Abstract
BackgroundAdequate migration of Schwann cells (Sc) is crucial for axon-guidance in the regenerative process after peripheral nerve injury (PNI). Considering neuregulin-erbB-FAK signaling is an essential pathway participating in the regulation of Sc migration during development, the present study is aimed to examine whether neuregulin would exert its beneficial effects on adult following PNI and further determine the potential changes of downstream pathway engaged in neuro-regeneration by both in vitro and in vivo approaches.Methodology and Principal FindingsCultured RSC96 cells treated with neuregulin were processed for erbB2/3 immunofluorescence and FAK immunoblotings. The potential effects of neuregulin on Sc were assessed by cell adherence, spreading, and migration assays. In order to evaluate the functional significance of neuregulin on neuro-regeneration, the in vivo model of PNI was performed by chronic end-to-side neurorrhaphy (ESN). In vitro studies indicated that after neuregulin incubation, erbB2/3 were not only expressed in cell membranes, but also distributed throughout the cytoplasm and nucleus of RSC96 cells. Activation of erbB2/3 was positively correlated with FAK phosphorylation. Neuregulin also increases Sc adherence, spreading, and migration by 127.2±5.0%, 336.8±3.0%, and 80.0±5.7%, respectively. As for in vivo study, neuregulin significantly accelerates the speed of Sc migration and increases Sc expression in the distal stump of injured nerves. Retrograde labeling and compound muscle action potential recordings (CMAP) also showed that neuregulin successfully facilitates nerve regeneration by eliciting noticeably larger CMAP and promoting quick re-innervation of target muscles.ConclusionsAs neuregulin successfully improves axo-glial interaction by speeding Sc migration via the erbB2/3-FAK pathway, therapeutic use of neuregulin may thus serve as a promising strategy to facilitate the progress of nerve regeneration after PNI.
Highlights
Peripheral nerve injury (PNI) is one of the most common and important injuries in the current societies [1,2,3]
As neuregulin successfully improves axo-glial interaction by speeding Schwann cells (Sc) migration via the erbB2/3-focal adhesion kinase (FAK) pathway, therapeutic use of neuregulin may serve as a promising strategy to facilitate the progress of nerve regeneration after peripheral nerve injury (PNI)
In order to evaluate whether NRG b1 would effectively activate the erbB2/3 receptor of RSC96 Schwann cells, the erbB2/3 expression was detected by immunofluorescence
Summary
Peripheral nerve injury (PNI) is one of the most common and important injuries in the current societies [1,2,3]. Biochemical reports demonstrated that following PNI, remnant Schwann cells (Sc) would gradually migrate to the injured site and provide supportive effects to proximal axons which promotes successive neuro-regeneration [6,7]. As the functional maintenance of peripheral nerves is crucially dependent on proper signaling between Sc and axons [10], detail investigating the signal pathway involved in axo-glial interaction will help us to better understand the molecular mechanisms of neuro-regeneration, and provides important insights into the clinical design of therapeutic agents that facilitate Sc migration following PNI. Adequate migration of Schwann cells (Sc) is crucial for axon-guidance in the regenerative process after peripheral nerve injury (PNI). Considering neuregulin-erbB-FAK signaling is an essential pathway participating in the regulation of Sc migration during development, the present study is aimed to examine whether neuregulin would exert its beneficial effects on adult following PNI and further determine the potential changes of downstream pathway engaged in neuro-regeneration by both in vitro and in vivo approaches
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