Enhanced Nerve Regeneration by Exosomes Secreted by Adipose-Derived Stem Cells with or without FK506 Stimulation

Abstract

Exosomes secreted by adipose-derived stem cells (ADSC-exo) reportedly improve nerve regeneration after peripheral nerve injury. Herein, we investigated whether pretreatment of ADSCs with FK506, an immunosuppressive drug that enhances nerve regeneration, could secret exosomes (ADSC-F-exo) that further augment nerve regeneration. Designed exosomes were topically applied to injured nerve in a mouse model of sciatic nerve crush injury to assess the nerve regeneration efficacy. Outcomes were determined by histomorphometric analysis of semi-thin nerve sections stained with toluidine blue, mouse neurogenesis PCR array, and neurotrophin expression in distal nerve segments. Isobaric tags for relative and absolute quantitation (iTRAQ) were used to profile potential exosomal proteins facilitating nerve regeneration. We observed that locally applied ADSC-exo and ADSC-F-exo significantly enhanced nerve regeneration after nerve crush injury. Pretreatment of ADSCs with FK506 failed to produce exosomes possessing more potent molecules for enhanced nerve regeneration. Proteomic analysis revealed that of 192 exosomal proteins detected in both ADSC-exo and ADSC-F-exo, histone deacetylases (HDACs), amyloid-beta A4 protein (APP), and integrin beta-1 (ITGB1) might be involved in enhancing nerve regeneration.

The Therapeutic Role of ADSC-EVs in Skin Regeneration

“…Recent studies have demonstrated the beneficial role of ADSC-EVs in multiple tissue regeneration, such as skin ( 59 ), tendon ( 60 ), bone ( 61 ), and nerve tissue ( 62 ). ADSC-EVs exert a regenerative effect by delivering signals to cells with single or coordinated actions of biomolecules.…”

The Therapeutic Potential of Exosomes in Soft Tissue Repair and Regeneration

“…The higher the levels, the more powerful the support for neuron regeneration. Consistently, Rau et al observed significantly increased expression of NGF and GDNF in the nerve segments of crush injury mice after ADSC-Exos treatment, compared with control mice [ 168 ].…”

“…It was not until recently that exosomes and their impact on SCs have come into focus. Studies have demonstrated that exosomes from various sources can enhance peripheral nerve development and regeneration by activating SCs, regulating their differentiation and proliferation, and inhibiting their apoptosis, as well as optimizing their functions during remyelination [ 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ].…”

Exosomes Secreted by Adipose-Derived Stem Cells Following FK506 Stimulation Reduce Autophagy of Macrophages in Spine after Nerve Crush Injury

“…The combined use of FK506 and ADSCs has been used in cell therapy for organ transplantation [38] or vascularized composite allotransplantation [39,40]. In a mouse model of sciatic nerve crush injury, we showed that the topically sprayed exosomes, which were secreted by ADSCs under the condition of FK506 stimulation (ADSC-F-exo), exhibit similar effects to those of ADSC-exo on enhancing nerve regeneration [41]. Under the hypothesis that the topically sprayed ADSC-F-exo around the crush nerve segment can also rescue the autophagy of macrophages in the milieu surrounding the innervated neurons, this study was performed with the aim to assess the effect of ADSC-F-exo treatment on the autophagy of macrophages in the spinal segments following nerve crush injury, with the additional goal of exploring the potential effective proteins inside the exosomes.…”