Neural Precursor Cells as a potential therapeutic approach for Rett Syndrome: identification of the involved molecular mechanisms

Rett syndrome (RTT) is a rare neurodevelopmental disorder, mostly caused by sporadic mutations in the X linked MECP2 gene. RTT, the primary cause of severe intellectual disability in females, currently lacks a cure; nonetheless, the FDA recently approved the first therapy utilizing a tripeptide of IGF1. Neural Precursor Cells (NPCs) can sense the pathological environment when transplanted in it, they secrete beneficial factors that promote immunomodulation, neuroprotection, brain plasticity. These healing functions render NPCs an interesting cellular therapy for treating several neurodegenerative disorders. Since no study addressed their efficacy in neurodevelopmental diseases, we investigated their therapeutic potential in RTT, demonstrating their efficacy in vitro and in vivo. In vivo, we proved significant amelioration of the cognitive and motor defects of RTT mice, together with an increased lifespan, after NPCs transplantation. Through a transwell-based co-culture system, we observed that NPCs promote morphological and synaptic rescues in Mecp2 null neurons, demonstrating that NPCs-mediated beneficial effects arise through “bystander” and paracrine mechanisms. RNA-seq studies of transplanted mice identified a candidate molecule involved in the benefic effects. Likely, the observed beneficial effects depend on the activation of different pathways. Therefore, my PhD studies are focused on exploiting a transwell-based co-culture system to identify the molecular mechanisms set in motion by NPCs in Mecp2-KO neurons. Through a Bulk RNA-seq performed on immature neurons maintained, or not, in co-culture with NPCs we demonstrated positive effects on KO neurons when exposed to the NPCs secreted factors (e.g., enhancement in the synaptic compartment, typically defective in Rett neurons). Simultaneously, to understand which molecules are secreted by NPCs when exposed to the Mecp2-KO environment, their transcriptional profile is being investigated. All data will be presented in the poster session to illustrate the value of this cellular approach in treating RTT and/or in identifying new defective pathways with putative therapeutic value.