| Background: Human adipose-derived stem cells(ASCs)have a potential for the treatment of peripheral nerve injury.Recent studies have demonstrated that stem cells play therapeutic role by secreting paracrine factors,and exosomes play a key role in paracrine mechanisms.We aimed to investigate the effect of human ASCs derived exosomes(ASC-Exos)on peripheral nerve regeneration in vitro and in vivo.Methods: ASC-Exos were isolated by differential ultracentrifugation and characterized by transmission electron microscope(TEM),nanoparticle tracking analysis(NTA)and Western blot(WB).ASC-Exos were labeled with Dil,and the uptake of ASC-Exos by SCs and DRGs was determined by immunofluorescence staining.We examined the effects of ASC-Exos on SC migration,proliferation,myelination and the neurite outgrowth of dorsal root ganglia(DRG)in vitro.Next,we analyzed the secretion and expression level of gene associated with neurotrophic factors in SCs after ASC-Exos stimulation.Furthermore,we evaluated the effect of ASC-Exos on axon regeneration,myelination and denervation muscle atrophy,using a rat sciatic nerve transection model in vivo.Results: ASC-Exos could be preferentially internalized by SCs and significantly promoted SC proliferation,migration,myelination and secretion of neurotrophic factors.The gene expression of proliferation(ccnd1,ccna2),migration(Rac1,Mmp9,Cthrc1)and neurotrophic factors(NGF,BDNF,CTNF)was obviously upregulated after ASC-Exos treatment.We next evaluated the efficacy of ASC-Exo therapy in a rat sciatic nerve transection model with a 10-mm gap.Axon regeneration,myelination and restoration of denervation muscle atrophy in ASC-Exos treated group was significantly improved compared to vehicle control.Conclusions: Our data suggest that ASC-Exos mainly optimize SC function to facilitate axon regeneration and myelination.Thus,our results demonstrate that ASC-Exos could be a novel treatment paradigm for peripheral nerve regeneration. |
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