful in the treatment of cerebral infarction and may represent a new strategy to enhance the efficacy of MSC therapy.