HEMATOPOIESIS CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34 stem/progenitor cells to bone marrow

tor cells (HSCs/HPCs) is regulated by chemokines, cytokines, proteolytic en-zymes, and adhesion molecules. We re-port that the adhesion receptor CD44 and its major ligand, hyaluronic acid (HA), are essential for homing into the bone mar-row (BM) and spleen of nonobese diabetic/ severe combined immunodeficient (NOD/ SCID) mice and engraftment by human HSCs. Homing was blocked by anti-CD44 monoclonal antibodies (mAbs) or by soluble HA, and it was significantly im-paired after intravenous injection of hyal-uronidase. Furthermore, stromal cell-derived factor-1 (SDF-1) was found to be a rapid and potent stimulator of progenitor adhesion to immobilized HA, leading to formation of actin-containing protrusions with CD44 located at their tips. HPCs migrating on HA toward a gradient of SDF-1 acquired spread and polarized mor-phology with CD44 concentrating at the pseudopodia at the leading edge. These morphologic alterations were not ob-served when the progenitors were first exposed to anti-CD44 mAbs, demonstrat-ing a crosstalk between CD44 and CXCR4 signaling. Unexpectedly, we found that HA is expressed on human BM sinusoidal endothelium and endosteum, the regions where SDF-1 is also abundant. Taken to-gether, our data suggest a key role for CD44 and HA in SDF-1–dependent transendothe-lial migration of HSCs/HPCs and their final anchorage within specific niches of the BM