Kashiwakura, I., Inanami, O., Takahashi, K., Takahashi, T. A., Kuwabara, M. and Takagi, Y. Protective Effects of Thrombopoietin and Stem Cell Factor on X-Irradiated CD34 Megakaryocytic Progenitor Cells from Human Placental and Umbilical Cord Blood. Radiat. Res. 160, 210–216 (2003).
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.