Dataset Information

Schwann Cell-Like Cells Derived from Human Amniotic Mesenchymal Stem Cells Promote Peripheral Nerve Regeneration through a MicroRNA-214/c-Jun Pathway.

ABSTRACT:

Background

The use of Schwann cell-like cells (SCLCs) derived from stem cells has been introduced as an effective strategy for promoting peripheral nerve regeneration (PNR). However, molecular mechanisms underlying therapeutic transplantation of SCLCs for PNR are often ignored.

Objectives

To explore the potential of SCLCs for the treatment of sciatic never injury and investigate the underlying molecule mechanisms.

Method

SCLCs differentiated from human amniotic mesenchymal stem cells (hAMSCs) and specific markers of Schwann cells were detected. SCLCs were transplanted into the injured sites of a rat model of sciatic nerve injury, and sciatic nerve functional index (SFI) was determined.

Results

SCLCs expressed specific markers of Schwann cells as well as secreted neurotrophic factors. The transplantation of SCLCs into injured sites of a rat model of sciatic nerve injury promoted the functional recovery. With regard to the underlying molecular mechanisms, we identified c-Jun as a negative regulator of the myelination of SCLCs. Moreover, we discovered a novel signaling transduction pathway in SCLCs; that is, miR-214 directly targets c-Jun to promote the myelination of SCLCs. Finally, we demonstrated that miR-214 upon overexpression in SCLCs enhanced the therapeutic effects of SCLCs on sciatic nerve injury.

Conclusions

We demonstrate that SCLCs have beneficial effect for myelination. Moreover, our results provide a previously unknown molecular basis underlying the treatment of peripheral nerve injury with SCLCs and also offer a practical strategy for future therapeutic promotion of PNR.

SUBMITTER: Chen W

PROVIDER: S-EPMC6636479 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Schwann Cell-Like Cells Derived from Human Amniotic Mesenchymal Stem Cells Promote Peripheral Nerve Regeneration through a MicroRNA-214/c-Jun Pathway.

Chen Wei W Xiao Shune S Wei Zairong Z Deng Chengliang C Nie Kaiyu K Wang Dali D

Stem cells international 20190701

<h4>Background</h4>The use of Schwann cell-like cells (SCLCs) derived from stem cells has been introduced as an effective strategy for promoting peripheral nerve regeneration (PNR). However, molecular mechanisms underlying therapeutic transplantation of SCLCs for PNR are often ignored.<h4>Objectives</h4>To explore the potential of SCLCs for the treatment of sciatic never injury and investigate the underlying molecule mechanisms.<h4>Method</h4>SCLCs differentiated from human amniotic mesenchymal ...[more]

PMID: 31354837

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Project description:Rationale: Peripheral nerves are unique in their remarkable elasticity. Schwann cells (SCs), important components of the peripheral nervous system (PNS), are constantly subjected to physiological and mechanical stresses from dynamic stretching and compression forces during movement. So far, it is not clear if SCs sense and respond to mechanical signals. It is also unknown whether mechanical stimuli can interfere with the intercellular communications between neurons and SCs, and what role extracellular vesicles (EVs) play in this process. The present study aimed to examine the effect of mechanical stimuli on the EV-mediated intercellular communication between neurons and SCs, explore their effect on axonal regeneration, and investigate the underlying mechanism. Methods: Purified SCs were stimulated using a magnetic force-based mechanical stimulation (MS) system and EVs were purified from mechanically stimulated SCs (MS-SCs-EVs) and non-stimulated SCs (SCs-EVs). The effect of MS-SCs-EVs on axonal elongation was examined in vitro and in vivo. High throughput miRNA sequencing was performed to compare the differential miRNA profiles between MS-SCs-EVs and SCs-EVs. The functional role of differentially expressed miRNAs on neurite extension in MS-SCs-EVs was examined. Also, the putative target genes of differentially expressed miRNAs in MS-SCs-EVs were predicted by bioinformatics tools, and the regulatory effect of those miRNAs on putative target genes was validated both in vitro and in vivo. Results: The MS-SCs-EVs showed an average size of 137.52±1.77 nm, and could be internalized by dorsal root ganglion (DRG) neurons. Compared to SCs-EVs, MS-SCs-EVs showed a stronger ability to enhance neurite outgrowth in vitro and nerve regeneration in vivo. High throughput miRNA sequencing identified a number of differentially expressed miRNAs in MS-SCs-EVs. Further analysis of those EV-miRNAs demonstrated that miR-23b-3p played a predominant role in MS-SCs-EVs since its deprivation abolished their enhanced axonal elongation. Furthermore, we identified neuropilin 1 (Nrp1) in neurons as the target gene of miR-23b-3p in MS-SCs-EVs. This observation was supported by the evidence that miR-23b-3p could decrease Nrp1-3'-UTR-WT luciferase activity in vitro and down-regulate Nrp1 expression in neurons. Conclusion: Our findings suggested that mechanical stimuli are capable of modulating the intercellular communication between neurons and SCs by altering miRNA composition in MS-SCs-EVs. Transfer of miR-23b-3p by MS-SCs-EVs from mechanically stimulated SCs to neurons decreased neuronal Nrp1 expression, which was responsible, at least in part, for the beneficial effect of MS-SCs-EVs on axonal regeneration. Our results highlighted the potential therapeutic value of MS-SCs-EVs and miR-23b-3p-enriched EVs in peripheral nerve injury repair.

Project description:BackgroundMaintaining the repair phenotype of denervated Schwann cells in the injured distal nerve is crucial for promoting peripheral nerve regeneration. However, when chronically denervated, the capacity of Schwann cells to support repair and regeneration deteriorates, leading to peripheral nerve regeneration and poor functional recovery. Herein, we investigated whether neurotrophin-3 (NT-3) could sustain the reparative phenotype of Schwann cells and promote peripheral nerve regeneration after chronic denervation and aimed to uncover its potential molecular mechanisms.MethodsWestern blot was employed to investigate the relationship between the expression of c-Jun and the reparative phenotype of Schwann cells. The inducible expression of c-Jun by NT-3 was examined both in vitro and in vivo with western blot and immunofluorescence staining. A chronic denervation model was established to study the role of NT-3 in peripheral nerve regeneration. The number of regenerated distal axons, myelination of regenerated axons, reinnervation of neuromuscular junctions, and muscle fiber diameters of target muscles were used to evaluate peripheral nerve regeneration by immunofluorescence staining, transmission electron microscopy (TEM), and hematoxylin and eosin (H&E) staining. Adeno-associated virus (AAV) 2/9 carrying shRNA, small molecule inhibitors, and siRNA were employed to investigate whether NT-3 could signal through the TrkC/ERK pathway to maintain c-Jun expression and promote peripheral nerve regeneration after chronic denervation.ResultsAfter peripheral nerve injury, c-Jun expression progressively increased until week 5 and then began to decrease in the distal nerve following denervation. NT-3 upregulated the expression of c-Jun in denervated Schwann cells, both in vitro and in vivo. NT-3 promoted peripheral nerve regeneration after chronic denervation, mainly by upregulating or maintaining a high level of c-Jun rather than NT-3 itself. The TrkC receptor was consistently presented on denervated Schwann cells and served as NT-3 receptors following chronic denervation. NT-3 mainly upregulated c-Jun through the TrkC/ERK pathway.ConclusionNT-3 promotes peripheral nerve regeneration by maintaining the repair phenotype of Schwann cells after chronic denervation via the TrkC/ERK/c-Jun pathway. It provides a potential target for the clinical treatment of peripheral nerve injury after chronic denervation.

Dataset Information

Schwann Cell-Like Cells Derived from Human Amniotic Mesenchymal Stem Cells Promote Peripheral Nerve Regeneration through a MicroRNA-214/c-Jun Pathway.

Background

Objectives

Method

Results

Conclusions

Publications

Schwann Cell-Like Cells Derived from Human Amniotic Mesenchymal Stem Cells Promote Peripheral Nerve Regeneration through a MicroRNA-214/c-Jun Pathway.

Similar Datasets

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