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Differential regulation of primitive human hematopoietic cells in long-
term cultures maintained on genetically engineered murine stromal cells
HJ Sutherland, CJ Eaves, PM Lansdorp, JD Thacker and DE Hogge
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, Canada.
Various growth factors are known to stimulate both early and late stages of
human hematopoietic cell development in semisolid assay systems, but their
role as microenvironmental regulators is poorly understood. To address this
problem, we developed a novel coculture system in which highly purified
primitive human hematopoietic cells were seeded onto an irradiated feeder
layer of cells from a murine marrow-derived stromal cell line (M2-10B4)
previously engineered by retroviral-mediated gene transfer to produce
specific human factors. Effects on cells at very early, intermediate, and
late stages of hematopoiesis were then evaluated by assessing the number of
clonogenic cell precursors (long-term culture initiating cells [LTC-IC]),
clonogenic cells, and mature granulocyte and macrophage progeny present in
the cultures after 5 weeks. In the absence of any feeders, cells at all
stages of hematopoiesis decreased to very low levels. In contrast,
maintenance of LTC-IC was found to be supported by control murine stromal
cells as effectively as by standard human marrow adherent layers. The
presence of granulocyte colony-stimulating factor (G-CSF) and
interleukin-3-producing M2-10B4 cells in combination was able to further
enhance the maintenance and early differentiation of these cells without a
decline in their proliferative potential as measured by the clonogenic
output per LTC-IC. However, this effect was lost if granulocyte-macrophage
CSF (GM-CSF)-producing feeders were also present. On the other hand, in the
presence of GM-CSF-producing feeders, the output of mature granulocytes and
macrophages increased 20- fold. These findings show that it is possible to
selectively improve the maintenance of very primitive human hematopoietic
cells in vitro or their output of mature progeny by appropriate
manipulation of the long- term marrow culture system. Further exploitation
of this approach should facilitate investigation of the mechanisms
operative within the human marrow microenvironment in vivo and the design
of protocols for in vitro manipulation of human marrow for future
therapeutic applications.
Volume 78,
Issue 3,
pp. 666-672,
08/01/1991
Copyright © 1991 by The American Society of Hematology
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