Direct lineage conversion of postnatal mouse cortical astrocytes to oligodendrocyte lineage cells

Abstract

SUMMARYOligodendrocyte lineage cells (OLCs) are lost in many CNS diseases. Here, we investigate the generation of new OLCs via ectopic expression ofSox10,Olig2orNkx6.2in mouse postnatal astrocytes. Using stringent analyses including, Aldh1l1-astrocyte fate mapping and live cell imaging we confirm thatSox10andOlig2, but notNkx6.2, directly convert Aldh1l1posastrocytes to MBP+ and PDGFRα+ induced OLCs (iOLCs), respectively. With single cell RNA sequencing (scRNA-seq) we uncover the molecular signatures of iOLCs. Transcriptomic analysis ofSox10- and control cultures over time reveals a clear trajectory from astrocytes to iOLCs. Finally, perturbation models CellOracle and Fatecode support the idea thatSox10drives cells towards a terminal iOLC fate. Altogether, this multidimensional analysis shows bonafide conversion of astrocytes to iOLCs usingSox10orOlig2and provides a foundation for astrocyte DLR strategies to promote OLC repair.