title: Migration of human hematopoietic progenitor cells across bone marrow endothelium is regulated by vascular endothelial cadherin.
abstract: The success of stem cell transplantation depends on the ability of i.v. infused stem cells to engraft the bone marrow, a process referred to as homing. Efficient homing requires migration of CD34(+) cells across the bone marrow endothelium, most likely through the intercellular junctions. In this study, we show that loss of vascular endothelial (VE)-cadherin-mediated endothelial cell-cell adhesion increases the permeability of monolayers of human bone marrow endothelial cells (HBMECs) and stimulates the transendothelial migration of CD34(+) cells in response to stromal cell-derived factor-1alpha. Stromal cell-derived factor-1alpha-induced migration was dependent on VCAM-1 and ICAM-1, even in the absence of VE-cadherin function. Cross-linking of ICAM-1 to mimic the leukocyte-endothelium interaction induced actin stress fiber formation but did not induce loss of endothelial integrity, whereas cross-linking of VCAM-1 increased the HBMEC permeability and induced gaps in the monolayer. In addition, VCAM-1-mediated gap formation in HBMEC was accompanied by and dependent on the production of reactive oxygen species. These data suggest that modulation of VE-cadherin function directly affects the efficiency of transendothelial migration of CD34(+) cells and that activation of ICAM-1 and, in particular, VCAM-1 plays an important role in this process through reorganization of the endothelial actin cytoskeleton and by modulating the integrity of the bone marrow endothelium through the production of reactive oxygen species.
authors.affiliation: Department of Experimental Immunohematology, CLB and Laboratory for Experimental and Clinical Immunology, and Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jaap D
authors.initials: JD
authors.lastname: van Buul
authors.forename: Carlijn
authors.initials: C
authors.lastname: Voermans
authors.forename: Veronique
authors.initials: V
authors.lastname: van den Berg
authors.forename: Eloise C
authors.initials: EC
authors.lastname: Anthony
authors.forename: Frederik P J
authors.initials: FP
authors.lastname: Mul
authors.forename: Sandra
authors.initials: S
authors.lastname: van Wetering
authors.forename: C Ellen
authors.initials: CE
authors.lastname: van der Schoot
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
mesh_terms: D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis; D001853:Bone Marrow / Q000502:physiology*; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000502:physiology*; D004727:Endothelium / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D017629:Gap Junctions / Q000378:metabolism / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D010539:Permeability; D017382:Reactive Oxygen Species / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D015820:Cadherins; D018799:Intercellular Adhesion Molecule-1; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D020741:rho GTP-Binding Proteins; D000099152:Cadherin 5