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Nerve growth factor is involved in the supportive effect by bone marrow-
-derived stromal cells of the factor-dependent human cell line UT-7
[published erratum appears in Blood 1996 Oct 1;88(7):2818]
I Auffray, S Chevalier, J Froger, B Izac, W Vainchenker, H Gascan and L Coulombel
INSERM U362, Institut Gustave Roussy, Villejuif, France.
We previously demonstrated that murine MS-5 and SI/SI4 cell lines induce
the proliferation of human factor-dependent UT-7 cells in the absence of
normally required human cytokines and also stimulate the differentiation of
CD34+/CD38-LTC-ICs. We report in this study that the effect of MS-5 cells
on UT-7 cells can be completely explained by the synergistic action of
nerve growth factor (NGF) and stem cell factor (SCF) produced by these
murine stromal cells. Purified murine NGF was able to support short-term
clone formation and long-term growth of UT-7 cells in suspension cultures
as efficiently as rhu-granulocyte- macrophage colony-stimulating factor.
NGF action was mediated through the TrkA receptor, in which messenger RNA
(mRNA) was easily detected in UT-7 cells by Northern blot. MS-5 cells
strongly expressed NGF mRNA in Northern blot, and direct implication of
MS-5-derived NGF in the induction of UT-7 cells proliferation was
demonstrated in inhibition assays with an anti-NGF monoclonal antibody
(MoAb) that neutralized by 84% +/- 4.1% (n = 5) UT-7 clone formation.
However, NGF did not act alone, and several arguments demonstrated the
synergistic action of MS- 5-derived SCF: (1) an anti-c-kit partially
inhibited UT-7 cells clone formation in coculture assays, (2) SCF and NGF
synergized in an H3-TdR incorporation assay, and (3) the stimulatory effect
of 10x-concentrated MS-5 supernatant was completely inhibited by an
anti-c-kit but not by an anti-NGF, and levels of soluble NGF (1.2 ng/mL)
detected by enzyme- linked immunosorbent assay in 10x supernatant of MS-5
cells cultures were below the biologically active concentrations. In
contrast, although MS-5 cells also promoted the differentiation of very
primitive CD34+/CD38- human stem cells both in colony assays and long-term
cultures, we could not incriminate MS-5-derived NGF in the observed effect:
an anti-NGF MoAb did not inhibit the synergistic effect of MS-5 cells in
colony assays or long-term cultures nor did soluble muNGF duplicate MS-5
effect and survival of CD34+/CD38- clonogenic progenitor cells promoted by
MS-5 was unaffected by an anti-NGF and was not induced by soluble NGF alone
or combined with SCF. In contrast, NGF in synergy with SCF supported the
short-term maintenance of high numbers of CD34+/CD38+ mature erythroid
progenitors probably through an indirect mechanism implying macrophages.
These results suggest that NGF, in which the primary target cells are
outside the hematopoietic system, is present in the marrow environment and
might act at some steps of hematopoietic stem cell development. These
results also underline that the response of cell lines and normal stem
cells to stromal cells is mediated by different pathways.
Volume 88,
Issue 5,
pp. 1608-1618,
09/01/1996
Copyright © 1996 by The American Society of Hematology
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