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Human umbilical vein endothelial cells display high-affinity c-kit
receptors and produce a soluble form of the c-kit receptor
VC Broudy, NL Kovach, LG Bennett, N Lin, FW Jacobsen and PG Kidd
Department of Medicine, University of Washington, Seattle 98195.
Stem cell factor (SCF) is a hematopoietic growth factor produced by
fibroblasts and endothelial cells that stimulates the growth of primitive
hematopoietic cells. SCF triggers cell growth by binding to the c-kit
receptor. Because endothelial cells can respond to certain hematopoietic
growth factors, we tested human umbilical vein endothelial cells for
display of the c-kit receptor and examined the effect of SCF on endothelial
cell proliferation, adhesion molecule expression, and production of tissue
factor. Quantitative binding experiments with 125I-SCF showed both
high-affinity (Kd = 42 pmol/L) and low-affinity (Kd = 1.7 nmol/L) c-kit
receptors. There were approximately 1,100 high-affinity c-kit receptors,
and 5,400 low- affinity c-kit receptors per endothelial cell. Enzyme
immunoassays showed that endothelial cells released soluble c-kit receptor
and SCF. The transmembrane form of SCF was detected by indirect
immunofluorescence analysis using monoclonal or polyclonal anti-SCF
receptor antibodies. The addition of SCF (100 ng/mL) did not alter
endothelial cell proliferation over a 7-day period. Similarly, there was no
change in the release of tissue factor or expression of inducible
endothelial adhesion molecules (intercellular adhesion molecule-1,
endothelial-leukocyte adhesion molecule-1, and vascular cell adhesion
molecule-1) measured by enzyme-linked immunosorbant assay at 4 and 24 hours
after SCF addition. The neutralizing anti-c-kit receptor monoclonal
antibody SR-1 blocked binding of 125I-SCF to the c- kit receptor by 98% but
did not alter endothelial cell proliferation or adhesion-molecule
expression. c-kit receptors were also detected on adult endothelial cells
lining small blood vessels in normal human lymph nodes. These data indicate
that normal human endothelial cells produce SCF and show high-affinity
c-kit receptors that have the capacity to dimerize. The lack of response to
exogenous SCF may be because of intracellular activation of the c-kit
receptor via autocrine production of SCF. Alternatively, SCF and c-kit may
play a role other than stimulation of proliferation, adhesion-molecule
display, or tissue factor production by endothelial cells. The production
of soluble c-kit receptors by normal human endothelial cells may serve to
regulate the bioactivity of SCF within the bone marrow microenvironment.
Volume 83,
Issue 8,
pp. 2145-2152,
04/15/1994
Copyright © 1994 by The American Society of Hematology
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