Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats

Abstract Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated...

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Main Authors: Ema Onode, Takuya Uemura, Kiyohito Takamatsu, Takuya Yokoi, Kosuke Shintani, Shunpei Hama, Yusuke Miyashima, Mitsuhiro Okada, Hiroaki Nakamura
Format: Article
Language:English
Published: Nature Portfolio 2021-02-01
Series:Scientific Reports
Online Access:https://doi.org/10.1038/s41598-021-83385-9
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author Ema Onode
Takuya Uemura
Kiyohito Takamatsu
Takuya Yokoi
Kosuke Shintani
Shunpei Hama
Yusuke Miyashima
Mitsuhiro Okada
Hiroaki Nakamura
author_facet Ema Onode
Takuya Uemura
Kiyohito Takamatsu
Takuya Yokoi
Kosuke Shintani
Shunpei Hama
Yusuke Miyashima
Mitsuhiro Okada
Hiroaki Nakamura
author_sort Ema Onode
collection DOAJ
description Abstract Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.
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spelling doaj.art-7221bf9f651842c291bb357744dca3222022-12-21T20:36:50ZengNature PortfolioScientific Reports2045-23222021-02-0111111310.1038/s41598-021-83385-9Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in ratsEma Onode0Takuya Uemura1Kiyohito Takamatsu2Takuya Yokoi3Kosuke Shintani4Shunpei Hama5Yusuke Miyashima6Mitsuhiro Okada7Hiroaki Nakamura8Department of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Pediatric Orthopaedic Surgery, Osaka City General HospitalDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineDepartment of Orthopaedic Surgery, Osaka City University Graduate School of MedicineAbstract Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.https://doi.org/10.1038/s41598-021-83385-9
spellingShingle Ema Onode
Takuya Uemura
Kiyohito Takamatsu
Takuya Yokoi
Kosuke Shintani
Shunpei Hama
Yusuke Miyashima
Mitsuhiro Okada
Hiroaki Nakamura
Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
Scientific Reports
title Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
title_full Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
title_fullStr Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
title_full_unstemmed Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
title_short Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats
title_sort bioabsorbable nerve conduits three dimensionally coated with human induced pluripotent stem cell derived neural stem progenitor cells promote peripheral nerve regeneration in rats
url https://doi.org/10.1038/s41598-021-83385-9
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