title: CD44 and hyaluronic acid cooperate with SDF-1 in the trafficking of human CD34+ stem/progenitor cells to bone marrow.
abstract: Trafficking of human CD34+ stem/progenitor cells (HSCs/HPCs) is regulated by chemokines, cytokines, proteolytic enzymes, and adhesion molecules. We report that the adhesion receptor CD44 and its major ligand, hyaluronic acid (HA), are essential for homing into the bone marrow (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 impaired after intravenous injection of hyaluronidase. 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 morphology with CD44 concentrating at the pseudopodia at the leading edge. These morphologic alterations were not observed when the progenitors were first exposed to anti-CD44 mAbs, demonstrating 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 together, our data suggest a key role for CD44 and HA in SDF-1-dependent transendothelial migration of HSCs/HPCs and their final anchorage within specific niches of the BM.
authors.affiliation: Immunology Department, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Abraham
authors.initials: A
authors.lastname: Avigdor
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Shoham
authors.initials: S
authors.lastname: Shivtiel
authors.forename: Ayelet
authors.initials: A
authors.lastname: Dar
authors.forename: Amnon
authors.initials: A
authors.lastname: Peled
authors.forename: Sarit
authors.initials: S
authors.lastname: Samira
authors.forename: Orit
authors.initials: O
authors.lastname: Kollet
authors.forename: Rami
authors.initials: R
authors.lastname: Hershkoviz
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
authors.forename: Izhar
authors.initials: I
authors.lastname: Hardan
authors.forename: Herzl
authors.initials: H
authors.lastname: Ben-Hur
authors.forename: David
authors.initials: D
authors.lastname: Naor
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018952:Antigens, CD34 / Q000378:metabolism*; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology*; D002633:Chemotaxis; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D018952:Antigens, CD34; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid