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Transforming growth factor-beta potently inhibits the viability- promoting
activity of stem cell factor and other cytokines and induces apoptosis of
primitive murine hematopoietic progenitor cells
FW Jacobsen, T Stokke and SE Jacobsen
Department of Immunology, Biophysics, Norwegian Radium Hospital, Oslo,
Norway.
In contrast with the extensively characterized effects of transforming
growth factor-beta (TGF-beta) on proliferation and differentiation of
hematopoietic progenitors, little is known about the effects of TGF- beta
on viability of normal hematopoietic progenitors. In the present report, we
demonstrate that TGF-beta potently counteracts hematopoietic growth factor
(HGF)-induced survival of individually cultured primitive Lin-Sca-1+ bone
marrow progenitors. Specifically, 74% of single Lin-Sca- 1+ cells cultured
for 40 hours in the presence of stem cell factor (SCF) survived, whereas
only 16% survived in the presence of SCF plus TGF-beta. Similarly, the
enhanced survival of primitive hematopoietic progenitors in response to
granulocyte colony-stimulating factor (G- CSF), interleukin (IL)-1, IL-6,
or IL-11 was also potently opposed by TGF-beta. Furthermore, it is
demonstrated that neutralization of endogenous TGF-beta present in the
cultures enhances survival of Lin- Sca-1+ progenitors in the absence, as
well as in the presence, of HGFs such as SCF and IL-6. The reduced
HGF-induced survival of primitive hematopoietic progenitors in the presence
of TGF-beta was associated with increased apoptosis, as detected by an in
situ terminal deoxynucleotidyl transferase (TdT) assay. After 16 hours of
incubation in the absence of HGFs, 61% +/- 6% of the hematopoietic
progenitors had DNA strand breaks characteristic of apoptosis. The presence
of SCF reduced the frequency of apoptic cells to 27% +/- 5%, whereas 55%
+/- 3% of the cells had signs of apoptosis in the presence of SCF plus TGF-
beta.
Volume 86,
Issue 8,
pp. 2957-2966,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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