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

Abstract

Oligodendrocyte lineage cells (OLCs) are lost in many CNS diseases. Here, we investigate the generation of new OLCs via ectopic expression of Sox10 , Olig2 or Nkx6.2 in mouse postnatal astrocytes. Using stringent analyses including, Aldh1l1-astrocyte fate mapping and live cell imaging we confirm that Sox10 and Olig2 , but not Nkx6.2 , directly convert Aldh1l1 pos astrocytes to MBP+ and PDGFRα+ induced OLCs (iOLCs), respectively. With single cell RNA sequencing (scRNA-seq) we uncover the molecular signatures of iOLCs. Transcriptomic analysis of Sox10 - and control cultures over time reveals a clear trajectory from astrocytes to iOLCs. Finally, perturbation models CellOracle and Fatecode support the idea that Sox10 drives cells towards a terminal iOLC fate. Altogether, this multidimensional analysis shows bonafide conversion of astrocytes to iOLCs using Sox10 or Olig2 and provides a foundation for astrocyte DLR strategies to promote OLC repair.