Deconstructing reprogramming competence: role of reactive gliosis and proliferation in glia-to-neuron conversion

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Lineage reprogramming of cell identity is an emerging concept for the remodelling and restoration of organs with limited regenerative capacity. In the context of neurological disease, this concept opens the possibility of regenerating neurons from other brain-resident cell types such as glial cells for the repair of diseased brain circuits. Over the past years, we and others have shown that various types of glial cells can be converted into induced neurons (iNs) in vitro and in vivo by forced expression of neurogenic transcription factors. In a recent collaboration between the French and German partners, we succeeded in showing that iNs induced from reactive glia during early stages of the disease can reduce seizure activity in a mouse model of Mesial Temporal Lobe Epilepsy (MTLE). While this opens exciting possibilities, a key question is whether the competence of glial cells to undergo reprogramming into iNs is restricted to reactive glia during early epileptogenesis or can still be induced during the chronic phase when the disease is firmly established. In fact, what confers reprogramming competence to reactive glial cells and whether reprogramming competence can be boosted in glia which has become refractory to neuronal conversion is currently unknown. To address these important questions, in FateXchange, we will therefore tackle the following complementary aims: i) Aim 1: Determine the impact of the transcriptional and chromatin landscapes of reactive glial cell types on reprogramming competence during hippocampal epileptogenesis; ii) Aim 2: Promote reprogramming competence of glia during chronic MTLE. Thus, FateXchange may yield innovative strategies of remodelling brain circuits during chronic disease stages, thereby addressing challenges currently impeding translation of lineage reprogramming to clinical demands.