Activity of acetyl-n-ser-asp-lys-pro (AcSDKP) on hematopoietic progenitor cells in short-term and long-term murine bone marrow cultures.
The tetrapeptide AcSDKP is a potent inhibitor of hematopoietic stem cell proliferation. Its activity was systematically examined in murine long-term bone marrow cultures (LTBMC) and short-term liquid cultures in the presence or absence of exogenous cytokines. The effects of AcSDKP on the production of granulocyte-macrophage colony-forming cells (CFU-GM) and high proliferative potential colony-forming cells (HPP-CFC) in LTBMCs were examined. AcSDKP was added daily to LTBMCs at various concentrations (10-3--10-16M) for up to 5 weeks. AcSDKP inhibited the entry of progenitor cells into S phase as measured by 3H-thymidine suicide assay and the absolute number of progenitor cells with peak activity at 10-12 M with less activity seen at higher or lower concentrations. The number of nonadherent CFU-GM per LTBMC was unchanged from control values at 1 week of treatment with AcSDKP but was significantly depressed at weeks 3 and 5. In contrast, HPP-CFC progenitor cells were decreased throughout the treatment period, and the numbers of CFU-GM and HPP-CFC in S phase were significantly decreased throughout the treatment period. Maximum S-phase inhibitory activity was observed at 10-12 M AcSDKP. AcSDKP had no effect on the number of adherent CFU-GM or HPP-CFC, cellularity per culture or percent of adherent progenitor cells in S phase. Murine short-term bone marrow cultures were also treated with AcSDKP in the presence or absence of cytokines (interleukin-3 [LI-3], stem cell factor [SCF], or granulocyte colony-stimulating factor [G-CSF]) for various time periods. Dose-response studies showed maximum effects at 10-12 M AcSDKP when no cytokines were added and 10-14 M AcSDKP when exogenous cytokines were added. These studies indicate that the concentration of the tetrapeptide critical in obtaining an effect on hematopoietic progenitor cells, and furthermore, we report that the presence of cytokines or stromal cells also affects the response of progenitor cells to AcSDKP.
Jackson
J D
JD
Department of Pathology and Microbiology, University of Nebraska Medical Center; Omaha, NE 68198-3135, USA.
Yan
Y
Y
Ewel
C
C
Talmadge
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006131:Growth Inhibitors / Q000494:pharmacology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D016196:S Phase / Q000187:drug effects
D006131:Growth Inhibitors; D009842:Oligopeptides; C058504:goralatide