Cellular and molecular control of myelin repair

While neuronal death is rarely followed by neuronal replacement, oligodendrocytic loss and demyelination often trigger a reactive response from progenitors that produce new oligodendrocytes (OLG) and regenerate myelin. However this spontaneous repair attempt is not always efficient, and better understanding of this regenerative process is needed to design new therapies. Two cell populations have been shown to contribute to OLG replacement: parenchymal oligodendrocyte precursor cells (pOPC) and neural stem / progenitor cells derived from the subventricular zone (SVZdNP). In mice exposed to cuprizone, a rodent model of multiple sclerosis leading to extensive demyelination, notably in the corpus callosum (CC), both cell populations contribute to comparable extent to OLG replacement in the CC, but show remarkable regional complementarity. Areas with high SVZdNP contribution exhibit less demyelination and lower density of activated microglia then areas where pOPC are the main actors of OLG replacement. This led us to hypothesize that these 2 sources of cells may play different roles in myelin repair. In particular, we would like to answer the following question: could endogenous SVZdNP present indirect beneficial effects on myelin repair through modifications of the microenvironment, as observed after stem cell grafts? In order to get insight into their immunomodulatory properties we isolated SVZdNP that had migrated to the demyelinated CC of cuprizone-treated mice and performed single cell RNA sequencing. We also sorted microglial cells from CC areas enriched in SVZdNP and from CC areas enriched in pOPC in order to compare their activation phenotype. These sequencing experiments have now been completed. Thorough bioinformatic analysis remains to be done to identify candidate genes involved in the dialog between SVZdNP and microglial cells. Candidates with available tools (antibodies, genetic models…) will be further examined. Their expression will be checked in our model, and their functional significance validated both in vitro and in vivo. This work should provide precious information to help decipher if and how SVZdNP render the microenvironment more favorable to spontaneous repair and to identify candidate factors involved in their dialog with microglia.

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