Monoclonal antibody crosslinking of the α4 or β1 integrin inhibits committed clonogenic hematopoietic progenitor proliferation

R. W. Hurley, J. B. McCarthy, E. A. Wayner, C. M. Verfaillie

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Adhesion receptors can serve as primary signal transduction molecules that convey information into cells that can affect cell proliferation and differentiation. Since hematopoietic progenitors adhere to marrow stroma and fibronectin via the α4β1 integrin and CD44, we examined the role of these receptors in the transfer of proliferation-regulatory signals to progenitors. Actively proliferating colony-forming cells (CFCs) present in cultured CD34+ cells were incubated with mouse monoclonal antibodies against the α4, β1, or CD44 receptors and crosslinking was performed with a secondary goat-anti-mouse antibody. The effect on CFC proliferation was examined with a 3H thymidine suicide assay. Compared with controls (39 to 51% kill), crosslinking the α4 or β1 integrins significantly reduced CFC proliferation (12 to 26% kill, p = 0.01), indicating that proliferation-inhibitory signals are transmitted through the VLA-4 integrin. Cytochalasin D, a compound that prevents actin polymerization, prevented not only α4 receptor capping, but also the inhibition of CFC proliferation observed following α4 crosslinking. However, crosslinking of the CD44 receptor with the antibodies Hermes-3 and 50B4, which inhibit adhesion of CFC to fibronectin, failed to cap the CD44 receptor in the majority of CD34+ cells. Furthermore, crosslinking of the CD44 receptor with these antibodies also failed to inhibit proliferation of CFCs. These studies demonstrate that adhesion receptor crosslinking of the α4β1 integrin, together with subsequent changes in F-actin polymerization, negatively regulates hematopoietic progenitor proliferation in a manner independent of the shape change associated with adhesion.

Original languageEnglish (US)
Pages (from-to)321-328
Number of pages8
JournalExperimental Hematology
Volume25
Issue number4
StatePublished - 1997

Keywords

  • actin
  • cell division
  • hematopoiesis
  • integrins
  • receptor aggregation

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