Tumor-promoting phorbol esters support the in vitro proliferation of murine pluripotent hematopoietic stem cells.
The effect of tumor-promoting phorbol esters on the in vitro proliferation of mouse pluripotent hematopoietic stem cells (CFU-S) was examined using a short-term in vitro culture system and an 11-d spleen colony assay. Phorbol myristate acetate (PMA, 10(-7) M), but not the inert compound phorbol, supported the in vitro survival of day 11 CFU-S for 72 h in a manner similar to IL 3. PMA also enhanced the effect of IL 3 on the in vitro survival of day 11 CFU-S and as little as 1 h of exposure to PMA was sufficient for this purpose. The effect of PMA on CFU-S survival in vitro was not mediated by prostaglandins, did not require an established adherent cell population, and was observed at a concentration of 10(-9) M. PMA alone did not enhance the in vitro survival of day 11 CFU-S at very low concentrations of FCS but was still able to potentiate the effect of IL 3 on these cells. PMA also enhanced the in vitro survival of day 11 CFU-S from mice treated with 5-fluorouracil or from marrow cells exposed to merocyanine 540 and light. The interaction of PMA with day 11 CFU-S was not inhibited by a neutralizing antiserum to IL 3 but was inhibited by the protein kinase inhibitor H-7. Together, the data indicate that tumor-promoting phorbol esters interact with pluripotent hematopoietic stem cells. Like IL 3, their effect appears to be permissive and involves stem cells with marrow repopulating ability.
Spivak
J L
JL
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Hogans
B B
BB
Stuart
R K
RK
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D003114:Colony-Forming Units Assay; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004921:Erythropoietin / Q000494:pharmacology; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D006133:Growth Substances / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D010704:Phorbols / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007377:Interleukin-3; D007546:Isoquinolines; D010704:Phorbols; D010879:Piperazines; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D013755:Tetradecanoylphorbol Acetate; C033085:phorbol; D007213:Indomethacin