Targeting the AKT/mTOR/p70S6K Pathway for Oligodendrocyte Differentiation and Myelin Regeneration in Neurological Disorders.

Chen Ge, Changwei Li
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Abstract

Background: The AKT/mTOR/p70S6K pathway has been shown to potentially promote spinal cord injury (SCI) repair in rats. However, its exact mechanism and beyond needs to be further explored.

Objective: This study aims to explore the AKT/mTOR/p70S6K pathway in oligodendrocyte precursor cell (OPC) differentiation, microglial polarization differentiation, and the role of these in myelin regeneration in vitro.

Methods: The isolation, induction and characterization of rat primary neuronal stem cells, OPCs and oligodendrocytes were investigated with immunofluorescence and RT-qPCR. Then, the role of AKT/mTOR/p70S6K signaling was explored using western blotting and immunofluorescence, the effect on myelination was examined with OPC-dorsal root ganglion (DRG) neurons co-culture, and the influence of M1/M2 polarization status of microglia on myelin formation was also observed by adding M1/M2 supernatants into OPC-DRG neurons co-culture.

Results: Activation of the AKT/mTOR/p70S6K pathway elevated the expression of oligodendrocyte differentiation markers, including MBP, PLP and MOG, which also promoted the colocalization of MBP and NFH in OPC-DRG neurons co-culture. More interestingly, stimulation of the AKT/mTOR/p70S6K pathway facilitated M2 polarization of rat microglia. M2 polarization of microglia enhanced OPC differentiation to oligodendrocytes and myelin formation.

Conclusion: Our findings highlight the potential of targeting the AKT/mTOR/p70S6K pathway in promoting oligodendrocyte differentiation and myelin regeneration in neurological disorders such as SCI.

针对神经系统疾病中少突胶质细胞分化和髓鞘再生的AKT/mTOR/p70S6K途径。
背景:AKT/mTOR/p70S6K通路已被证明有可能促进大鼠脊髓损伤(SCI)的修复。然而,它的确切机制及其超越还有待进一步探索。目的:探讨AKT/mTOR/p70S6K通路在少突胶质细胞前体细胞(OPC)分化、小胶质细胞极化分化中的作用及其在体外髓鞘再生中的作用。方法:采用免疫荧光和RT-qPCR方法对大鼠原代神经干细胞、OPCs和少突胶质细胞的分离、诱导和特性进行研究。然后,用蛋白质印迹和免疫荧光法探讨了AKT/mTOR/p70S6K信号传导的作用,并用共培养的OPC背根神经节(DRG)神经元检测了其对髓鞘形成的影响,结果:AKT/mTOR/p70S6K通路的激活使少突胶质细胞分化标志物MBP、PLP和MOG的表达升高,并促进了MBP和NFH在OPC-DRG神经元共培养中的共定位。更有趣的是,刺激AKT/mTOR/p70S6K通路促进了大鼠小胶质细胞的M2极化。小胶质细胞的M2极化增强了OPC向少突胶质细胞的分化和髓鞘的形成。结论:我们的研究结果突出了靶向AKT/mTOR/p70S6K通路在促进SCI等神经系统疾病中少突胶质细胞分化和髓鞘再生方面的潜力。
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