Jie yu Ye

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

Background 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. Design and Methods 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. Results 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. Conclusions 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.

Serotonin Enhances Megakaryopoiesis and Proplatelet Formation via p‐Erk1/2 and F‐Actin Reorganization

Our previous studies have shown that serotonin (5‐hydroxytryptamine; 5‐HT) is a growth factor for hematopoietic stem/progenitor cells. In this study, we proposed a possible mechanism: 5‐HT may enhance megakaryopoiesis and proplatelet formation via Erk1/2 pathway and cytoskeleton reorganization. Here, 5‐HT2BR was first identified in megakaryocytic cells. 5‐HT also promoted the megakaryocytes (MKs) proliferation and reduced the cell apoptosis via the activation of 5‐HT2BR and Akt pathway. The effects were reduced by the 5‐HT2BR inhibitor ketanserin. The effect of 5‐HT on proplatelet formation in bone marrow MKs were further confirmed: the 5‐HT treated group had more proplatelet bearing MKs compared with the control group. To determine whether 5‐HT has effects on cytoskeleton reorganization of MKs, and whether these effects could be reduced by ketanserin or Erk1/2 inhibitor PD98059, MKs were stained with the F‐actin specific binder rhodamine–phalloidin. The polymerized actin level was lower in the control group than the 5‐HT group and was distributed throughout the cytoplasm with occasional aggregations. Our data demonstrated that Erk1/2 was activated in MKs treated with 5‐HT. This study suggests that 5‐HT has a potent effect on platelet formation and this effect is likely mediated via 5HT2BR with subsequent activation of p‐Erk1/2 and consequent F‐actin reorganization and proplatelet formation. We also demonstrated that melatonin, the metabolite of 5‐HT, exerts a protective effect on MK and platelet recovery in the irradiated mouse model. This study suggested that 5‐HT plays an important role in platelet formation via 5HT2BR, p‐Erk1/2, and F‐actin reorganization. Stem Cells 2014;32:2973–2982