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Optimal electrical stimulation boosts stem cell therapy in nerve regeneration.

ABSTRACT: Peripheral nerve injuries often lead to incomplete recovery and contribute to significant disability to approximately 360,000 people in the USA each year. Stem cell therapy holds significant promise for peripheral nerve regeneration, but maintenance of stem cell viability and differentiation potential in vivo are still major obstacles for translation. Using a made-in-house 96-well vertical electrical stimulation (ES) platform, we investigated the effects of different stimulating pulse frequency, duration and field direction on human neural crest stem cell (NCSC) differentiation. We observed dendritic morphology with enhanced neuronal differentiation for NCSCs cultured on cathodes subject to 20?Hz, 100?s pulse at a potential gradient of 200?mV/mm. We further evaluated the effect of a novel cell-based therapy featuring optimized pulsatile ES of NCSCs for in vivo transplantation following peripheral nerve regeneration. 15 mm critical-sized sciatic nerve injuries were generated with subsequent surgical repair in sixty athymic nude rats. Injured animals were randomly assigned into five groups (N = 12 per group): blank control, ES, NCSC, NCSC + ES, and autologous nerve graft. The optimized ES was applied immediately after surgical repair for 1 h in ES and NCSC + ES groups. Recovery was assessed by behavioral (CatWalk gait analysis), wet muscle-mass, histomorphometric, and immunohistochemical analyses at either 6 or 12 weeks after surgery (N = 6 per group). Gastrocnemius muscle wet mass measurements in ES + NCSC group were comparable to autologous nerve transplantation and significantly higher than other groups (p < 0.05). Quantitative histomorphometric analysis and catwalk gait analysis showed similar improvements by ES on NCSCs (p < 0.05). A higher number of viable NCSCs was shown via immunochemical analysis, with higher Schwann cell (SC) differentiation in the NCSC + ES group compared to the NCSC group (p < 0.05). Overall, ES on NCSC transplantation significantly enhanced nerve regeneration after injury and repair, and was comparable to autograft treatment. Thus, ES can be a potent alternative to biochemical and physical cues for modulating stem cell survival and differentiation. This novel cell-based intervention presents an effective and safe approach for improved outcomes after peripheral nerve repair.

SUBMITTER: Du J

PROVIDER: S-EPMC6201278 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Optimal electrical stimulation boosts stem cell therapy in nerve regeneration.

Du Jian J Zhen Gehua G Chen Huanwen H Zhang Shuming S Qing Liming L Yang Xiuli X Lee Gabsang G Mao Hai-Quan HQ Jia Xiaofeng X

Biomaterials 20180720

Peripheral nerve injuries often lead to incomplete recovery and contribute to significant disability to approximately 360,000 people in the USA each year. Stem cell therapy holds significant promise for peripheral nerve regeneration, but maintenance of stem cell viability and differentiation potential in vivo are still major obstacles for translation. Using a made-in-house 96-well vertical electrical stimulation (ES) platform, we investigated the effects of different stimulating pulse frequency, ...[more]

PMID: 30098570

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Project description:BACKGROUND:High-frequency transcutaneous neuromuscular electrical nerve stimulation (TENS) is currently used for the administration of electrical current in denervated muscle to alleviate muscle atrophy and enhance motor function; however, the time window (i.e. either immediate or delayed) for achieving benefit is still undetermined. In this study, we conducted an intervention of sciatic nerve crush injury using high-frequency TENS at different time points to assess the effect of motor and sensory functional recovery. RESULTS:Animals with left sciatic nerve crush injury received TENS treatment starting immediately after injury or 1 week later at a high frequency(100 Hz) or at a low frequency (2 Hz) as a control. In SFI gait analysis, either immediate or late admission of high-frequency electrical stimulation exerted significant improvement compared to either immediate or late administration of low-frequency electrical stimulation. In an assessment of allodynia, immediate high frequency electrical stimulation caused a significantly decreased pain threshold compared to late high-frequency or low-frequency stimulation at immediate or late time points. Immunohistochemistry staining and western blot analysis of S-100 and NF-200 demonstrated that both immediate and late high frequency electrical stimulation showed a similar effect; however the effect was superior to that achieved with low frequency stimulation. Immediate high frequency electrical stimulation resulted in significant expression of TNF-? and synaptophysin in the dorsal root ganglion, somatosensory cortex, and hippocampus compared to late electrical stimulation, and this trend paralleled the observed effect on somatosensory evoked potential. The CatWalk gait analysis also showed that immediate electrical stimulation led to a significantly high regularity index. In primary dorsal root ganglion cells culture, high-frequency electrical stimulation also exerted a significant increase in expression of TNF-?, synaptophysin, and NGF in accordance with the in vivo results. CONCLUSION:Immediate or late transcutaneous high-frequency electrical stimulation exhibited the potential to stimulate the motor nerve regeneration. However, immediate electrical stimulation had a predilection to develop neuropathic pain. A delay in TENS initiation appears to be a reasonable approach for nerve repair and provides the appropriate time profile for its clinical application.

Project description:BackgroundFunctional Electrical Stimulation (FES) is a technique that aims to rehabilitate or restore functionality of skeletal muscles using external electrical stimulation. Despite the success achieved within the field of FES, there are still a number of questions that remain unanswered. One way of providing input to the answers is through the use of computational models.MethodsThis paper describes the development of an anatomically based computer model of the motor neurons in the lower limb of the human leg and shows how it can be used to simulate electrical signal propagation from the beginning of the sciatic nerve to a skeletal muscle. One-dimensional cubic Hermite finite elements were used to represent the major portions of the lower limb nerves. These elements were fit to data that had been digitised using images from the Visible Man project. Nerves smaller than approximately 1 mm could not be seen in the images, and thus a tree-branching algorithm was used to connect the ends of the fitted nerve model to the respective skeletal muscle. To simulate electrical propagation, a previously published mammalian nerve model was implemented and solved on the anatomically based nerve mesh using a finite difference method. The grid points for the finite difference method were derived from the fitted finite element mesh. By adjusting the tree-branching algorithm, it is possible to represent different levels of motor-unit recruitment.ResultsTo illustrate the process of a propagating nerve stimulus to a muscle in detail, the above method was applied to the nerve tree that connects to the human semitendinosus muscle. A conduction velocity of 89.8 m/s was obtained for a 15 mum diameter nerve fibre. This signal was successfully propagated down the motor neurons to a selected group of motor units in the muscle.ConclusionAn anatomically and physiologically based model of the posterior motor neurons in the human lower limb was developed. This model can be used to examine the effect of external stimulation on nerve and muscle activity, as may occur, for example, in the field of FES.

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Optimal electrical stimulation boosts stem cell therapy in nerve regeneration.

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Optimal electrical stimulation boosts stem cell therapy in nerve regeneration.

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