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Mechanisms that regulate the cell cycle status of very primitive
hematopoietic cells in long-term human marrow cultures. II. Analysis of
positive and negative regulators produced by stromal cells within the
adherent layer
CJ Eaves, JD Cashman, RJ Kay, GJ Dougherty, T Otsuka, LA Gaboury, DE Hogge, PM Lansdorp, AC Eaves and RK Humphries
Terry Fox Laboratory, B.C. Cancer Agency, Vancouver, Canada.
Numerous factors that can influence the proliferation and differentiation
in vitro of cells at various stages of hematopoiesis have been identified,
but the mechanisms used by stromal cells to regulate the cycling status of
the most primitive human hematopoietic cells are still poorly understood.
Previous studies of long-term cultures (LTC) of human marrow have suggested
that cytokine-induced variations in stromal cell production of one or more
stimulators and inhibitors of hematopoiesis may be important. To identify
the specific regulators involved, we performed Northern analyses on RNA
extracted from human marrow LTC adherent layers, or stromal cell types
derived from or related to those present in the adherent layer. These
analyses showed marked increases in interleukin-1 beta (IL-1 beta), IL-6,
and granulocyte colony-stimulating factor (G-CSF) mRNA levels within 8
hours after treatments that lead to the activation within 2 days of
primitive hematopoietic progenitors in such cultures. Increases in
granulocyte-macrophage (GM)-CSF and M-CSF mRNA were also sometimes seen.
Bioassays using cell lines responsive to G-CSF, GM-CSF, and IL-6 showed
significant elevation in growth factor levels 24 hours after IL- 1 beta
stimulation. Neither IL-3 nor IL-4 mRNA was detectable at any time. In
contrast, transforming growth factor-beta (TGF-beta) mRNA and nanogram
levels of TGF-beta bioactivity in the medium were detected at all times in
established LTC, and these levels were not consistently altered by any of
the manipulations that stimulated hematopoietic growth factor production
and primitive progenitor cycling. We also found that addition of
anti-TGF-beta antibody could prolong or reactivate primitive progenitor
proliferation when added to previously stimulated or quiescent cultures,
respectively. Together, these results indicate a dominant negative
regulatory role of endogenously produced TGF-beta in unperturbed LTC, with
activation of primitive hematopoietic cells being achieved by mechanisms
that stimulate stromal cells to produce G-CSF, GM-CSF, and IL-6. Given the
similarities between the LTC system and the marrow microenvironment, it
seems likely that the control of human stem cell activation in vivo may
involve similar variations in the production of these factors by stromal
cells.
Volume 78,
Issue 1,
pp. 110-117,
07/01/1991
Copyright © 1991 by The American Society of Hematology
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