In the mouse cortex, oligodendrocytes regain a plastic capacity, transforming into astrocytes after acute injury

Acute brain injuries evoke various response cascades directing the formation of the glial scar. Here, we report that acute lesions associated with hemorrhagic injuries trigger a re-programming of oligodendrocytes. Single-cell RNA sequencing highlighted a subpopulation of oligodendrocytes activating astroglial genes after acute brain injuries. By using PLP-DsRed1/GFAP-EGFP and PLP-EGFPmem/GFAP-mRFP1 transgenic mice, we visualized this population of oligodendrocytes that we termed AO cells based on their concomitant activity of astro- and oligodendroglial genes. By fate mapping using PLP- and GFAP-split Cre complementation and repeated chronic in vivo imaging with two-photon laser-scanning microscopy, we observed the conversion of oligodendrocytes into astrocytes via the AO cell stage. Such conversion was promoted by local injection of IL-6 and was diminished by IL-6 receptor-neutralizing antibody as well as by inhibiting microglial activation with minocycline. In summary, our findings highlight the plastic potential of oligodendrocytes in acute brain trauma due to microglia-derived IL-6. [Display omitted] •Upon acute brain injuries, oligodendrocytes can activate astroglial genes•Oligodendrocytes can become astrocytes via the transitional AO cell status•Microglia-derived IL-6 drives the transition of oligodendrocytes to AO cells Bai et al. identify a subset of cells in mice with concomitant activation of astro- and oligo-dendroglial genes (termed AO cells), derived from oligodendrocytes upon acute brain injury. AO cells differentiate into astrocytes, oligodendrocytes, and oligodendrocyte precursors, and microglial-derived interleukin-6 promotes the transition of mature oligodendrocytes to AO cells.