Protective effects of thrombopoietin and stem cell factor on X-irradiated CD34+ megakaryocytic progenitor cells from human placental and umbilical cord blood.
In previous studies we characterized the radiosensitivity of CFU-megakaryocytes from human placental and umbilical cord blood and the effects of various early-acting cytokines. We found that the maximal clonal growth of CFU-megakaryocytes in vitro and maximal protection against X-ray damage were supported by a combination of thrombopoietin and stem cell factor. However, the mechanism by which the two cytokines exert a synergistic effect remained unclear, so we extended these studies to investigate the radioprotective action of synergistic thrombopoietin and stem cell factor on the survival of X-irradiated CD34(+) CFU-megakaryocytes. A combination of thrombopoietin and stem cell factor led to activation of mitogen-activated protein kinase and extracellular signal-regulated protein kinase and to suppression of caspase 3 in X-irradiated CD34(+) cells. When PD98059 and various synthetic substrates-specific inhibitors of these proteins-were used, the combination had less effect on the clonal growth of X-irradiated CD34(+) CFU-megakaryocytes. However, the addition of wortmannin, a specific inhibitor of the phosphatidylinositol-3 kinase pathway, did not alter the synergistic action of thrombopoietin plus stem cell factor. We suggest that part of this synergistic effect can be explained by activation of mitogen-activated protein kinase and extracellular signal-regulated protein kinase and by suppression of the caspase cascade.
Kashiwakura
Ikuo
I
Department of Radiological Technology, Hirosaki University School of Health Sciences, 66-1 Hon-cho, Hirosaki, Aomori 036-8564, Japan. ikashi@cc.hirosaki-u.ac.jp
Inanami
Osamu
O
Takahashi
Kenji
K
Takahashi
Tsuneo A
TA
Kuwabara
Mikinori
M
Takagi
Yoshinari
Y
D018952:Antigens, CD34 / Q000097:blood / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D005312:Fetal Blood / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects*; D010920:Placenta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance / Q000187:drug effects; D011837:Radiation-Protective Agents / Q000494:pharmacology; D019089:Stem Cell Factor / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D014965:X-Rays
D018952:Antigens, CD34; D011837:Radiation-Protective Agents; D019089:Stem Cell Factor