Department of Biological Sciences, Rutgers University, Newark, New Jersey, USA.
Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, Newark, New Jersey, USA.
Glia. 2020 Oct;68(10):2070-2085. doi: 10.1002/glia.23827. Epub 2020 Mar 14.
Myelin loss in the brain is a common occurrence in traumatic brain injury (TBI) that results from impact-induced acceleration forces to the head. Fast and abrupt head motions, either resulting from violent blows and/or jolts, cause rapid stretching of the brain tissue, and the long axons within the white matter tracts are especially vulnerable to such mechanical strain. Recent studies have shown that mechanotransduction plays an important role in regulating oligodendrocyte progenitors cell differentiation into oligodendrocytes. However, little is known about the impact of mechanical strain on mature oligodendrocytes and the stability of their associated myelin sheaths. We used an in vitro cellular stretch device to address these questions, as well as characterize a mechanotransduction mechanism that mediates oligodendrocyte responses. Mechanical stretch caused a transient and reversible myelin protein loss in oligodendrocytes. Cell death was not observed. Myelin protein loss was accompanied by an increase in intracellular Ca and Erk1/2 activation. Chelating Ca or inhibiting Erk1/2 activation was sufficient to block the stretch-induced loss of myelin protein. Further biochemical analyses revealed that the stretch-induced myelin protein loss was mediated by the release of Ca from the endoplasmic reticulum (ER) and subsequent Ca -dependent activation of Erk1/2. Altogether, our findings characterize an Erk1/2-dependent mechanotransduction mechanism in mature oligodendrocytes that de-stabilizes the myelination program.
脑内髓鞘丢失是创伤性脑损伤（TBI）的常见现象，是由头部受到撞击引起的加速力引起的。快速和突然的头部运动，无论是由于剧烈的打击和/或颠簸引起的，都会导致脑组织的快速拉伸，而白质束内的长轴突特别容易受到这种机械应变的影响。最近的研究表明，力学转导在调节少突胶质细胞前体细胞分化为少突胶质细胞中起着重要作用。然而，对于机械应变对成熟少突胶质细胞及其相关髓鞘鞘稳定性的影响知之甚少。我们使用体外细胞拉伸装置来解决这些问题，并描述介导少突胶质细胞反应的力学转导机制。机械拉伸导致少突胶质细胞中的髓鞘蛋白发生短暂和可逆的丢失。没有观察到细胞死亡。髓鞘蛋白丢失伴随着细胞内 Ca 增加和 Erk1/2 激活。螯合 Ca 或抑制 Erk1/2 激活足以阻止拉伸诱导的髓鞘蛋白丢失。进一步的生化分析表明，拉伸诱导的髓鞘蛋白丢失是通过内质网（ER）中 Ca 的释放和随后 Ca 依赖性 Erk1/2 的激活介导的。总之，我们的研究结果描述了成熟少突胶质细胞中依赖 Erk1/2 的力学转导机制，该机制使髓鞘化程序不稳定。
