Advancing in vivo glia-to-neuron reprogramming as an innovative approach for brain repair: promises, disappointments, and breakthroughs
1: Institute of Psychiatry, Psychology & Neuroscience Centre for Developmental Neurobiology & MRC Centre for Neurodevelopmental Disorders, King's College London
With the completion of developmental neurogenesis before birth, no new neurons are added naturally to the mammalian cerebral cortex. I will present our efforts of aiming at lineage-conversion of glial cells (i.e., astrocytes and NG2 glia) into induced interneurons by virus-mediated expression of the proneural gene achaete-scute complex-like 1 (Ascl1) and the cell death regulator Bcl2 in the healthy and injured mouse cerebral cortex. I will discuss our evidence for successful reprogramming of proliferative glia into interneuron-like cells by retrovirus-mediated expression of reprogramming factors and, , albeit encoding the same cocktail of reprogramming factors, for failed reprogramming upon targeting non-dividing glia by adeno-associated viruses. Supporting the authenticity of reprogramming of glia into induced interneuron-like cells, converted cells are found to be dividing by the time of retrovirus transduction and a substantial proportion of them can be genetically-fate mapped as originating from astrocytes. I will furthermore present data that indicate enhanced reprogramming by a phosphorylation-defective variant of Ascl1. Surprisingly, this variant can induce molecular and electrophysiological hallmarks of fast-spiking, parvalbumin-positive interneurons, even in cortical layers naturally devoid of this interneuron type. Finally, I will discuss some of the barriers induced interneuron-like cells face on their way to full maturation.