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Pre-CFU-S quiescence and stem cell exhaustion after cytostatic drug
treatment: protective effects of the inhibitory peptide pGlu-Glu-Asp-
Cys-Lys (pEEDCK)
WR Paukovits, MH Moser and JB Paukovits
Laboratory of Growth Regulation, University of Vienna, Austria.
Pre--CFU-S are characterized by their ability to generate spleen colony-
forming cells (CFU-S) and by their ability to repopulate the hematopoietic
system after damage. We have investigated their response to three
consecutive injections of cytosine arabinoside (ara-C), given at t = 0, 12,
and 20 hours. Nine hours after treatment, the number of CFU-S and
pre--CFU-S was reduced to 10% or 30%, respectively. No pre-- CFU-S were in
S-phase at this time, indicating that the pre--CFU-S losses were not caused
by direct drug killing. Up to 1 year after treatment, pre--CFU-S were still
depleted to 10% of normal, indicating that their proliferative quiescence
was permanent. We have previously shown that inhibition of CFU-S
recruitment with pGlu-Glu-Asp-Cys-Lys (pEEDCK) makes them ara-C resistant
and prevents their decimation. We now found that this also prevented the
excessive drainage of the pre-- CFU-S pool, suggesting that pre--CFU-S
allocation into active hematopoiesis is triggered by the CFU-S deficit.
pEEDCK may thus be applicable as a protector of the hematopoietic
repopulation potential against cytostatic drug-induced aplasia.
Postchemotherapeutic stimulator treatment with (pEEDCK)2-dimer did not
ameliorate pre--CFU-S losses. Long-term culture-initiating cells (LTC-ICs)
showed a similar pattern of irreversible reduction after cytostatic drug
treatment, which could be prevented by pEEDCK. Our results suggest, that
certain subclasses of hematopoietic stem cells (pre--CFU-S) are permanently
quiescent and exhaustible and that the capacity for self-renewal is not a
necessary property of all stem cell-like cells.
Volume 81,
Issue 7,
pp. 1755-1761,
04/01/1993
Copyright © 1993 by The American Society of Hematology
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