-Original-

Dextran Sulfate and Stromal Cell Derived Factor-1 Promote CXCR4 Expression and Improve Bone Marrow Homing Efficiency of Infused Hematopoietic Stem Cells

Jun Hayakawa¹, Makoto Migita^1-3, Takahiro Ueda¹, Ryuji Fukazawa¹, Kumi Adachi^2,3, Yuki Ooue¹, Mari Hayakawa¹, Takashi Shimada^2,3 and Yoshitaka Fukunaga¹

¹Department of Pediatrics, Graduate School of Medicine, Nippon Medical School
²Department of Molecular and Medical Genetics, Graduate School of Medicine, Nippon Medical School
³Division of Gene Therapy Research, Center for Advanced Medical Technology

Although the homing of hematopoietic stem cells (HSC) to the bone marrow (BM) is a crucial step in hematopoietic development and BM repopulation, the mechanisms underlying these processes have not been fully clarified. Recent studies suggest that interaction between the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor 1 (SDF-1), plays a critical role in these processes. In addition, dextran sulfate increases plasma SDF-1 levels in mice and nonhuman primates. Thus, we examined the effects of preconditioning with SDF-1 and dextran sulfate on the homing efficiency of HSCs following BM transplantation in mice. We found that the preconditioning of donor mice with either SDF-1 or dextran sulfate enhanced the homing efficiency of infused HSCs in vivo. The greatest effects were obtained with dextran sulfate. Moreover, reverse transcriptase polymerase chain reaction analysis demonstrated that SDF-1 and dextran sulfate increased transcription of a variety of homing-related genes, including those for CXCR4, lymphocyte function associated antigen-1, matrix metalloproteinase-9, very late antigen-4/5, and macrophage inflammatory protein-1. We suggest that whereas SDF-1 directly acts to upregulate CXCR4 expression in HSCs, dextran sulfate acts via multiple pathways involved in the induction of various homing-related molecules, in addition to SDF-1. Thus, preconditioning donors with dextran sulfate offers a novel clinical approach for improving the homing and engraftment of HSCs in the BM.

J Nippon Med Sch 2009; 76: 198-208

Keywords
stromal cell-derived factor 1, dextran sulfate, CXCR4, bone marrow transplantation, hematopoietic stem cells

Correspondence to
Makoto Migita, MD, PhD, Department of Pediatrics, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan
mmigita@nms.ac.jp

Received, February 21, 2008
Accepted, March 23, 2009