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Early CD34high cells can be separated into KIThigh cells in which
transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow
cells in which anti-TGF-beta upmodulates c-kit
P Sansilvestri, AA Cardoso, P Batard, B Panterne, A Hatzfeld, B Lim, JP Levesque, MN Monier and J Hatzfeld
Centre National de la Recherche Scientifique UPR 9044, Villejuif, France.
We have previously shown that early human CD34high hematopoietic
progenitors are maintained quiescent in part through autocrine transforming
growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the
presence of interleukin-3, interleukin-6, granulocyte colony-stimulating
factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or
anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor
[SF]), which suggests that they control different pathways of regulation in
these conditions. This finding also suggests that autocrine TGF-beta 1
might suppress c-kit expression in primitive human hematopoietic
progenitors. We have now distinguished two subpopulations of CD34high
cells. One subpopulation expresses a c- kit mRNA that can be downmodulated
by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early
CD34high cells expresses a low or undetectable level of c-kit mRNA, but its
expression can be upmodulated within 6 hours by anti-TGF-beta. These
effects disappear 48 hours after induction and cannot be maintained longer
than 72 hours, even if TGF- beta 1 or anti-TGF-beta serum are added every
day. Similar kinetics, although delayed, are observed with KIT protein
expression. On the contrary, no specific effect of TGF-beta 1 was observed
on c-fms, GAPDH, and transferrin receptor gene expression in these early
progenitors. These results clarify the complex interaction between TGF-
beta 1 and SF in normal early hematopoietic progenitors. SF does not switch
off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to
maintain these cells in a quiescent state, suppressing cell division by
downmodulating the receptor of SF, a key cytokine costimulator of early
progenitors.
Volume 86,
Issue 5,
pp. 1729-1735,
09/01/1995
Copyright © 1995 by The American Society of Hematology
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