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

Close interaction of human hematopoietic progenitors with the bone mar row microenvironment is important for the ordered progression of human hematopoiesis. Progenitor cell adhesion to stroma has a complex molec ular 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 pepti des (FN-C/H I and FN-C/H II) and the alpha 4 beta 1 integrin-binding p eptide 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 th e 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 prot eoglycans, because removal of cell surface chondroitin-sulfate proteog lycans resulted in decreased adhesion of CFC to FN-C/H I and FN-C/H II . The core protein of this proteoglycan was identified by immunoprecip itation as a 90-kD member of the CD44 group of adhesion molecules. Int erestingly, although the proteoglycan core protein failed to adhere to FN-C/H II affinity columns, anti-CD44 monoclonal antibodies blocked C FC adhesion to FN-C/H II, indicating that these monoclonal antibodies may interfere with core protein-mediated intracellular signalling. Fin ally, we show that CD44 and alpha 4 beta 1 may cooperate in establishi ng progenitor adhesion, because anti-CD44 antibodies potentiated the a dhesion-inhibitory effects of suboptimal concentrations of anti-alpha 4 or anti-beta 1 monoclonal antibodies. These results provide a workin g model for progenitor cell recognition of fibronectin (and possibly t he marrow microenvironment) in which the coordinated action of integri ns and cell surface proteoglycans is necessary for cell adhesion. This model can now be used to study the complex relationship between proge nitor cell adhesion and the regulation of their proliferation and diff erentiation. (C) 1994 by The American Society of Hematology.