title: Adhesion of committed human hematopoietic progenitors to synthetic peptides from the C-terminal heparin-binding domain of fibronectin: cooperation between the integrin alpha 4 beta 1 and the CD44 adhesion receptor.
abstract: Close interaction of human hematopoietic progenitors with the bone marrow microenvironment is important for the ordered progression of human hematopoiesis. Progenitor cell adhesion to stroma has a complex molecular basis, involving various cell-extracellular matrix and cell-cell interactions. We have previously shown that adhesion of colony-forming cells (CFC) to fibronectin, present in stromal extracellular matrix, involves multiple sites, including two heparin-binding synthetic peptides (FN-C/H I and FN-C/H II) and the alpha 4 beta 1 integrin-binding peptide CS1. These synthetic peptides are located in close proximity in the type III repeat 14 and the immediately adjacent type IIIcs region of fibronectin. In the current study, we evaluate receptors expressed by CFC responsible for their adhesion to fibronectin. We show that the alpha 4 beta 1 integrin mediates adhesion to CFC to the peptides FN-C/H I and CS1. Adhesion of CFC to fibronectin is also mediated by proteoglycans, because removal of cell surface chondroitin-sulfate proteoglycans resulted in decreased adhesion of CFC to FN-C/ I and FN-C/H II. The core protein of this proteoglycan was identified by immunoprecipitation as a 90-kD member of the CD44 group of adhesion molecules. Interestingly, although the proteoglycan core protein failed to adhere to FN-C/H II affinity columns, anti-CD44 monoclonal antibodies blocked CFC adhesion to FN-C/H II, indicating that these monoclonal antibodies may interfere with core protein-mediated intracellular signalling. Finally, we show that CD44 and alpha 4 beta 1 may cooperate in establishing progenitor adhesion, because anti-CD44 antibodies potentiated the adhesion-inhibitory effects of suboptimal concentrations of anti-alpha 4 or anti-beta 1 monoclonal antibodies. These results provide a working model for progenitor cell recognition of fibronectin (and possibly the marrow micro-environment) in which the coordinated action of integrins and cell surface proteoglycans is necessary for cell adhesion. This model can now be used to study the complex relationship between progenitor cell adhesion and the regulation of their proliferation and differentiation.
authors.affiliation: Department of Medicine, University of Minnesota, Minneapolis.
authors.forename: C M
authors.initials: CM
authors.lastname: Verfaillie
authors.forename: A
authors.initials: A
authors.lastname: Benis
authors.forename: J
authors.initials: J
authors.lastname: Iida
authors.forename: P B
authors.initials: PB
authors.lastname: McGlave
authors.forename: J B
authors.initials: JB
authors.lastname: McCarthy
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001665:Binding Sites; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism*; D002448:Cell Adhesion; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005353:Fibronectins / Q000737:chemistry / Q000378:metabolism*; D006098:Granulocytes / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006493:Heparin / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism*; D046911:Macromolecular Substances; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D016201:Receptors, Lymphocyte Homing / Q000276:immunology / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D005353:Fibronectins; D018960:Hyaluronan Receptors; D039041:Integrin alpha4beta1; D016023:Integrins; D046911:Macromolecular Substances; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D016201:Receptors, Lymphocyte Homing; D006493:Heparin