Exosomes derived from miR-26a-modified MSCs promote axonal regeneration via the PTEN/AKT/mTOR pathway following spinal cord injury

Abstract

Background Exosomes derived from the bone marrow mesenchymal stem cell (MSC) have shown great potential in spinal cord injury (SCI) treatment. This research was designed to investigate the therapeutic effects of miR-26a-modified MSC-derived exosomes (Exos-26a) following SCI. Methods Bioinformatics and data mining were performed to explore the role of miR-26a in SCI. Exosomes were isolated from miR-26a-modified MSC culture medium by ultracentrifugation. A series of experiments, including assessment of Basso, Beattie and Bresnahan scale, histological evaluation, motor-evoked potential recording, diffusion tensor imaging, and western blotting, were performed to determine the therapeutic influence and the underlying molecular mechanisms of Exos-26a in SCI rats. Results Exos-26a was shown to promote axonal regeneration. Furthermore, we found that exosomes derived from miR-26a-modified MSC could improve neurogenesis and attenuate glial scarring through PTEN/AKT/mTOR signaling cascades. Conclusions Exosomes derived from miR-26a-modified MSC could activate the PTEN-AKT-mTOR pathway to promote axonal regeneration and neurogenesis and attenuate glia scarring in SCI and thus present great potential for SCI treatment. Graphical abstract

The Effect of miRNA-Modified Exosomes in Animal Models of Spinal Cord Injury: A meta-Analysis

“…Several studies reported intravenous administration of the same dose of exosomes (100 μg, 200 µg). The studies used many different miRNAs to modify exosomes, including miR-26a ( Chen et al, 2021 ), miR-126 ( Huang et al, 2020 ), miR-145-5p ( Jiang and Zhang, 2021 ), miR-381 ( Jia et al, 2021 ), miR-21 ( Ji et al, 2019 ; Kang et al, 2019 ), miR-216a-5p ( Liu et al, 2020 ), miR-421-3p ( Wang et al, 2020 ), miR-29b ( Yu et al, 2019 ) and miR-181c ( Zhang M. et al, 2021 ).…”

“…Li ( Li S.-P. et al, 2018 ) found that rats that received miR-133-modified exosomes recovered well, and that these exosomes promoted axon growth and reduced the levels of RhoA protein in the injured spinal cord, indicating that RhoA is a direct target of miR-133, and suggesting that the RhoA/ROCK signaling pathway plays a critical role in spinal cord neuron death after acute SCI ( Wu et al, 2017 ). Chen found that exosomes derived from miR-26a-modified MSCs activate the PTEN-AKT-mTOR pathway, and promote axon regeneration and neurogenesis, and reduce glial scar formation in SCI( Chen et al, 2021 ). Our current meta-analysis findings suggest that miRNA-modified exosomes can significantly improve motor function in the rodent SCI model.…”

Emerging Exosomes and Exosomal MiRNAs in Spinal Cord Injury

“…Therefore, in the early stage of SCI, if one can effectively reduce neuronal cells apoptosis, promote vascular remodeling, stimulate neuronal regeneration, promote axon regeneration, regulate microglial activation, and inhibit inflammation, it is possible to effectively slow down the process of SCI and improve the prognosis of SCI patients. Because of the presence of various therapeutic growth factors and miRNAs in exosomes (Tomasoni et al, 2013;Anderson et al, 2016;Chen et al, 2021), in recent years, many studies have reported that exosomes have shown therapeutic effects on CNS diseases, including SCI (Table 1 and Figure 3).…”

Dorsal Root Injury—A Model for Exploring Pathophysiology and Therapeutic Strategies in Spinal Cord Injury

“…MiR-155 resulted in improved regeneration and functional recovery after spinal cord dorsal column injury, effects that appear to be mediated through the reduced inflammatory response as well as induction of regeneration-associated genes [ 93 ]. miRNA-26a primed mesenchymal stem cells were shown to promote spinal cord repair through the mTOR pathway [ 94 ], and miR-20a and miR 155-5p promotes the growth of injured sensory axons in the spinal cord dorsal column via the cAMP/PKA [ 95 ] and PDZ-RhoGEF/RhoA/GAP43 [ 96 ] pathways, respectively. Non-coding RNAs have also been implicated in neuropathic pain [ 97 , 98 ], a common, severely disabling sequelae of spinal root or spinal cord lesion.…”