Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: Role in homing efficiency in NOD/SCID mice

Abstract

Background and Objectives: The use of mesenchymal stem cells (MSC) for cell therapy relies on the capacity of these cells to home and engraft long-term into the appropriate target tissue(s). Homing of MSC to bone marrow (BM) post-transplantation can occur, but does so with only poor efficiency. This study was designed to evaluate the role of the SDF-1/CXCR4 axis in the homing of Flk1 + MSC derived from human fetal BM. Design and Methods: We investigated the expression of CXCR4 in Flk1 + MSC stimulated with a cytokine cocktail and explored their homing ability 24 hours after intravenous infusion into sublethally irradiated NOD/SCID mice. The peripheral blood was analyzed and human cells in recipients' BM were quantified from 2 to 6 months after transplantation. Results: We found that Flk1 + MSC harbored intracellular CXCR4 which can be rapidly induced to the cell surface within a few hours. Short-term (24 hours) stimulation with the cocktail of cytokines resulted in up-regulation of both cell surface and intracellular CXCR4, increasing in vitro migration capacity to SDF-1 and homing to the BM of irradiated NOD/SCID mice. Moreover, compared to non-treated cells, transplantation of cytokine-treated Flk1 + MSC resulted in faster hematologic recovery and higher levels of donor chimerism in BM. Neutralization of CXCR4 significantly reduced homing and engraftment of Flk1 + MSC in murine BM. Interpretation and Conclusions: These results suggest that the SDF-1/CXCR4 axis plays an important role in the regulation of motility of Flk1 + MSC. Increasing CXCR4 expression might be a potential strategy to improve engraftment of MSC in BM and accelerate the recovery of hematopoiesis. ©2007 Ferrata Storti Foundation.