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Cytokine regulation of proliferation and cell adhesion are correlated
events in human CD34+ hemopoietic progenitors
JP Levesque, DN Haylock and PJ Simmons
Department of Haematology, Hanson Centre for Cancer Research,
Adelaide,Australia.
Adhesive interactions with the extracellular matrix of the bone marrow (BM)
stroma are of critical importance in the regulation of hematopoiesis. In
part, these interactions are presumed to play an important role in
retaining CD34+ hematopoietic progenitor cells (HPCs) within the BM
environment, in close proximity with BM stromal cells and the cytokines
they produce. Evidence of a more direct role for cell adhesion in the
regulation of hematopoiesis is provided by recent data showing that
adhesive interactions can also provide important costimulatory signals. We
have previously shown that normal CD34+ HPCs express high levels of
fibronectin (Fn) receptors very late antigen-4 (VLA-4) and VLA-5 in a
low-affinity state, which do not allow HPCs to strongly adhere on
immobilized Fn, and that cytokines such as interleukin-3,
granulocyte-monocyte colony-stimulating factor, and stem cell factor
transiently activate these receptors, providing HPCs with an adhesive
phenotype on Fn. Thus, knowledge of the functional states of adhesion
receptors is critical to our understanding of the physiological mechanisms
responsible for the regulation of normal hematopoiesis. Herein, we show
that combinations of cytokines that synergize to stimulate the
proliferation of CD34+ HPCs result in additive stimulation of the adhesion
of these cells to Fn. Thus, the activation level of Fn receptors expressed
by normal CD34+ HPCs is highly correlated with their proliferative state,
suggesting a functional link between these two events. Therefore, we
propose a 2- step model with an initial activation of VLA-4 and VLA-5
generated by cytokine receptors that is followed by a secondary signal
resulting from Fn binding to VLA-4 and VLA-5, which may cooperate with
those generated by cytokine receptors.
Volume 88,
Issue 4,
pp. 1168-1176,
08/15/1996
Copyright © 1996 by The American Society of Hematology
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