Transformation Of Astrocytes Into OPCs And Its Molecu Lar Mechanism

Mammalian central nervous system(CNS)is mainly composed of neurons,oligodendrocytes(OLs)and astrocytes(ACs).OLs wrap neuronal axons to form myelin,and are differentiated from oligodendrocyte progenitor cells(OPCs).OPCs rapidly differentiate into astrocytes when stimu Lated by serum,however they be obtained by cu Lturing mammalian brain or spinal cord cells in serum-containing medium,which suggests that OPCs obtained in the primary cu Lture are not derived from the existing OPCs,they may be transformed from other cells.Recent studies have shown that activated astrocytes possess progenitor cell properties or "stemness." Therefore,we hypothesized that the OPCs obtained in serum-containing cu Lture were converted from astrocytes.In this study,we explore this scientific question and investigate the molecu Lar mechanisms involved.The resu Lts showed that the astrocytes isolated from mouse cerebral cortex expressed neural progenitor cell genes(such as Nestin and EGFR)in addition to astrocyte specific markers such as GFAP,Glast and Aldh1l1,which confirmed that they did possess stem cell characteristics.In single cell cloning experiment,it was found that GFAP+ astrocytes produced Sox10+ OPCs during dividing,which proved that OPCs can be generated from astrocytes.Then,most Sox10+ OPCs obtained in the primary cortical cu Lture of mGFAP-cre/Rosa-tdTomato transgenic mice were found to be tdTomato+,indicating that they evolved from astrocytes.The resu Lts of primary cortical cu Lture of adu Lt mGFAP-cre/Rosa-tdTomato mice were similar as above.mGFAP-cre virus was employed to infect Rosa-tdTomato mouse astrocytes,and it was found that most OPCs also originated from tdTomato+ cells.We then investigated the role of Notch signaling in astrocyte conversion to OPCs by knockout and overexpression.The resu Lts showed that Notch knockout promoted the conversion of astrocytes to OPCs,while enhancement reduced the trend.OPCs converted from astrocytes can be supported by other astrocytes to combat the induced differentiation by serum.We knocked out or enhanced Notch signaling in OPCs,and the resu Lts showed that Notch knockout was beneficial to the self-renewal of OPCs.These resu Lts indicate that primary astrocytes possess the characteristics of stem cells and can be converted to OPCs,and Notch knockout is conducive to the cell fate transformation.Moreover,it has been proved that astrocytes do not support OPCs against the adverse effects of serum through Notch,and the underlying mechanism needs to be further studied.