Mechanical Strain Promotes Oligodendrocyte Differentiation by Global Changes of Gene Expression.
Mechanical Strain Promotes Oligodendrocyte Differentiation by Global Changes of Gene Expression.
复制标题
DOI：
10.3389/fncel.2017.00093
复制
发表时间：
2017
影响因子：
5.3
通讯作者：
Van Vliet KJ
中科院分区：
文献类型：
--
作者：
Jagielska A;Lowe AL;Makhija E;Wroblewska L;Guck J;Franklin RJM;Shivashankar GV;Van Vliet KJ
少突胶质细胞祖细胞（OPC）向少突胶质细胞的分化以及随后的轴突髓鞘形成是脊椎动物中枢神经系统（CNS）发育和再生的关键步骤。越来越多的证据支持机械因素在少突胶质细胞生物学中的重要性。在这里，我们探讨了生理范围内的机械应变对OPC增殖和分化的影响，以及染色质结构，表观遗传学和基因表达的应变相关变化。10-15%的持续拉伸应变抑制OPC增殖并促进向少突胶质细胞的分化。这种应变反应需要与细胞外基质配体的OPC的特异性相互作用。应用应变诱导核形状，染色质组织的变化，并导致增强组蛋白脱乙酰化，与少突胶质细胞分化增加一致。这种反应与表观遗传修饰剂组蛋白去乙酰化酶Hdac 11的mRNA水平增加同时发生。HDAC蛋白的抑制消除了菌株介导的OPC分化的增加，证明了HDAC在菌株向染色质的机械转导中的作用。RNA测序揭示了与菌株相关的基因表达的全球变化。具体而言，与少突胶质细胞分化和轴突-少突胶质细胞相互作用相关的多个基因的表达增加，包括细胞表面配体（Ncam，ephrins），细胞和核骨架基因（Fyn，辅肌动蛋白，肌球蛋白，nesprin，Sun 1），转录因子（Sox 10，Zfp 191，Nkx2.2）和髓鞘基因（Cnp，Plp，Mag）。这些发现显示了机械应变如何传递到细胞核以促进少突胶质细胞分化，并确定了参与机械转导的信号转导途径的全球景观。这些数据提供了一个潜在的新的治疗途径，以提高体内OPC分化的来源。
Differentiation of oligodendrocyte progenitor cells (OPC) to oligodendrocytes and subsequent axon myelination are critical steps in vertebrate central nervous system (CNS) development and regeneration. Growing evidence supports the significance of mechanical factors in oligodendrocyte biology. Here, we explore the effect of mechanical strains within physiological range on OPC proliferation and differentiation, and strain-associated changes in chromatin structure, epigenetics, and gene expression. Sustained tensile strain of 10–15% inhibited OPC proliferation and promoted differentiation into oligodendrocytes. This response to strain required specific interactions of OPCs with extracellular matrix ligands. Applied strain induced changes in nuclear shape, chromatin organization, and resulted in enhanced histone deacetylation, consistent with increased oligodendrocyte differentiation. This response was concurrent with increased mRNA levels of the epigenetic modifier histone deacetylase Hdac11. Inhibition of HDAC proteins eliminated the strain-mediated increase of OPC differentiation, demonstrating a role of HDACs in mechanotransduction of strain to chromatin. RNA sequencing revealed global changes in gene expression associated with strain. Specifically, expression of multiple genes associated with oligodendrocyte differentiation and axon-oligodendrocyte interactions was increased, including cell surface ligands (Ncam, ephrins), cyto- and nucleo-skeleton genes (Fyn, actinins, myosin, nesprin, Sun1), transcription factors (Sox10, Zfp191, Nkx2.2), and myelin genes (Cnp, Plp, Mag). These findings show how mechanical strain can be transmitted to the nucleus to promote oligodendrocyte differentiation, and identify the global landscape of signaling pathways involved in mechanotransduction. These data provide a source of potential new therapeutic avenues to enhance OPC differentiation in vivo.