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The kinetics of murine hematopoietic stem cells in vivo in response to
prolonged increased mature blood cell production induced by granulocyte
colony-stimulating factor
G de Haan, B Dontje, C Engel, M Loeffler and W Nijhof
Groningen Institute for Drug Studies, Department of Hematology, University
of Groningen, The Netherlands.
Because of the complexity of appropriate stem cell assays, little
information on the in vivo regulation of murine stem cell biology or
stemmatopoiesis is available. It is unknown whether and how in vivo the
primitive hematopoietic stem cell compartment is affected during a
continued increased production of mature blood cells. In this study, we
present data showing that prolonged (3 weeks) administration of granulocyte
colony-stimulating factor (G-CSF), which is a major regulator of mature
granulocyte production, has a substantial impact on both the size and the
location of various stem cell subset pools in mice. We have used the novel
cobblestone area forming cell (CAFC) assay to assess the effects of G-CSF
on the stem cell compartment (CAFC days 7, 14, 21, and 28). In marrow, in
which normally 99% of the total number of stem cells can be found, G-CSF
induced a severe depletion of particularly the most primitive stem cells to
5% to 10% of normal values. The response after 7 days of G-CSF treatment
was an increased amplification between CAFC day 14 and 7. However, this
response occurred at the expense of the number of CAFC day 14. It is likely
that the resulting gap of CAFC day 14 cell numbers was subsequently
replenished from the more primitive CAFC day 21 and 28 compartments,
because these cell numbers remained low during the entire treatment period.
In the spleen, the number of stem cells increased, likely caused by a
migration from the marrow via the blood, leading to an accumulation in the
spleen. The increased number of stem cells in the spleen overcompensated
for the loss in the marrow. When total body (marrow and spleen) stem cell
numbers were calculated, it appeared that a continued increased production
of mature granulocytes resulted in the establishment of a higher, new
steady state of the stem cell compartment; most committed stem cells (CAFC
day 7) were increased threefold, CAFC day 14 were increased 2.3-fold,
CAFC-day 21 were increased 1.8-fold, and the most primitive stem cells
evaluated, CAFC day 28, were not different from normal, although now 95% of
these cells were located in the spleen. Four weeks after discontinuation of
the G- CSF treatment, the stem cell reserve in the spleen had returned to a
normal level, whereas stem cell numbers in marrow had recovered to values
above normal. This study shows that the primitive stem cell compartment is
seriously perturbed during an increased stimulation of the production of
mature blood cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Volume 86,
Issue 8,
pp. 2986-2992,
10/15/1995
Copyright © 1995 by The American Society of Hematology
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