Pre-CFU-S quiescence and stem cell exhaustion after cytostatic drug treatment: protective effects of the inhibitory peptide pGlu-Glu-Asp-Cys-Lys (pEEDCK).
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.
Paukovits
W R
WR
Laboratory of Growth Regulation, University of Vienna, Austria.
Moser
M H
MH
Paukovits
J B
JB
D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000633:toxicity*; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D007399:Interphase / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives
D006131:Growth Inhibitors; D009842:Oligopeptides; D003561:Cytarabine; C040758:hemoregulatory peptide 5b; D011761:Pyrrolidonecarboxylic Acid