Microglia-Derived Exosomal microRNA-151-3p Enhances Functional Healing After Spinal Cord Injury by Attenuating Neuronal Apoptosis via Regulating the p53/p21/CDK1 Signaling Pathway.

Chengjun Li,Chunyue Duan,Zixiang Luo,Tian Qin,Yudong Liu,Jianzhong Hu,Jinyun Zhao,Wei Peng,Yong Cao,Hongbin Lu,Haicheng Wen

doi:10.3389/fcell.2021.783017

Abstract

Spinal cord injury (SCI) is a catastrophic event mainly involving neuronal apoptosis and axonal disruption, and it causes severe motor and sensory deficits. Due to the complicated pathological process of SCI, there is currently still a lack of effective treatment for SCI. Microglia, a type of immune cell residing in the central nervous system (CNS), need to respond to various stimuli to protect neuronal cells from death. It was also reported that microRNAs (miRNAs) had been identified in microglia-derived exosomes that can be taken up by neurons. However, the kinds of miRNAs in exosome cargo derived from microglia and the underlying mechanisms by which they contribute to neuroprotection after SCI remain unknown. In the present study, a contusive SCI mouse model and in vitro experiments were applied to explore the therapeutic effects of microglia-derived exosomes on neuronal apoptosis, axonal regrowth, and functional recovery after SCI. Then, miRNA analysis, rescue experiments, and luciferase activity assays for target genes were performed to confirm the role and underlying mechanism of microglia-derived exosomal miRNAs in SCI. We revealed that microglia-derived exosomes could promote neurological functional recovery by suppressing neuronal apoptosis and promoting axonal regrowth both in vivo and in vitro. MicroRNA-151-3p is abundant in microglia-derived exosomes and is necessary for mediating the neuroprotective effect of microglia-derived exosomes for SCI repair. Luciferase activity assays reported that P53 was the target gene for miR-151-3p and that p53/p21/CDK1 signaling cascades may be involved in the modulation of neuronal apoptosis and axonal regrowth by microglia-derived exosomal microRNA-151-3p. In conclusion, our data demonstrated that microglia-derived exosomes (microglia-Exos) might be a promising, cell-free approach for the treatment of SCI. MicroRNA-151-3p is the key molecule in microglia-derived exosomes that mediates the neuroprotective effects of SCI treatments.

Highlights

Spinal cord injury (SCI) is a devastating central nervous traumatic disease that can lead to temporary or permanent neurological deficits (Ahuja CS. et al, 2017; Khorasanizadeh et al, 2019)
TEM, nanotracking analysis, and Western blot were used to identify the exosomes isolated from miR-151-3pIN microglia and miR-151-3pNC microglia, and we found no difference in exosome diameters and surface markers between the two groups (Supplementary Figure S1B,D)
Our present study demonstrated that exosomes derived from microglial cells could be taken up by neurons and further inhibited neuronal apoptosis, promoted axonal growth, and facilitated functional neurological recovery after SCI

Summary

Introduction

Spinal cord injury (SCI) is a devastating central nervous traumatic disease that can lead to temporary or permanent neurological deficits (Ahuja CS. et al, 2017; Khorasanizadeh et al, 2019). Spinal cord injury (SCI) is a devastating central nervous traumatic disease that can lead to temporary or permanent neurological deficits Et al, 2017; Khorasanizadeh et al, 2019). The incidence of SCI is high, approximately 23.7/ million in China (Hao et al, 2021). A flourishing number of novel strategies have been demonstrated that could promote functional recovery after spinal cord injury in animal models. There are no fully restorative treatments for SCI in the clinic Most SCI patients are young men and are a main part of the social workforce, and long-term disability imposes a high psychological and financial burden. There is a high need to identify a novel effective intervention for repairing injured spinal cord tissue

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Results

Conclusion