Ethyl Pyruvate–Derived Transdifferentiation of Astrocytes to Oligodendrogenesis in Cuprizone-Induced Demyelinating Model

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.