Electroacupuncture-Regulated miR-34a-3p/PDCD6 Axis Promotes Post-Spinal Cord Injury Recovery in Both In Vitro and In Vivo Settings

Abstract

Electroacupuncture (EA) could enhance neuroregeneration and posttraumatic conditions; however, the underlying regulatory mechanisms remain ambiguous. PDCD6 (programmed cell death 6) is an established proapoptotic regulator which is responsible for motoneuronal death. However, its potential regulatory role in post-spinal cord injury (SCI) regeneration has remained largely unknown. Further investigations are warranted to clarify the involvement of PDCD6 post-SCI recovery and the underlying mechanisms. In our study, based on bioinformatics prediction, we found that miR-34a-3p might be an upstream regulator miRNA for PDCD6, which was subsequently validated through combined utilization of the qRT-PCR, western blot, and dual-luciferase reporter system. Our in vitro results showed that miR-34a-3p might promote the in vitro differentiation of neural stem cell (NSC) through suppressing PDCD6 and regulating other important neural markers such as fibroblast growth factor receptor 1 (FGFR1), MAP1/2 (MAP kinase kinases 1/2), myelin basic protein (MBP), βIII-tubulin Class III β-tubulin (βIII tubulin), and glial fibrillary acidic protein (GFAP). Notably, in the post-SCI rat model, exogenous miR-34a-3p agomir obviously inhibited the expression of PDCD6 at the protein level and promoted neuronal proliferation, motoneurons regeneration, and axonal myelination. The restorations at cellular level might contribute to the improved hindlimbs functions of post-SCI rats, which was manifested by the Basso-Beattie-Bresnahan (BBB) locomotor test. The impact of miR-34a-3p was further promoted by EA treatment in vivo. Conclusively, this paper argues that a miR-34a-3p/PDCD6 axis might be a candidate therapeutic target for treating SCI and that the therapeutic effect of EA is driven through this pathway.

Transcranial direct current stimulation-mediated miR-298-5p downregulation enhances autophagy by targeting LC3 to promote motor recovery after spinal cord injury

“…Previously, some studies had suggested that SCI may perturb miRNA homeostasis [11]. Depending on their downstream target genes, the dysregulation of these miRNAs might result in either alleviated or aggravated post-SCI conditions [23,48].…”

“…However, to date, only a few satisfactory therapies for neural repair have been established [9,10]. This is likely due to the multidimensional pathophysiological changes that develop in injured regions [10][11][12]. The pathophysiology of SCI involves primary and secondary injury mechanisms [13].…”

Electroacupuncture-Modulated MiR-106b-5p Expression Enhances Autophagy by Targeting Beclin-1 to Promote Motor Function Recovery After Spinal Cord Injury in Rats

“…As important regulators of normal nervous functions, miRNAs are closely related to morphological and functional changes in the nervous system [ 31 ]. Following a SCI, the homeostasis of many miRNAs is disturbed, and the aberrantly dysregulated miRNAs can either alleviate or aggravate conditions after an SCI, as dictated by their downstream target genes [ 32 ]. For example, miR-21 has been found to play an important role in limiting secondary neuronal apoptosis following an SCI [ 24 ], while Zhou et al [ 33 ] demonstrated that miR-27a can facilitate SCI recovery by regulating the autophagy flux for neuroprotection.…”

Multifaceted roles of PDCD6 both within and outside the cell

“…PDCD6 is also implicated in the pathogenesis of other diseases. Recent work showed that suppressing PDCD6 expression appears to promote neuronal proliferation, motoneuron regeneration, and axonal myelination in a rat model of spinal cord injury (Ma et al, 2022). A new study demonstrated that PDCD6 is widely expressed in both mouse and human inner ear hair cells and it was identified as a new age‐related hearing loss gene by rare‐variant association analysis (Cornejo‐Sanchez et al, 2023).…”