Pre-CFU-S quiescence and stem cell exhaustion after cytostatic drug treatment: protective effects of the inhibitory peptide pGlu-Glu-Asp- Cys-Lys (pEEDCK)
| Autor: | Marie-HBIene Moser, Walter R. Paukovits, Johanna B. Paukovits |
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| Rok vydání: | 1993 |
| Předmět: | |
| Zdroj: | Blood. 81:1755-1761 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.v81.7.1755.1755 |
| Popis: | 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, pdFU-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 pGluGlu-Asp-Cys-Lys (pEEDCK) makes them ara-C resistant and prevents their decimation. We now found that this also N AN ADULT ORGANISM, a high output of functional I blood cells is sustained by a slowly dividing population of primitive stem cells.’ The size of the stem cell pool remains relatively constant over prolonged times despite a continuous drain through differentiation-accompanied cell divisions. To explain this apparent constancy, each stem cell is thought to have the ability to either divide and differentiate or to selfrenew, with both daughter cells remaining in the stem cell compartment.* The balance between these alternatives seems to be determined by the requirements of the organism in such a way that the number of stem cells is kept constant. The most important functional property of stem cells is their capability of long-term repopulation of the hematopoietic ~ystem.~ Through this property they have recently become accessible to experimental investigation”* but accumulating evidence indicates that the term stem cells comprises several distinct subclasses of primitive hematopoietic cells. Among these, ~re-cFU-s’,~ are defined by their ability to generate pluripotent spleen colony-forming cells (CFU-S) in two-step transplantation assays. It has been shown4,&’ ’ that they share physical, antigenic, and biologic properties with other primitive cells detected by various in vitro and in vivo assays. 3-5,s. 10-1 6) M ost of these primitive cells are capable of resisting’ the toxic effects of cycle-specific cytostatic drugs like 5-fluorouracil, but some subtypes are sensitive to repeated drug applications.17 We investigated the behavior of CFU-S-generating preCFU-S in mice under conditions causing CFU-S decimation and extreme proliferation of surviving CFU-S. Such conditions were induced by repeated cytosine arabinosine (ara-C) treatment and modulated by application of the hemoregulatory peptide pEEDCK as described earlier.” By combining the pre-CFU-S assay4 with suicide techniques, we have found |
| Databáze: | OpenAIRE |
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