The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation
The aminosteroid U73122 promotes oligodendrocytes generation and myelin formation
复制标题
DOI：
10.1038/s41401-023-01183-7
复制
发表时间：
2023-11-07
影响因子：
8.2
通讯作者：
Xie，Xin
中科院分区：
文献类型：
--
作者：
Cui，Shi-hao;Suo，Na;Xie，Xin
少突胶质细胞是一种在中枢神经系统中包裹神经元轴突并形成髓鞘的神经胶质细胞。在发育和髓鞘修复期间，OL与少突胶质前体细胞(OPC)分化，后者在多发性硬化症(MS)等脱髓鞘疾病中通常是不够的。据报道，许多因素调节OPC向OL的分化，包括一些G蛋白偶联受体(GPCRs)。为了寻找GPCRs下游可能参与OPC分化的途径，我们发现在实验性自身免疫性脑脊髓炎模型中，磷脂酰肌醇特异性磷脂酶C(PI-PLC)抑制剂U73122显著促进OPC向OL的分化和髓鞘再生。与U73122相近但缺乏PI-PLC抑制活性的类似物U73343也有促进OPC分化的作用，而另一种已报道的PI-PLC抑制剂依德福辛则没有这种作用，提示U73122和U73343促进OPC分化不依赖PLC。尽管U73122和U73343的结构与17-β-雌二醇非常相似，并且这两个化合物都激活雌激素受体erα和erβ，但进一步的研究表明，这些化合物并不是通过erα和/或erβ来促进OPC的分化。RNA-Seq和生物信息学分析表明，U73122和U73343可能调节胆固醇的生物合成。进一步的研究表明，这两种化合物在OPC培养中都增加了14-脱氢酵母醇，这是一种据报道促进OPC分化的类固醇。综上所述，氨基类固醇U73122和U73343通过调节胆固醇生物合成途径促进OPC-to-OL的生成和髓鞘的形成。
Oligodendrocytes (OLs) are glial cells that ensheath neuronal axons and form myelin in the central nervous system (CNS). OLs are differentiated from oligodendrocyte precursor cells (OPCs) during development and myelin repair, which is often insufficient in the latter case in demyelinating diseases such as multiple sclerosis (MS). Many factors have been reported to regulate OPC-to-OL differentiation, including a number of G protein-coupled receptors (GPCRs). In an effort to search pathways downstream of GPCRs that might be involved in OPC differentiation, we discover that U73122, a phosphoinositide specific phospholipase C (PI-PLC) inhibitor, dramatically promotes OPC-to-OL differentiation and myelin regeneration in experimental autoimmune encephalomyelitis model. Unexpectedly, U73343, a close analog of U73122 which lacks PI-PLC inhibitory activity also promotes OL differentiation, while another reported PI-PLC inhibitor edelfosine does not have such effect, suggesting that U73122 and U73343 enhance OPC differentiation independent of PLC. Although the structures of U73122 and U73343 closely resemble 17β-estradiol, and both compounds do activate estrogen receptors Erα and Erβ with low efficacy and potency, further study indicates that these compounds do not act through Erα and/or Erβ to promote OPC differentiation. RNA-Seq and bioinformatic analysis indicate that U73122 and U73343 may regulate cholesterol biosynthesis. Further study shows both compounds increase 14-dehydrozymostenol, a steroid reported to promote OPC differentiation, in OPC culture. In conclusion, the aminosteroids U73122 and U73343 promote OPC-to-OL generation and myelin formation by regulating cholesterol biosynthesis pathway.