Phloretin enhances remyelination by stimulating OPC differentiation

the number of activated and quiescent NSCs, indicating that ET-1 signaling is required for maintenance of NSCs in the healthy adult mouse. Following focal demyelination of the corpus callosum, SVZ NSCs upregulated expression of ET-1. Ablation of ET-1 reduced the percentages of proliferating NSCs and proliferating OPCs in the SVZ, suggesting that ET-1 plays a critical role in the SVZ proliferative response to injury. RNAseq of cultured primary NSCs and OPCs treated with ET-1 identified genes involved in stem cell maintenance, including Notch signaling, and OPC migration. Lastly, we confirmed that ET-1 and EDNRB expression are conserved in the adult human SVZ, indicating that this pathway may be a potential target for promoting SVZ-mediated cellular repair. Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Why endogenous repair mechanisms frequency fail in these disorders is poorly understood, however, there is now strong evidence that this is related to an overly inflammatory microenvironment combined with the intrinsic inability of oligodendrocyte precursor cells (OPCs) to differentiate into mature myelinating cells. Previously, we found that phloretin, a flavonoid abundantly present in apples and strawberries reduces neuroinflammation by driving macrophages towards an anti-inflammatory phenotype. Here, we show that phloretin also markedly stimulates remyelination in ex vivo and in vivo animals models. However, improved remyelination was attributed to a direct impact of phloretin on OPC maturation and occurred autonomously from alterations in microglia function and inflammation. Mechanistically, phloretin activated the fatty acid sensing nuclear receptor peroxisome proliferator-activated receptor gamma PPARy, thereby promoting the maturation of OPC. Altogether, our findings indicate that phloretin has pro-regenerative properties in CNS disorders, with potentially broad implications for the development of therapeutic strategies and dietary interventions.

Publication year:2021

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