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Human CD34+ Bone Marrow Cells Regulate Stromal
Production of Interleukin-6 and Granulocyte Colony-Stimulating Factor
and Increase the Colony-Stimulating Activity of Stroma
Pankaj Gupta,
Bruce R. Blazar,
Kalpna Gupta, and
Catherine M. Verfaillie
From the Departments of Medicine and Pediatrics, University of
Minnesota Medical School and Veterans Affairs Medical Center,
Minneapolis, MN.
Cytokines produced by stromal cells induce the proliferation and
differentiation of hematopoietic cells in the marrow microenvironment. We hypothesized that cross-talk between hematopoietic cells at different stages of differentiation and stromal cells influences stromal cytokine production and is responsible for maintaining steady-state hematopoiesis and responding to stress situations. We show
that coculture of primitive CD34+ cells in contact with
or separated by a transwell membrane from irradiated human bone marrow
stromal layers induces a fourfold to fivefold increase in interleukin-6
(IL-6) and granulocyte colony-stimulating factor (G-CSF) levels in the
stromal supernatant (SN) during the first week. Levels of both
cytokines decreased to baseline after coculture of CD34+
cells for 3 to 5 weeks. Coculture of more mature
CD15+/CD14 myeloid precursors induced only
a transient 1.5- to 2-fold increase in IL-6 and G-CSF at 48 hours.
Neither CD34+ nor CD15+/CD14
cells produced IL-6, G-CSF, IL-1 , or tumor necrosis factor  . When
CD34+ cells were cultured in methylcellulose medium
supplemented with cytokines at concentrations found in stromal SN or
supplemented with stromal SN, a fourfold to fivefold increase in colony
formation was seen over cultures supplemented with erythropoietin (EPO) only. When cultures were supplemented with the increased concentrations of IL-6 and G-CSF detected in cocultures of stroma and
CD34+ cells or when CD34+ cells were
cocultured in methylcellulose medium in a transwell above a stromal
layer, a further increase in the number and size of colonies was seen.
The colony-forming unit-granulocyte-macrophage-stimulating activity
of stromal SN was neutralized by antibodies against G-CSF or IL-6.
These studies indicate that primitive CD34+ progenitors
provide a soluble positive feedback signal to induce cytokine
production by stromal cells and that the observed increase in cytokine
levels is biologically relevant.
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3724-3733
© 1998 by The American Society of Hematology.
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