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

• Published in: Haematologica (Roma) 2007-07, Vol.92 (7), p.897-904
• Main Authors: Shi, Mingxia, Li, Jing, Liao, Lianming, Chen, Bin, Li, Bingzong, Chen, Lei, Jia, Hairong, Zhao, Robert Chunhua
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Movement; Cytokines - pharmacology; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Humans; Medical sciences; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells - physiology; Mice; Mice, SCID; Receptors, CXCR4 - genetics; Transplantation, Heterologous
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.10669

From the Institute of Basic Medical Sciences and School of Basic Medicine, Center of Excellence in Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China (MS, JL, LL, BC, BL, RCZ); State Key Lab of Experimental Haematology, Institute of Haematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences (LC, HJ, RZC) Peking Union Medical College, Tianjin 300020, China (MS) Correspondence: Robert Chunhua Zhao, M.D., Ph.D., Professor of Institute of Basic Medical Sciences and School of Basic Medicine, Director of Center for Tissue Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dongdansantiao, Beijing 100005, P.R. China. E-mail: chunhuaz{at}public.tpt.tj.cn 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. Key words: mesenchymal stem cells, ho