title: MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1.
abstract: BACKGROUND
  Mobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs.
  
  
  METHODS
  We analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells.
  
  
  RESULTS
  We show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor.
  
  
  CONCLUSIONS
  Our results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.
authors.affiliation: Laboratory of Cellular Oncology, CCR, NCI, NIH, Bethesda, MD 20892, USA. salvucco@mail.nih.gov
authors.forename: Ombretta
authors.initials: O
authors.lastname: Salvucci
authors.forename: Kan
authors.initials: K
authors.lastname: Jiang
authors.forename: Paola
authors.initials: P
authors.lastname: Gasperini
authors.forename: Dragan
authors.initials: D
authors.lastname: Maric
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.forename: Shuhei
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Georgina
authors.initials: G
authors.lastname: Espigol-Frigole
authors.forename: Shushang
authors.initials: S
authors.lastname: Wang
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tosato
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D022162:Cytoplasmic Vesicles / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology
chemical_list: C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs; D019010:Vascular Cell Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor