Exosomes Derived From miR-133b-Modified Mesenchymal Stem Cells Promote Recovery After Spinal Cord Injury.

Dong Li,Xiyang Yao,Haitao Shen,Xiang Li,Xiaocheng Lu,Haiying Li,Peng Zhang,Jiang Wu

doi:10.3389/fnins.2018.00845

Abstract

Dysregulation of microRNAs (miRNAs) has been found in injured spinal cords after spinal cord injury (SCI). Previous studies have shown that miR-133b plays an important role in the differentiation of neurons and the outgrowth of neurites. Recently, exosomes have been used as novel biological vehicles to transfer miRNAs locally or systemically, but little is known about the effect of the delivery of exosome-mediated miRNAs on the treatment of SCI. In the present study, we observed that mesenchymal stem cells, the most common cell types known to produce exosomes, could package miR-133b into secreted exosomes. After SCI, tail vein injection of miR-133b exosomes into rats significantly improved the recovery of hindlimb function when compared to control groups. Additionally, treatment with miR-133b exosomes reduced the volume of the lesion, preserved neuronal cells, and promoted the regeneration of axons after SCI. We next observed that the expression of RhoA, a direct target of miR-133b, was decreased in the miR-133b exosome group. Moreover, we showed that miR-133b exosomes activated ERK1/2, STAT3, and CREB, which are signaling pathway proteins involved in the survival of neurons and the regeneration of axons. In summary, these findings demonstrated that systemically injecting miR-133b exosomes preserved neurons, promoted the regeneration of axons, and improved the recovery of hindlimb locomotor function following SCI, suggesting that the transfer of exosome-mediated miRNAs represents a novel therapeutic approach for the treatment of SCI.

Highlights

Traumatic spinal cord injury (SCI) often results in irreversible neurological deficits, with an annual incidence of 15–40 cases per million throughout the world (Sekhon and Fehlings, 2001)
The results revealed that the expression of miR-133b was significantly downregulated at 24 h or later following SCI (Figure 1A)
QRTPCR revealed that the expression levels of miR-133b were approximately 2.5-fold higher in exosomes derived from miR133b-transfected mesenchymal stem cells (MSCs) than in those from MSCs transfected with miR-con. These results demonstrated that MSCs efficiently packaged miR-133b into secreted exosomes

Summary

Introduction

Traumatic spinal cord injury (SCI) often results in irreversible neurological deficits, with an annual incidence of 15–40 cases per million throughout the world (Sekhon and Fehlings, 2001). Major progress has been made on neuroprotection and regeneration in preclinical studies; miR-133b Promotes Recovery After SCI finding effective treatments for SCI remains a challenge for basic science and clinical investigators (Dietz and Fouad, 2014). Recent studies have shown that miRNAs play important roles in synaptic activity, regeneration, and neurogenesis in the central nervous system (CNS). Several miRNAs have been reported as potentially novel targets for the treatment of SCI, including miR-486, miR-21, and miR-126 (Jee et al, 2012; Hu et al, 2013, 2015). Our previous study indicated that miR-133b promotes the outgrowth of neurites by targeting Ras homolog gene family member A (RhoA) in vitro (Lu et al, 2015)

Methods

Results

Conclusion