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Use of 5-fluorouracil to analyze the effect of macrophage inflammatory
protein-1 alpha on long-term reconstituting stem cells in vivo
VF Quesniaux, GJ Graham, I Pragnell, D Donaldson, SD Wolpe, NN Iscove and B Fagg
Sandoz Pharma Ltd, Basel, Switzerland.
A macrophage-derived inhibitor of early hematopoietic progenitors
(colony-forming unit-spleen, CFU-A) called stem cell inhibitor was found to
be identical to macrophage inflammatory protein-1 alpha (MIP-1 alpha). We
investigated the effect of MIP-1 alpha on the earliest stem cells that
sustain long-term hematopoiesis in vivo in a competitive bone marrow
repopulation assay. Because long-term reconstituting (LTR) stem cells are
normally quiescent, an in vivo model was first developed in which they are
triggered to cycle. A first 5-fluorouracil (5-FU) injection was used to
eliminate later progenitors, causing the LTR stem cells, which are normally
resistant to 5-FU, to enter the cell cycle and become sensitive to a second
5-FU injection administered 5 days later. Human MIP-1 alpha administered
from day 0 to 7 was unable to prevent the depletion of the LTR stem cells
by the second 5-FU treatment, as observed on day 7 in this model,
suggesting that the LTR stem cells were not prevented from being triggered
into cycle despite the MIP-1 alpha treatment. However, the MIP-1 alpha
protocol used here did substantially decrease the number of more mature
hematopoietic progenitors (granulocyte-macrophage colony-forming cells
[CFC], burst- forming unit-erythroid, CFCmulti, and preCFCmulti) recovered
in the bone marrow shortly after a single 5-FU injection. In vitro, MIP-1
alpha had no inhibitory effect on the ability of these progenitors to form
colonies. This study confirms the in vivo inhibitory effect of MIP- 1 alpha
on subpopulations of hematopoietic progenitors that are activated in
myelodepressed animals. However, MIP-1 alpha had no effect on the long-term
reconstituting stem cells in vivo under conditions in which it effectively
reduced all later progenitors.
Volume 81,
Issue 6,
pp. 1497-1504,
03/15/1993
Copyright © 1993 by The American Society of Hematology
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