Adipose-Derived Stem Cells Promote Peripheral Nerve Regeneration In Vivo without Differentiation into Schwann-Like Lineage

Sowa, Yoshihiro; Kishida, Tsunao; Imura, Tetsuya; Numajiri, Toshiaki; Nishino, Koichi; Tabata, Yasuhiko; Mazda, Osam

doi:10.1097/01.prs.0000475762.86580.36

Cited by 101 publications

(61 citation statements)

References 48 publications

(58 reference statements)

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“…Since the posterior tibial branch of the sciatic nerve innervates the gastrocnemius muscle, transection of the sciatic nerve results in atrophy of this muscle, while the gastrocnemius muscle regains its mass depending on the amount of axonal reinnervation . The weight of the gastrocnemius muscle indicated that the transplantation of pSCs and dSCs within nerve guide conduits significantly reversed the muscle atrophy (Fig.…”

Section: Resultsmentioning

confidence: 91%

Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo

Sowa

Kishida

Tomita

et al. 2017

Stem Cells Translational Medicine

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Schwann cells (SCs) play pivotal roles in the maintenance and regeneration of the peripheral nervous system. Although transplantation of SCs enhances repair of experimentally damaged peripheral and central nerve tissues, it is difficult to prepare a sufficient number of functional SCs for transplantation therapy without causing adverse events for the donor. Here, we generated functional SCs by somatic cell reprogramming procedures and demonstrated their capability to promote peripheral nerve regeneration. Normal human fibroblasts were phenotypically converted into SCs by transducing SOX10 and Krox20 genes followed by culturing for 10 days resulting in approximately 43% directly converted Schwann cells (dSCs). The dSCs expressed SC‐specific proteins, secreted neurotrophic factors, and induced neuronal cells to extend neurites. The dSCs also displayed myelin‐forming capability both in vitro and in vivo. Moreover, transplantation of the dSCs into the transected sciatic nerve in mice resulted in significantly accelerated regeneration of the nerve and in improved motor function at a level comparable to that with transplantation of the SCs obtained from a peripheral nerve. The dSCs induced by our procedure may be applicable for novel regeneration therapy for not only peripheral nerve injury but also for central nerve damage and for neurodegenerative disorders related to SC dysfunction. Stem Cells Translational Medicine 2017;6:1207–1216

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Section: Resultsmentioning

confidence: 91%

Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo

Sowa

Kishida

Tomita

et al. 2017

Stem Cells Translational Medicine

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“…This may be due to the number of survived stem cells and the number of differentiated stem cells not meeting the level necessary for therapeutic effect. Another possibility is that 6 th passage hNCSCs may have been less effective in treatment due to changes in its ability to produce growth factors that have been shown to contribute to the positive influence on nerve regeneration in previous studies 31–33 . While the mechanism by which hNCSCs lose their efficacy with increasing passage number is largely unknown, studies on MSCs have shown that the growth rate, differentiation ability, and growth factors secretion progressively are decreased with additional passages, possibly due to senescence, spontaneous differentiation, or loss of differentiation potential 34–36 .…”

Section: Discussionmentioning

confidence: 99%

Quantitative Multimodal Evaluation of Passaging Human Neural Crest Stem Cells for Peripheral Nerve Regeneration

Chen

Zhou

et al. 2017

Stem Cell Rev and Rep

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Peripheral nerve injury is a major burden to societies worldwide, however, current therapy options (e.g. autologous nerve grafts) are unable to produce satisfactory outcomes. Many studies have shown that stem cell transplantation holds great potential for peripheral nerve repair, and human neural crest stem cells (NCSCs), which give rise to a variety of tissues in the peripheral nervous system, are particularly promising. NCSCs are one of the best candidates for clinical translation, however, to ensure the viability and quality of NCSCs for research and clinical use, the effect of in vitro cell passaging on therapeutic effects need be evaluated given that passaging is required to expand NCSCs to meet the demands of transplantation in preclinical research and clinical trials. To date, no study has investigated the quality of NCSCs past the 5th passage in vivo. In this study, we employed a multimodal evaluation system to investigate changes in outcomes between transplantation with 5th (p5) and 6th passage (p6) NCSCs in a 15mm rat sciatic nerve injury and repair model. Using CatWalk gait analysis, gastrocnemius muscle index, electrophysiology, immunohistochemistry, and histomorphometric analysis, we showed that p6 NCSCs demonstrated decreased cell survival, Schwann-cell differentiation, axonal growth, and functional outcomes compared to p5 NCSCs (all p<0.05). In conclusion, p6 NCSCs showed significantly reduced therapeutic efficacy compared to p5 NCSCs for peripheral nerve regeneration.

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“…To date, a range of nerve guidance conduits (NGCs) based on the natural biology of nerve regeneration have been developed and studied in vivo and/or in vitro . In order to acquire ideal repair outcomes, a variety of strategies have been proposed to fabricate NGCs, which range from simple hollow tubes to filled tubes combined with intraluminal fillings, neurotrophic factors, or stem cells . At present, NGCs in hollow tubular structures made by collagen, non‐resorbable hydrogels, or resorbable biopolymers are approved by the Food and Drug Administration (FDA) …”

Section: Introductionmentioning

confidence: 99%

Collagen/β‐TCP nerve guidance conduits promote facial nerve regeneration in mini‐swine and the underlying biological mechanism: A pilot in vivo study

Zhang

et al. 2018

J Biomed Mater Res

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This study aimed to evaluate the efficiency of new nerve guidance conduits (NGCs) in bridging facial nerve gaps, and investigate the underlying biological mechanisms implicated in the regeneration process. A collagen/β-TCP conduit was prepared and applied to a facial nerve gap in a mini-swine model. Functional recovery and axonal regeneration were further evaluated by electrophysiological and histological examinations at 3 months after surgery. Furthermore, the global transcriptomic profiles of regenerated and normal tissues were analyzed by gene microarray to identify the differentially expressed genes at day three and seven, postoperatively. Subsequently, associated biological processes were analyzed by gene ontology (GO) enrichment analysis. The electrophysiological examination and morphological analysis revealed that significant nerve regeneration effects were achieved in the Col/β-TCP group (p < 0.05). Transcriptional analysis revealed that at day three post-surgery, the majority of overexpressed genes were associated with inflammatory, immune and stimuli response, accompanied by angiogenesis, while at day seven, the majority of overexpressed genes were associated with cell, tissue and organ regeneration and development, synaptic transmission, neurogenesis, and neuronal differentiation, as well as the WNT, MAPK/ERK, and JAK/STAT signaling pathways. In conclusion, the present results suggest that collagen/ β-TCP NGCs provide a promising tubular micro-environment for nerve regeneration.

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Adipose-Derived Stem Cells Promote Peripheral Nerve Regeneration In Vivo without Differentiation into Schwann-Like Lineage

Cited by 101 publications

References 48 publications

Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo

Direct Conversion of Human Fibroblasts into Schwann Cells that Facilitate Regeneration of Injured Peripheral Nerve In Vivo

Quantitative Multimodal Evaluation of Passaging Human Neural Crest Stem Cells for Peripheral Nerve Regeneration

Collagen/β‐TCP nerve guidance conduits promote facial nerve regeneration in mini‐swine and the underlying biological mechanism: A pilot in vivo study

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