Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model

Kurimoto, Shigeru; Kato, Shigeaki; Nakano, Tomonori; Yamamoto, Masayuki; Nishizuka, Takanobu; Hirata, Hitoshi

doi:10.1002/term.1844

Cited by 18 publications

(17 citation statements)

References 32 publications

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“…As we described previously, the peripheral nerve has several advantages over the spinal cord as a recipient site for NSC therapy for unrecoverable spinal cord injuries (Kato et al, ; Kurimoto et al, ). In the latter strategy, restoration of the damaged spinal cord requires millions of stem cells, but this does not guarantee either restoration of the complex neural network in the spinal cord or the extremely long axonal regeneration needed to extend down to peripheral target muscles (Pakkenberg & Gundersen, ).…”

Section: Discussionmentioning

confidence: 93%

“…For the green rat study, the sciatic nerve of Fischer 344 rats was transected only on the proximal side; as previously described, no surgery was performed on the distal side (Kurimoto et al, ).…”

Section: Methodsmentioning

confidence: 99%

“…On the other hand, damaged cardiac and smooth muscle tissue, which comprise the internal organs, can start working again immediately after vascular anastomosis. We and other researchers have hypothesized that neural stem cells (NSCs) transplanted into the peripheral nerves can overcome this difference and have successfully demonstrated rapid restoration of functional use in an animal skeletal muscle model by NSC transplantation, without CNS reconnection (Kurimoto et al, ; Thomas, Erb, Grumbles, & Bunge, ). However, few previous publications have addressed how transplanted stem cells are incorporated and differentiate into mature neurons.…”

Section: Introductionmentioning

confidence: 99%

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Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion

Nakano

Kurimoto

Kato

et al. 2018

J Tissue Eng Regen Med

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Neurogenesis in the adult peripheral nervous system remains to be demonstrated. We transplanted embryonic neural stem cells into a Wallerian degenerating nerve graft and observed development of a nodular structure consisting of neurons, glia, and Schwann cells. Histological analysis revealed a structure loosely resembling the spinal cord, including a synaptic network that formed along the neuron. Furthermore, the new axons reinnervated the paralysed muscle, forming both de novo and revived neuromuscular junctions. Reinnervation of the paralysed muscle resulted in significantly greater mean wet muscle weight and muscle fibre cross-sectional area on the cell transplantation side than on the surgical control side (body weight 0.071 ± 0.011% vs. 0.051 ± 0.007%, p = .006; area 355.6 ± 345.2 vs. 114.0 ± 132.0 μm , p < .001). Electrophysiological experiments demonstrated a functional connection between the neurons and muscle; hence, we identified this nodule as an ectopic ganglion. Surprisingly, in green rat experiments, most of these glial cells, but none of the neurons, expressed enhanced green fluorescent protein, suggesting that the cells constituting the ectopic ganglion were derived from both transplanted stem cells and endogenous stem cells. Such adult neurogenesis in a peripheral nerve related to neural stem cell transplantation has not been reported previously, and these results form the basis for a novel regenerative medicine approach in paralysed muscle.

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Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion

Nakano

Kurimoto

Kato

et al. 2018

J Tissue Eng Regen Med

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“…Cell transplantation within NGTs are able to provide neurotrophic support with in vivo feedback loops have demonstrated some initial promise in short-gap, long-gap, and delayed nerve repairs. 84,85 However, in cases of cell transplantation, the host immune response should be considered. 86,87 TENGs have continued to demonstrate the potential to overcome major limitations in current NGT technology.…”

Section: Discussionmentioning

confidence: 99%

Tissue Engineered Axon-Based “Living Scaffolds” Promote Survival of Spinal Cord Motor Neurons Following Peripheral Nerve Repair

Maggiore

Burrell

Browne

et al. 2019

Preprint

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Peripheral nerve injury (PNI) impacts millions annually, often leaving debilitated patients with minimal repair options to improve functional recovery. Our group has previously developed tissue engineered nerve grafts (TENGs) featuring long, aligned axonal tracts from dorsal root ganglia (DRG) neurons that are fabricated in custom bioreactors using the process of axon "stretch-growth". We have shown that TENGs effectively serve as "living scaffolds" to promote regeneration across segmental nerve defects by exploiting the newfound mechanism of axonfacilitated axon regeneration, or "AFAR", by simultaneously providing haptic and neurotrophic support. To extend this work, the current study investigated the efficacy of living versus non-living regenerative scaffolds in preserving host sensory and motor neuron cell health, using retrograde dye transport as a proxy, following bridging of segmental nerve defects. Rats were assigned across five groups: naïve or repair using autograft, nerve guidance tube (NGT) with collagen, NGT + non-aligned DRG populations in collagen, or TENGs. We found that TENG repairs yielded equivalent regenerative capacity as autograft repairs based on preserved health of host spinal cord motor neurons and acute axonal regeneration, whereas NGT repairs or DRG neurons within an NGT exhibited reduced motor neuron preservation and diminished regenerative capacity.These acute regenerative benefits ultimately resulted in enhanced levels of functional recovery in animals receiving TENGs, at levels matching those attained by autografts. Our findings indicate that when used to bridge segmental nerve defects, TENGs preserve host spinal cord motor neuron health and regenerative capacity without sacrificing an otherwise uninjured nerve (as in the case of the autograft), and therefore represent a promising alternative strategy for neurosurgical repair following PNI.2 HIGHLIGHTS

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“…The transplantation of motor neurons onto peripheral nerves with the FES treatment is one approach for preventing the degeneration of denervated muscles. Recovery of muscle activity has previously been seen to occur following electrical stimulation of the peroneal or tibial nerve after injection of motor neurons into the sciatic nerve of a rat [3,4]. The application of FES has demonstrated its potential for slowing down the atrophy of denervated muscles and allowing the retention of muscle functionality [5].…”

Section: Introductionmentioning

confidence: 99%

Visual Feedback Control of a Rat Ankle Angle Using a Wirelessly Powered Two-Channel Neurostimulator

Takeuchi

Watanabe

Ishihara

et al. 2020

Sensors

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Peripheral nerve disconnections cause severe muscle atrophy and consequently, paralysis of limbs. Reinnervation of denervated muscle by transplanting motor neurons and applying Functional Electrical Stimulation (FES) onto peripheral nerves is an important procedure for preventing irreversible degeneration of muscle tissues. After the reinnervation of denervated muscles, multiple peripheral nerves should be stimulated independently to control joint motion and reconstruct functional movements of limbs by the FES. In this study, a wirelessly powered two-channel neurostimulator was developed with the purpose of applying selective FES to two peripheral nerves—the peroneal nerve and the tibial nerve in a rat. The neurostimulator was designed in such a way that power could be supplied wirelessly, from a transmitter coil to a receiver coil. The receiver coil was connected, in turn, to the peroneal and tibial nerves in the rat. The receiver circuit had a low pass filter to allow detection of the frequency of the transmitter signal. The stimulation of the nerves was switched according to the frequency of the transmitter signal. Dorsal/plantar flexion of the rat ankle joint was selectively induced by the developed neurostimulator. The rat ankle joint angle was controlled by changing the stimulation electrode and the stimulation current, based on the Proportional Integral (PI) control method using a visual feedback control system. This study was aimed at controlling the leg motion by stimulating the peripheral nerves using the neurostimulator.

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Transplantation of embryonic motor neurons into peripheral nerve combined with functional electrical stimulation restores functional muscle activity in the rat sciatic nerve transection model

Cited by 18 publications

References 32 publications

Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion

Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion

Tissue Engineered Axon-Based “Living Scaffolds” Promote Survival of Spinal Cord Motor Neurons Following Peripheral Nerve Repair

Visual Feedback Control of a Rat Ankle Angle Using a Wirelessly Powered Two-Channel Neurostimulator

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