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

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。在丙酮酸乙酯（EP）治疗改善行为异常和脱髓鞘的基础上，我们进一步探讨了EP是否影响星形胶质细胞的功能，尤其是星形胶质细胞向少突胶质细胞的转分化。结果表明，EP治疗增加在髓鞘星形胶质细胞的积累和星形胶质细胞促进髓鞘碎片的吞噬体内和体外. 同时，EP处理诱导星形胶质细胞上调胼胝体和纹状体以及培养的星形胶质细胞中CNTF和BDNF的表达，伴随星形胶质细胞nestin、Sox2和β-catenin的表达增加，Notch1的表达降低。因此，EP 治疗有效地促进了 NG2 ⁺和 PDGF-Ra ⁺少突胶质前体细胞 (OPCs) 的产生，这些细胞部分表达了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行进一步确认。正如预期的那样，NG2 ⁺移植后用 EP 处理的小鼠胼胝体中表达 CFSE 和 Sox2 的 OPCs 升高，表明 EP 可以将星形胶质细胞转化为髓鞘细胞。我们的结果表明 EP 可能导致髓鞘形成缺陷患者有效的髓鞘修复。

图形概要