Dataset Information

SPIONs mediated magnetic actuation promotes nerve regeneration by inducing and maintaining repair-supportive phenotypes in Schwann cells.

ABSTRACT:

Background

Schwann cells, the glial cells in the peripheral nervous system, are highly plastic. In response to nerve injury, Schwann cells are reprogrammed to a series of specialized repair-promoting phenotypes, known as repair Schwann cells, which play a pivotal role in nerve regeneration. However, repair Schwann cells represent a transient and unstable cell state, and these cells progressively lose their repair phenotypes and repair-supportive capacity; the transience of this state is one of the key reasons for regeneration failure in humans. Therefore, the ability to control the phenotypic stability of repair Schwann cells is of great practical importance as well as biological interest.

Results

We designed and prepared a type of fluorescent-magnetic bifunctional superparamagnetic iron oxide nanoparticles (SPIONs). In the present study, we established rat sciatic nerve injury models, then applied SPIONs to Schwann cells and established an effective SPION-mediated magnetic actuation system targeting the sciatic nerves. Our results demonstrate that magnetic actuation mediated by SPIONs can induce and maintain repair-supportive phenotypes of Schwann cells, thereby promoting regeneration and functional recovery of the sciatic nerve after crush injury.

Conclusions

Our research indicate that Schwann cells can sense these external, magnetically driven mechanical forces and transduce them to intracellular biochemical signals that promote nerve regeneration by inducing and maintaining the repair phenotypes of Schwann cells. We hope that this study will provide a new therapeutic strategy to promote the regeneration and repair of injured peripheral nerves.

SUBMITTER: Liu T

PROVIDER: S-EPMC8966266 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

SPIONs mediated magnetic actuation promotes nerve regeneration by inducing and maintaining repair-supportive phenotypes in Schwann cells.

Liu Ting T Wang Yang Y Lu Laijin L Liu Yi Y

Journal of nanobiotechnology 20220327 1

<h4>Background</h4>Schwann cells, the glial cells in the peripheral nervous system, are highly plastic. In response to nerve injury, Schwann cells are reprogrammed to a series of specialized repair-promoting phenotypes, known as repair Schwann cells, which play a pivotal role in nerve regeneration. However, repair Schwann cells represent a transient and unstable cell state, and these cells progressively lose their repair phenotypes and repair-supportive capacity; the transience of this state is ...[more]

PMID: 35351151

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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.

Project description:After nerve injury, Schwann cells convert to a phenotype specialized to promote repair. But during the slow process of axonal regrowth, these repair Schwann cells gradually lose their regeneration-supportive features and eventually die. Although this is a key reason for the frequent regeneration failures in humans, the transcriptional mechanisms that control long-term survival and phenotype of repair cells have not been studied, and the molecular signaling underlying their decline is obscure. We show, in mice, that Schwann cell STAT3 has a dual role. It supports the long-term survival of repair Schwann cells and is required for the maintenance of repair Schwann cell properties. In contrast, STAT3 is less important for the initial generation of repair Schwann cells after injury. In repair Schwann cells, we find that Schwann cell STAT3 activation by Tyr705 phosphorylation is sustained during long-term denervation. STAT3 is required for maintaining autocrine Schwann cell survival signaling, and inactivation of Schwann cell STAT3 results in a striking loss of repair cells from chronically denervated distal stumps. STAT3 inactivation also results in abnormal morphology of repair cells and regeneration tracks, and failure to sustain expression of repair cell markers, including Shh, GDNF, and BDNF. Because Schwann cell development proceeds normally without STAT3, the function of this factor appears restricted to Schwann cells after injury. This identification of transcriptional mechanisms that support long-term survival and differentiation of repair cells will help identify, and eventually correct, the failures that lead to the deterioration of this important cell population.SIGNIFICANCE STATEMENT Although injured peripheral nerves contain repair Schwann cells that provide signals and spatial clues for promoting regeneration, the clinical outcome after nerve damage is frequently poor. A key reason for this is that, during the slow growth of axons through the proximal parts of injured nerves repair, Schwann cells gradually lose regeneration-supporting features and eventually die. Identification of signals that sustain repair cells is therefore an important goal. We have found that in mice the transcription factor STAT3 protects these cells from death and contributes to maintaining the molecular and morphological repair phenotype that promotes axonal regeneration. Defining the molecular mechanisms that maintain repair Schwann cells is an essential step toward developing therapeutic strategies that improve nerve regeneration and functional recovery.

Project description:At present, the functional recovery after nerve injury is not satisfactory in clinical practice. The aim of this study was to explore the molecular mechanism of miR-21 promoting Schwann cells (SC) proliferation and axon regeneration after peripheral nerve injury, providing a theoretical basis for injured nerve repair. Nerve injury models were constructed to determine the expression of miR-21 in the injured nerve by Quantitative Real-Time PCR (qRT-PCR). After miR-21 over-expression SC (mimic-miR-21) group, control SC (control-miR-21) group and blank SC (RSC96) group were constructed, SC proliferation was determined by CCK-8, cell cycle was analysed by flow cytometry, dorsal root ganglion neuron (DRGn) axon regeneration was observed after DRGn was cultured with SCs for 7 days, the expressions of TGFβI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were detected by qRT-PCR and Western blot in the three groups, respectively. Target genes were confirmed by dual-luciferase reporter gene assay. The expressions of TGFβI, TIMP3 and EPHA4 were assessed by immunofluorescence in vivo. qRT-PCR indicated that miR-21 expression was significantly higher in the model group than in the sham operation and blank groups. SC proliferation index (PI) was significantly higher, the apoptosis rate was significantly lower, the axon was significantly longer, and mRNA and protein expressions of TGFβI, TIMP3, EPHA4 as well as apoptosis-related proteins caspase-3 and caspase-9 were significantly lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. The double luciferase assay confirmed that TGFβI, TIMP3 and EPHA4 were potential target genes of miR-21. In vivo immunofluorescence also indicated that expressions of TGFβI, TIMP3, EPHA4 were lower in the mimic-miR-21 group than in the control-miR-21 and RSC96 groups. We conclude that during injured peripheral nerve repair, miRNA-21 plays an important role in promoting SC proliferation and axon regeneration by regulating TGFβI, TIMP3 and EPHA4 target genes.

Dataset Information

SPIONs mediated magnetic actuation promotes nerve regeneration by inducing and maintaining repair-supportive phenotypes in Schwann cells.

Background

Results

Conclusions

Publications

SPIONs mediated magnetic actuation promotes nerve regeneration by inducing and maintaining repair-supportive phenotypes in Schwann cells.

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