IGF-1 facilitates thrombopoiesis primarily through Akt activation

Abstract

It is known that insulin-like growth factor-1 (IGF-1) also functions as a hematopoietic factor, although its direct effect on thrombopoiesis remains unclear. In this study, we show that IGF-1 is able to promote CD34 cell differentiation toward megakaryocytes (MKs), as well as the facilitation of proplatelet formation (PPF) and platelet production from cultured MKs. The in vivo study demonstrates that IGF-1 administration accelerates platelet recovery in mice after 6.0 Gy of irradiation and in mice that received bone marrow transplantation following 10.0 Gy of lethal irradiation. Subsequent investigations reveal that extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt activation mediate the effect of IGF-1 on thrombopoiesis. Notably, Akt activation induced by IGF-1 is more apparent than that of ERK1/2, compared with that of thrombopoietin (TPO) treatment. Moreover, the effect of IGF-1 on thrombopoiesis is independent of TPO signaling because IGF-1 treatment can also lead to a significant increase of platelet counts in homozygous TPO receptor mutant mice. Further analysis indicates that the activation of Akt triggered by IGF-1 requires the assistance of steroid receptor coactivator-3 (SRC-3). Therefore, our data reveal a distinct role of IGF-1 in regulating thrombopoiesis, providing new insights into TPO-independent regulation of platelet generation.

Melatonin enhances thrombopoiesis through ERK1/2 and Akt activation orchestrated by dual adaptor for phosphotyrosine and 3‐phosphoinositides

“…Therefore, the effect of MT3 receptor on MK activities needs to be further evaluated. The influence of MT during thrombopoiesis described in this study is consistent with our previous works in which we showed that some neuroendocrine hormones mainly affect the later stages of thrombopoiesis, where they induce a quick elevation of circulating platelets . This is different from some well‐known thrombopoietic cytokines such as TPO, IL‐3, and GM‐CSF, which mainly act during the early and middle stages of platelet production .…”

“…Both the ERK1/2 and Akt signal pathways are likely active during thrombopoiesis . Activation of ERK1/2 signaling may primarily affect the early stages of thrombopoiesis, while Akt signaling activation is mainly required for the late phases of thrombopoiesis . We find that DAPP1 expression likely acts as a positive modulator for the expression of phosphorylated ERK1/2 to expand MKs, but negatively regulates Akt activation to promote PPF and platelet release.…”

“…Both human and mouse MKs were induced and cultured as previously reported . Briefly, human MKs were cultured from CD34 + cells that were isolated from human cord blood by positive selection with an immunomagnetic cell sorting system (EasySep, Human CD34 Positive Selection kit; Stem Cell Technologies).…”

“…1,2 Previous studies, including our own work, have revealed that various factors, primarily the specific cytokine thrombopoietin (TPO), can directly promote platelet production by acting at different stages through the extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways. [3][4][5] In addition, some factors may also indirectly facilitate platelet production through TPO, which is suggested by the data that approximately 60% of TPO in circulation is controlled by the platelet glycoprotein Ibα (GPIbα). 6 Interestingly, the activities of HSCs and MKs are intrinsically influenced by the nervous system.…”

MicroRNA 34a promotes ionizing radiation–induced DNA damage repair in murine hematopoietic stem cells

“…IR exposure procedure Mice were exposed to various doses of total body irradiation (TBI) in a [ 60 Co] g-irradiator at the Third Military Medical University Irradiation Center as previously described in Chen et al (25).…”