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The action of bryostatin on normal human hematopoietic progenitors is
mediated by accessory cell release of growth factors
SJ Sharkis, RJ Jones, ML Bellis, GD Demetri, JD Griffin, C Civin and WS May
Johns Hopkins Oncology Center, Baltimore, MD 21205.
Since enrichment of human bone-marrow hematopoietic progenitors is becoming
more feasible and since purified growth factors are now available, we
sought to study the action of growth factors on CD34- positive enriched
cultures of human bone-marrow cells. We tested the effect of recombinant
human (rh) granulocyte-macrophage colony- stimulating factor (GM-CSF), rh
interleukin-3 (IL-3), or a unique biologic response modifier, bryostatin 1,
on the growth of purified CD34 cells obtained by limiting dilution in
single-cell cultures. We have shown previously that bryostatin 1 stimulates
both myeloid and erythroid progenitors of human origin in vitro. In this
study both IL-3 and GM-CSF supported colony formation from 500, 100, or
single-cell cultures at equivalent plating efficiences, suggesting a direct
action of these factors on hematopoietic cell growth. Conversely,
bryostatin 1 did not support the growth of CD34 cells in single-cell
cultures, and the cloning efficiency increased with increasing the number
of cells in the culture. To test whether the indirect action of bryostatin
1 might be mediated through the production of growth factors by accessory
cells, studies were performed using antibodies directed against human IL-3
and GM-CSF in culture with bryostatin 1 and normal human bone- marrow
cells. Results are consistent with the hypothesis that bryostatin 1 could
have a stimulatory effect on the accessory cell populations to produce
either IL-3 or GM-CSF. Further support for this notion was obtained by
demonstrating that T cells, which are cells known to be able to produce
IL-3 and GM-CSF, are stimulated by bryostatin 1 to express messenger RNA
(mRNA) for specific growth factors, including GM-CSF. These results provide
further support that bryostatin 1 may be a useful clinical agent to
stimulate hematopoiesis in vivo.
Volume 76,
Issue 4,
pp. 716-720,
08/15/1990
Copyright © 1990 by The American Society of Hematology
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