The Key Research Laboratory of Benefiting Qi for Acting Blood Circulation Method to Treat Multiple Sclerosis of State Administration of Traditional Chinese Medicine, Shanxi University of Chinese Medicine, Taiyuan, 030024, China.
Department of Neurology, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, 200040, China.
Neurotherapeutics. 2021 Jan;18(1):488-502. doi: 10.1007/s13311-020-00947-x. Epub 2020 Nov 2.
Astrocytes redifferentiate into oligodendrogenesis, raising the possibility that astrocytes may be a potential target in the treatment of adult demyelinated lesion. Upon the basis of the improvement of behavior abnormality and demyelination by ethyl pyruvate (EP) treatment, we further explored whether EP affects the function of astrocytes, especially the transdifferentiation of astrocytes into oligodendrogenesis. The results showed that EP treatment increased the accumulation of astrocytes in myelin sheath and promoted the phagocytosis of myelin debris by astrocytes in vivo and in vitro. At the same time, EP treatment induced astrocytes to upregulate the expression of CNTF and BDNF in the corpus callosum and striatum as well as cultured astrocytes, accompanied by increased expression of nestin, Sox2, and β-catenin and decreased expression of Notch1 by astrocytes. As a result, EP treatment effectively promoted the generation of NG2 and PDGF-Ra oligodendrocyte precursor cells (OPCs) that, in part, express astrocyte marker GFAP. Further confirmation was performed by intracerebral injection of primary astrocytes labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). As expected, NG2 OPCs expressing CFSE and Sox2 were elevated in the corpus callosum of mice treated with EP following transplantation, revealing that EP can convert astrocytes into myelinating cells. Our results indicate the possibility that EP lead to effective myelin repair in patients suffering from myelination deficit.Graphical Abstract The diagram of EP action for promoting myelin regeneration in CPZ model. EP promoted migration and enrichment of astrocytes to demyelinated tissue and induced astrocytes to express neurotrophic CNTF and BDNF as well as translation factor nestin, Sox2, and β-catenin, which should contribute to astrocytes to differentiate of oligodendrogenesis. At the same time, EP promoted astrocytes to phagocytized myelin debris for removing the harmful substances of myelin regeneration.
星形胶质细胞再分化为少突胶质细胞，这增加了星形胶质细胞可能成为治疗成人脱髓鞘病变的潜在靶点的可能性。基于丙酮酸乙酯 (EP) 治疗改善行为异常和脱髓鞘的效果，我们进一步探讨了 EP 是否影响星形胶质细胞的功能，特别是星形胶质细胞向少突胶质细胞的转分化。结果表明，EP 处理增加了髓鞘鞘内星形胶质细胞的积累，并促进了星形胶质细胞在体内和体外对髓鞘碎片的吞噬。同时，EP 处理诱导星形胶质细胞在胼胝体和纹状体以及培养的星形胶质细胞中上调 CNTF 和 BDNF 的表达，伴随着星形胶质细胞中巢蛋白、Sox2 和 β-连环蛋白的表达增加和 Notch1 的表达减少。结果，EP 处理有效地促进了 NG2 和 PDGF-Ra 少突胶质前体细胞 (OPC) 的生成，部分表达星形胶质细胞标志物 GFAP。通过脑内注射用羧基荧光素二乙酸琥珀酰亚胺酯 (CFSE) 标记的原代星形胶质细胞进一步证实。正如预期的那样，在 EP 处理后移植到小鼠的胼胝体中，表达 CFSE 和 Sox2 的 NG2 OPC 增加，这表明 EP 可以将星形胶质细胞转化为髓鞘形成细胞。我们的结果表明，EP 有可能导致髓鞘缺陷患者的有效髓鞘修复。
