Regenerative Potential of Injured Spinal Cord in the Light of Epigenetic Regulation and Modulation

Abstract

A spinal cord injury is a form of physical harm imposed on the spinal cord that causes disability and, in many cases, leads to permanent mammalian paralysis, which causes a disastrous global issue. Because of its non-regenerative aspect, restoring the spinal cord’s role remains one of the most daunting tasks. By comparison, the remarkable regenerative ability of some regeneration-competent species, such as some Urodeles (Axolotl), Xenopus, and some teleost fishes, enables maximum functional recovery, even after complete spinal cord transection. During the last two decades of intensive research, significant progress has been made in understanding both regenerative cells’ origins and the molecular signaling mechanisms underlying the regeneration and reconstruction of damaged spinal cords in regenerating organisms and mammals, respectively. Epigenetic control has gradually moved into the center stage of this research field, which has been helped by comprehensive work demonstrating that DNA methylation, histone modifications, and microRNAs are important for the regeneration of the spinal cord. In this review, we concentrate primarily on providing a comparison of the epigenetic mechanisms in spinal cord injuries between non-regenerating and regenerating species. In addition, we further discuss the epigenetic mediators that underlie the development of a regeneration-permissive environment following injury in regeneration-competent animals and how such mediators may be implicated in optimizing treatment outcomes for spinal cord injurie in higher-order mammals. Finally, we briefly discuss the role of extracellular vesicles (EVs) in the context of spinal cord injury and their potential as targets for therapeutic intervention.

Epigenetic processes associated with neonatal spinal transection

“…Other studies report that exercise shortly after injury (Brown et al., 2011) may in part restore synaptic plasticity and BDNF levels following SCI and promote locomotive recovery (Leech & Hornby, 2017; Ying et al., 2005), and that BDNF upregulation is often associated with functional recovery (Garraway & Huie, 2016). Given that epigenetic regulation of several genes is associated with spinal cord regeneration in reparative species (Gupta et al., 2023), perturbing BDNF‐associated epigenetic mechanisms in the injured spinal cord warrants further research in both the mechanistic etiology and treatment efforts associated with SCI. A combination of intervention strategies including neurotrophin delivery and exercise has been proposed as being a sound intervention strategy (Fu et al., 2016).…”

“…However, the administration of an HDACi ameliorated these epigenetic consequences of injury, promoting neuronal rewiring and a minor increase in functional recovery on a pellet grasping task (Sada et al., 2020). Moreover, several miRNA's associated with posttranscriptional modifications of downstream gene targets are associated with promoting axonal growth and functional recovery following SCI (Diaz Quiroz et al., 2014; Gupta et al., 2023; Yu et al., 2011). Indeed, one proposed treatment effort is the delivery of engineered extracellular vesicles (EV's) containing a cocktail of miRNA's and enzymes to alter DNA methylation, histone modifications, and posttranscriptional modification (Gupta et al., 2023) after SCI.…”

“…Moreover, several miRNA's associated with posttranscriptional modifications of downstream gene targets are associated with promoting axonal growth and functional recovery following SCI (Diaz Quiroz et al., 2014; Gupta et al., 2023; Yu et al., 2011). Indeed, one proposed treatment effort is the delivery of engineered extracellular vesicles (EV's) containing a cocktail of miRNA's and enzymes to alter DNA methylation, histone modifications, and posttranscriptional modification (Gupta et al., 2023) after SCI. One recent meta‐analysis assessing the efficacy of miRNA associated EV delivery to promote recovery was efficacious in improving hindlimb motor function if delivered within 2 weeks of injury (Yang et al., 2022), which aligns with our observed heightened BDNF expression levels and improved functional recovery after 2 weeks observed here.…”

“…A combination of intervention strategies including neurotrophin delivery and exercise has been proposed as being a sound intervention strategy (Fu et al, 2016). Indeed, the use of multiple Although sound reparative mechanisms in rodents and humans remains partially elusive, work using species that can self-regenerate has been informative regarding additional mechanisms to explore in future research, including other epigenetic regulators (for review, see Gupta et al, 2023;Zhang et al, 2020). Indeed, other work has suggested mechanisms implicated in spinal cord regeneration in numerous species that are regenerative-competent include histone deacetylation associated with HDAC proteins (Tseng et al, 2011;Voss et al, 2019) or specific acetylation of histone octamers on their lysine tails such as h3k9ac (Suzuki et al, 2016).…”

Epigenetic cross-talk between Sirt1 and Dnmt1 promotes axonal regeneration after spinal cord injury in zebrafish

“…The intricate regulation of stage-specific gene expression in the nervous system during repair and regeneration involves not only transcriptional mechanisms but also encompasses epigenetic modulation. Recent investigations have highlighted that SCI can instigate epigenetic modifications capable of influencing regeneration-associated genes (RAGs), thereby exerting control over the capacity for regeneration and axonal regrowth (11,12).…”