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The role of undifferentiated adipose-derived stem cells in peripheral nerve repair.

ABSTRACT: Peripheral nerve injuries impose significant health and economic consequences, yet no surgical repair can deliver a complete recovery of sensory or motor function. Traditional methods of repair are less than ideal: direct coaptation can only be performed when tension-free repair is possible, and transplantation of nerve autograft can cause donor-site morbidity and neuroma formation. Cell-based therapy delivered via nerve conduits has thus been explored as an alternative method of nerve repair in recent years. Stem cells are promising sources of the regenerative core material in a nerve conduit because stem cells are multipotent in function, abundant in supply, and more accessible than the myelinating Schwann cells. Among different types of stem cells, undifferentiated adipose-derived stem cell (uASC), which can be processed from adipose tissue in less than two hours, is a promising yet underexplored cell type. Studies of uASC have emerged in the past decade and have shown that autologous uASCs are non-immunogenic, easy to access, abundant in supply, and efficacious at promoting nerve regeneration. Two theories have been proposed as the primary regenerative mechanisms of uASC: in situ trans-differentiation towards Schwann cells, and secretion of trophic and anti-inflammatory factors. Future studies need to fully elucidate the mechanisms, side effects, and efficacy of uASC-based nerve regeneration so that uASCs can be utilized in clinical settings.

SUBMITTER: Zhang R

PROVIDER: S-EPMC5998619 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The role of undifferentiated adipose-derived stem cells in peripheral nerve repair.

Zhang Rui R Rosen Joseph M JM

Neural regeneration research 20180501 5

Peripheral nerve injuries impose significant health and economic consequences, yet no surgical repair can deliver a complete recovery of sensory or motor function. Traditional methods of repair are less than ideal: direct coaptation can only be performed when tension-free repair is possible, and transplantation of nerve autograft can cause donor-site morbidity and neuroma formation. Cell-based therapy delivered via nerve conduits has thus been explored as an alternative method of nerve repair in ...[more]

PMID: 29862994

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Project description:BackgroundEfficient and stable delivery of neurotrophic factors (NTFs) is crucial to provide suitable microenvironment for peripheral nerve regeneration. Neurotrophin-3 (NT-3) is an important NTF during peripheral nerve regeneration which is scarce in the first few weeks of nerve defect. Exosomes are nanovesicles and have been served as promising candidate for biocarrier. In this work, NT-3 mRNA was encapsulated in adipose-derived stem cell (ADSC)-derived exosomes (ExoNT-3). These engineered exosomes were applied as NT-3 mRNA carrier and then were loaded in nerve guidance conduit (ExoNT-3-NGC) to bridge rat sciatic nerve defect.MethodNT-3 mRNA was encapsulated in exosomes by forcedly expression of NT-3 mRNA in the donor ADSCs. ExoNT-3 were co-cultured with SCs in vitro; after 24 h of culture, the efficiency of NT-3 mRNA delivery was evaluated by qPCR, western blotting and ELISA. Then, ExoNT-3 were loaded in alginate hydrogel to construct the nerve guidance conduits (ExoNT-3-NGC). ExoNT-3-NGC were implanted in vivo to reconstruct 10 mm rat sciatic nerve defect. The expression of NT-3 was measured 2 weeks after the implantation operation. The sciatic nerve functional index (SFI) was examined at 2 and 8 weeks after the operation. Moreover, the therapeutic effect of ExoNT-3-NGC was also evaluated by morphology assay, immunofluorescence staining of regenerated nerves, function evaluation of gastrocnemius muscles after 8 weeks of implantation.ResultsThe engineered exosomes could deliver NT-3 mRNA to the recipient cells efficiently and translated into functional protein. The constructed NGC could realize stable release of exosomes at least for 2 weeks. After NGC implantation in vivo, ExoNT-3-NGC group significantly promote nerve regeneration and improve the function recovery of gastrocnemius muscles compared with control exosomes (Exoempty-NGC) group.ConclusionIn this work, NGC was constructed to allow exosome-mediated NT-3 mRNA delivery. After ExoNT-3-NGC implantation in vivo, the level of NT-3 could restore which enhance the nerve regeneration. Our study provide a potential approach to improve nerve regeneration.

Project description:Skeletal muscle-derived cells have strong secretory function, while skeletal muscle-derived stem cells, which are included in muscle-derived cells, can differentiate into Schwann cell-like cells and other cell types. However, the effect of muscle-derived cells on peripheral nerve defects has not been reported. In this study, 5-mm-long nerve defects were created in the right sciatic nerves of mice to construct a peripheral nerve defect model. Adult female C57BL/6 mice were randomly divided into four groups. For the muscle-derived cell group, muscle-derived cells were injected into the catheter after the cut nerve ends were bridged with a polyurethane catheter. For external oblique muscle-fabricated nerve conduit and polyurethane groups, an external oblique muscle-fabricated nerve conduit or polyurethane catheter was used to bridge the cut nerve ends, respectively. For the sham group, the sciatic nerves on the right side were separated but not excised. At 8 and 12 weeks post-surgery, distributions of axons and myelin sheaths were observed, and the nerve diameter was calculated using immunofluorescence staining. The number, diameter, and thickness of myelinated nerve fibers were detected by toluidine blue staining and transmission electron microscopy. Muscle fiber area ratios were calculated by Masson's trichrome staining of gastrocnemius muscle sections. Sciatic functional index was recorded using walking footprint analysis at 4, 8, and 12 weeks after operation. The results showed that, at 8 and 12 weeks after surgery, myelin sheaths and axons of regenerating nerves were evenly distributed in the muscle-derived cell group. The number, diameter, and myelin sheath thickness of myelinated nerve fibers, as well as gastrocnemius muscle wet weight and muscle area ratio, were significantly higher in the muscle-derived cell group compared with the polyurethane group. At 4, 8, and 12 weeks post-surgery, sciatic functional index was notably increased in the muscle-derived cell group compared with the polyurethane group. These criteria of the muscle-derived cell group were not significantly different from the external oblique muscle-fabricated nerve conduit group. Collectively, these data suggest that muscle-derived cells effectively accelerated peripheral nerve regeneration. This study was approved by the Animal Ethics Committee of Plastic Surgery Hospital, Chinese Academy of Medical Sciences (approval No. 040) on September 28, 2016.

Project description:BackgroundNeuropathic pain is one of the most difficult to treat chronic pain syndromes. It has significant effects on patients' quality of life and substantially adds to the burden of direct and indirect medical costs. There is a critical need to improve therapies for peripheral nerve regeneration. The aim of this study is to address this issue by performing a detailed analysis of the therapeutic benefits of two treatment options: adipose tissue derived-mesenchymal stem cells (ASCs) and ASC-conditioned medium (CM).MethodsTo this end, we used an in vivo rat sciatic nerve damage model to investigate the molecular mechanisms involved in the myelinating capacity of ASCs and CM. Furthermore, effect of TNF and CM on Schwann cells (SCs) was evaluated. For our in vivo model, biomaterial surgical implants containing TNF were used to induce peripheral neuropathy in rats. Damaged nerves were also treated with either ASCs or CM and molecular methods were used to collect evidence of nerve regeneration. Post-operatively, rats were subjected to walking track analysis and their sciatic functional index was evaluated. Morphological data was gathered through transmission electron microscopy (TEM) of sciatic nerves harvested from the experimental rats. We also evaluated the effect of TNF on Schwann cells (SCs) in vitro. Genes and their correspondent proteins associated with nerve regeneration were analyzed by qPCR, western blot, and confocal microscopy.ResultsOur data suggests that both ASCs and CM are potentially beneficial treatments for promoting myelination and axonal regeneration. After TNF-induced nerve damage we observed an upregulation of c-Jun along with a downregulation of Krox-20 myelin-associated transcription factor. However, when CM was added to TNF-treated nerves the opposite effect occurred and also resulted in increased expression of myelin-related genes and their corresponding proteins.ConclusionFindings from our in vivo model showed that both ASCs and CM aided the regeneration of axonal myelin sheaths and the remodeling of peripheral nerve morphology.

Dataset Information

The role of undifferentiated adipose-derived stem cells in peripheral nerve repair.

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The role of undifferentiated adipose-derived stem cells in peripheral nerve repair.

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