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Mechanisms that regulate the cell cycle status of very primitive
hematopoietic cells in long-term human marrow cultures. I. Stimulatory role
of a variety of mesenchymal cell activators and inhibitory role of TGF-beta
JD Cashman, AC Eaves, EW Raines, R Ross and CJ Eaves
Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver,
Canada.
Long-term marrow cultures (LTMC) allow the proliferation and
differentiation of primitive human hematopoietic progenitor cells to be
maintained for many weeks in the absence of exogenously provided
hematopoietic growth factors. Previous investigations focused on defining
various types of cells that are present in this culture system and on
measuring the cycling behavior of the different subpopulations of
colony-forming cells maintained within it. These studies suggested that
mesenchymal stromal elements derived from the input marrow play a key role
in regulating the turnover of the most primitive, high- proliferative
potential erythroid and granulopoietic colony-forming cells that are found
almost exclusively in the adherent layer of LTMC. In this study we show
that the re-entry into S-phase of these primitive hematopoietic progenitors
that occurs after each weekly medium change is due to an as yet undefined
constituent of horse serum, which is absent from fetal calf serum. However,
this effect is not unique to the factor present in horse serum. It is also
elicited by the addition to LTMC of several well-defined growth regulatory
molecules, ie, platelet- derived growth factor (PDGF), interleukin-1
(IL-1), transforming growth factor alpha (TGF-alpha), and IL-2. None of
these was able to stimulate hematopoietic colony-forming cells in
methylcellulose assays, although all have known actions on mesenchymal
cells including, in some cases, the ability to increase production of
growth factors that can stimulate primitive high-proliferative potential
hematopoietic progenitors in clonogenic assays. Interestingly, a
stimulating effect was not obtained after addition of endotoxin to LTMC.
TGF-beta, a direct-acting negative regulator that acts selectively on
primitive hematopoietic progenitor cells if added to LTMC simultaneously
with new medium or IL-1, blocked their stimulating activity. These results
suggest a model in which indirect, local modulation of both positive and
negative regulatory factors via effects on mesenchymal elements determines
the rate of turnover of adjacent populations of very primitive
hematopoietic cells that are normally maintained in a quiescent state in
vivo.
Volume 75,
Issue 1,
pp. 96-101,
01/01/1990
Copyright © 1990 by The American Society of Hematology
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