Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss.
Lithium Reversibly Inhibits Schwann Cell Proliferation and Differentiation Without Inducing Myelin Loss.
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DOI：
10.1007/s12035-016-0262-z
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发表时间：
2017-12
影响因子：
5.1
通讯作者：
Monje PV
中科院分区：
文献类型：
--
作者：
Piñero G;Berg R;Andersen ND;Setton-Avruj P;Monje PV
本研究旨在探讨锂对体外培养的雪旺细胞生长、存活、增殖和分化的生物活性、特异性和可逆性影响。在分离的SC中，锂促进了细胞周期停滞的状态，其特征是在没有髓鞘相关标志物表达增加的情况下广泛的细胞增大和c-Jun下调。此外，锂有效地防止了丝裂原诱导的S期进入，而不损害细胞活力。当锂与不同浓度的cAMP类似物一起施用时，观察到髓鞘形成的主调节因子Krox-20的表达的显著抑制。同样地，锂拮抗了各种髓鞘标记物如蛋白零、周蛋白和半乳糖苷的cAMP依赖性表达，并允许SC即使在高水平cAMP和低水平c-Jun的存在下也保持高水平的未成熟SC标记物的表达。最重要的是，锂对SC增殖和分化的抑制作用显示为剂量依赖性的，在除去锂化合物时是特异的和可逆的。在SC神经元培养物中，锂抑制髓鞘形成，同时保持轴突完整性、SC轴突接触和基底膜形成。锂在防止髓鞘形成而不促进髓鞘降解或SC去分化方面是独特的。总之，我们的研究结果强调了锂对SC有丝分裂和髓鞘基因表达的意外拮抗作用。我们认为，锂是一种有吸引力的药理学试剂，可以安全、可逆地抑制SC增殖、分化和髓鞘形成，同时保持原有有髓纤维的完整性。
This study was undertaken to examine the bioactivity, specificity and reversibility of lithium’s action on the growth, survival, proliferation and differentiation of cultured Schwann cells (SCs). In isolated SCs, lithium promoted a state of cell cycle arrest that featured extensive cell enlargement and c-Jun downregulation in the absence of increased expression of myelin-associated markers. In addition, lithium effectively prevented mitogen-induced S-phase entry without impairing cell viability. When lithium was administered together with differentiating concentrations of cAMP analogs, a dramatic inhibition of the expression of the master regulator of myelination Krox-20 was observed. Likewise, lithium antagonized the cAMP-dependent expression of various myelin markers such as protein zero, periaxin and galactocerebroside and allowed SCs to maintain high levels of expression of immature SC markers even in the presence of high levels of cAMP and low levels of c-Jun. Most importantly, the inhibitory action of lithium on SC proliferation and differentiation was shown to be dose dependent, specific and reversible upon removal of lithium compounds. In SC-neuron cultures, lithium suppressed myelin sheath formation while preserving axonal integrity, SC-axon contact and basal lamina formation. Lithium was unique in its ability to prevent the onset of myelination without promoting myelin degradation or SC dedifferentiation. To conclude, our results underscored an unexpected antagonistic action of lithium on SC mitogenesis and myelin gene expression. We suggest that lithium represents an attractive pharmacological agent to safely and reversibly suppress the onset of SC proliferation, differentiation and myelination while maintaining the integrity of pre-existing myelinated fibers.