WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury

Abstract

The treatment of traumatic brain injury (TBI) remains a challenge due to limited knowledge about the mechanisms underlying neuronal regeneration. This current study compared the expression of WNT genes during regeneration of injured cortical neurons. Recombinant WNT3A showed positive effect in promoting neuronal regeneration via in vitro, ex vivo, and in vivo TBI models. Intranasal administration of WNT3A protein to TBI mice increased the number of NeuN+ neurons without affecting GFAP+ glial cells, compared to control mice, as well as retained motor function based on functional behavior analysis. Our findings demonstrated that WNT3A, 8A, 9B, and 10A promote regeneration of injured cortical neurons. Among these WNTs, WNT3A showed the most promising regenerative potential in vivo, ex vivo, and in vitro.

Epigenetic Regulation of WNT3A Enhancer during Regeneration of Injured Cortical Neurons

“…For the in vitro TBI model, cortical neurons were injured by scraping with a p20 tip to generate gaps over the culture on DIV8 ( Figure 1A). During neuronal regeneration, re-growing neurites extend into the injured gaps as previously demonstrated [14], and the neuronal cultures were then subjected to further experimental approaches.…”

“…Our laboratory previously characterized WNT3A as a promising RAG of which expression was induced during regeneration of injured cortical neurons [14]. Addition of recombinant WNT3A significantly promotes neurite re-growth of injured cortical neurons and organotypic brain slices.…”

“…During regeneration, injured neurites re-grew into the injury gaps ( Figure 1B). Based on our previous data, neuronal regeneration of injured cortical neurons are relatively active in 48 h upon injury [14]. Therefore, un-injured control or injured neuronal samples on DIV9 and 10 were collected respectively for ChIP-seq experiments.…”

“…To this point, we performed chromatin immunoprecipitation-sequencing (ChIP-seq) of histone marks, tri-methylation of histone H3 at lysine 4 (H3K4me3) and histone H3 lysine 27 acetylation (H3K27ac), to investigate transcriptional regulation of candidate regeneration-associated genes (RAGs). Our laboratory identified WNT3A gene as a promising RAG of which expression was up-regulated during regeneration of injured cortical neurons [14]. Nonetheless, the transcriptional regulation of WNT3A expression remains to be determined.…”

Gene Expression in the Physiology and Pathology of Neurons

“…The two articles included in the SI expand the relevance of two aspects already emphasized in the reviews. Linyi Chen, together with his colleagues, illustrates the role of the WNT3A gene in neuronal regeneration [ 8 ]. Such important results are connected to the neuronal reprogramming presented in the review by Wong.…”