Platelet-derived growth factor enhances platelet recovery in a murine model of radiation-induced thrombocytopenia and reduces apoptosis in megakaryocytes via its receptors and the PI3-k/Akt pathway

• Published in: Haematologica (Roma) 2010-10, Vol.95 (10), p.1745-1753
• Main Authors: Ye, Jie Yu, Chan, Godfrey Chi Fung, Qiao, Liang, Lian, Qizhou, Meng, Fan Yi, Luo, Xue Qun, Khachigian, Levon M, Ma, Ming, Deng, Ruixia, Chen, Jian Liang, Chong, Beng H, Yang, Mo
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - radiation effects; Hematologic and hematopoietic diseases; Medical sciences; Megakaryocytes - pathology; Mice; Original; Phosphatidylinositol 3-Kinases - metabolism; Platelet diseases and coagulopathies; Platelet-Derived Growth Factor - pharmacology; Platelet-Derived Growth Factor - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Thrombocytopenia - drug therapy; Thrombocytopenia - etiology; Whole-Body Irradiation - adverse effects
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2009.020958

Platelet-derived growth factor is involved in the regulation of hematopoiesis. Imatinib mesylate, a platelet-derived growth factor receptor inhibitor, induces thrombocytopenia in a significant proportion of patients with chronic myeloid leukemia. Although our previous studies showed that platelet-derived growth factor enhances megakaryocytopoiesis in vitro, the in vivo effect of platelet-derived growth factor in a model of radiation-induced thrombocytopenia has not been reported. In this study, we investigated the effect of platelet-derived growth factor on hematopoietic stem/progenitor cells and platelet production using an irradiated-mouse model. We also explored the potential molecular mechanisms of platelet-derived growth factor on thrombopoiesis in M-07e cells. Platelet-derived growth factor, like thrombopoietin, significantly promoted the recovery of platelets and the formation of bone marrow colony-forming unit-megakaryocyte in irradiated mice. Histology confirmed the protective effect of platelet-derived growth factor, as shown by an increased number of hematopoietic stem/progenitor cells and a reduction of apoptosis. In a megakaryocytic apoptotic model, platelet-derived growth factor had a similar anti-apoptotic effect as thrombopoietin on megakaryocytes. We also demonstrated that platelet-derived growth factor activated the PI3-k/Akt signaling pathway, while addition of imatinib mesylate reduced p-Akt expression. Our findings show that platelet-derived growth factor enhances platelet recovery in mice with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via platelet-derived growth factor receptors with subsequent activation of the PI3-k/Akt pathway. We also provide a possible explanation that blockage of platelet-derived growth factor receptors may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.