title: Modulation of homing properties of primitive progenitor cells generated by ex vivo expansion.
abstract: OBJECTIVE
  The maintenance of adequate interactions with the bone marrow (BM) microenvironment is critical to ensure efficient homing of ex vivo-expanded hematopoietic cells. This study was intended to assess adhesion and migration properties of long-term culture-initiating cells (LTC-IC) harvested after self-renewal division in ex vivo culture and to determine their susceptibility to growth-inhibitory signals mediated by adhesion to BM stromal ligands.
  
  
  METHODS
  We used cell tracking to isolate primitive LTC-IC that had accomplished 1 or 2 divisions ex vivo. Adhesion, migration and growth inhibition of divided LTC-IC were determined in the presence of purified BM ligands, and compared to the properties of uncultured LTC-IC.
  
  
  RESULTS
  As compared to undivided LTC-IC, adhesion and migration mediated by very late antigen (VLA)-4 integrin across both vascular cell adhesion molecule-1 (VCAM-1) and fibronectin (Fn) were downregulated in post-mitotic LTC-IC. Conversely, binding and motility via VLA-5 across Fn were stimulated. No changes occurred in LTC-IC interactions with intercellular adhesion molecule-1 (ICAM-1) or with E- or P-selectin. Proliferation of uncultured LTC-IC was inhibited by VLA-4-mediated binding to VCAM-1 and the CS-1 domain of Fn, as well as binding to P-selectin. Growth of ex vivo-generated LTC-IC became unresponsive to these 3 ligands but was suppressed through VLA-5 engagement by the cell binding domain of Fn.
  
  
  CONCLUSIONS
  The generation of LTC-IC in expansion culture is associated with functional alterations of adhesion receptors, modulating not only binding and migration in the BM but also responsiveness to adhesion-mediated growth inhibitory signals. Such changes may limit homing and engraftment of expanded primitive stem/progenitor cells.
authors.affiliation: Department of Medicine/Hematology, University of Liège, Liège, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Foguenne
authors.forename: Sandra
authors.initials: S
authors.lastname: Huygen
authors.forename: Roland
authors.initials: R
authors.lastname: Greimers
authors.forename: Yves
authors.initials: Y
authors.lastname: Beguin
authors.forename: André
authors.initials: A
authors.lastname: Gothot
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000097:blood; D001853:Bone Marrow; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D015536:Down-Regulation; D005353:Fibronectins / Q000378:metabolism; D006023:Glycoproteins / Q000097:blood; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D039041:Integrin alpha4beta1 / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008938:Mitosis / Q000502:physiology; D010455:Peptides / Q000097:blood; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D006023:Glycoproteins; D039041:Integrin alpha4beta1; D010455:Peptides; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1