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Phenotypic and functional changes induced at the clonal level in
hematopoietic stem cells after 5-fluorouracil treatment
TD Randall and IL Weissman
Department of Pathology, Stanford Medical School, CA 94305, USA.
A significant fraction of hematopoietic stem cells (HSCs) have been shown
to be resistant to the effects of cytotoxic agents such as 5- fluorouracil
(5-FU), which is thought to eliminate many of the rapidly dividing, more
committed progenitors in the bone marrow and to provide a relatively
enriched population of the most primitive hematopoietic progenitor cells.
Although differences between 5-FU-enriched progenitor populations and those
from normal bone marrow have been described, it remained unclear if these
differences reflected characteristics of the most primitive stem cells that
were revealed by 5-FU, or if there were changes in the stem-cell population
itself. Here, we have examined some of the properties of the stem cells in
the bone marrow before and after 5-FU treatment and have defined several
activation-related changes in the stem-cell population. We found that
long-term reconstituting stem cells decrease their expression of the growth
factor receptor c-kit by 10-fold and increase their expression of the
integrin Mac-1 (CD11b). These changes begin as early as 24 hours after 5-FU
treatment and are most pronounced within 2 to 3 days. This activated
phenotype of HSCs isolated from 5-FU-treated mice is similar to the
phenotype of stem cells found in the fetal liver and to the phenotype of
transiently repopulating progenitors in normal bone marrow. We found that
cell cycle is induced concomitantly with these physical changes, and within
2 days as many as 29% of the stem-cell population is in the S/G2/M phases
of the cell cycle. Furthermore, when examined at a clonal level, we found
that 5-FU did not appear to eliminate many of the transient, multipotent
progenitors from the bone marrow that were found to be copurified with
long-term repopulating, activated stem cells. These results demonstrate the
sensitivity of the hematopoietic system to changes in its homeostasis and
correlate the expression of several important surface molecules with the
activation state of HSCs.
Volume 89,
Issue 10,
pp. 3596-3606,
05/15/1997
Copyright © 1997 by The American Society of Hematology
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