Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury
Abstract Background Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for imp...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Inflammation and Regeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41232-024-00319-4 |
| _version_ | 1827328257812332544 |
|---|---|
| author | Takayuki Nishijima Kentaro Okuyama Shinsuke Shibata Hiroo Kimura Munehisa Shinozaki Takehito Ouchi Yo Mabuchi Tatsukuni Ohno Junpei Nakayama Manabu Hayatsu Keiko Uchiyama Tomoko Shindo Eri Niiyama Sayaka Toita Jiro Kawada Takuji Iwamoto Masaya Nakamura Hideyuki Okano Narihito Nagoshi |
| author_facet | Takayuki Nishijima Kentaro Okuyama Shinsuke Shibata Hiroo Kimura Munehisa Shinozaki Takehito Ouchi Yo Mabuchi Tatsukuni Ohno Junpei Nakayama Manabu Hayatsu Keiko Uchiyama Tomoko Shindo Eri Niiyama Sayaka Toita Jiro Kawada Takuji Iwamoto Masaya Nakamura Hideyuki Okano Narihito Nagoshi |
| author_sort | Takayuki Nishijima |
| collection | DOAJ |
| description | Abstract Background Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected. Methods Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing. Result After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system’s role in recovery. Conclusion The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application. |
| first_indexed | 2024-03-07T15:15:06Z |
| format | Article |
| id | doaj.art-86440490ff964447b6e85a0598b21320 |
| institution | Directory Open Access Journal |
| issn | 1880-8190 |
| language | English |
| last_indexed | 2024-03-07T15:15:06Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Inflammation and Regeneration |
| spelling | doaj.art-86440490ff964447b6e85a0598b213202024-03-05T17:58:47ZengBMCInflammation and Regeneration1880-81902024-02-0144112010.1186/s41232-024-00319-4Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injuryTakayuki Nishijima0Kentaro Okuyama1Shinsuke Shibata2Hiroo Kimura3Munehisa Shinozaki4Takehito Ouchi5Yo Mabuchi6Tatsukuni Ohno7Junpei Nakayama8Manabu Hayatsu9Keiko Uchiyama10Tomoko Shindo11Eri Niiyama12Sayaka Toita13Jiro Kawada14Takuji Iwamoto15Masaya Nakamura16Hideyuki Okano17Narihito Nagoshi18Department of Orthopaedic Surgery, Keio University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Orthopaedic Surgery, Keio University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Physiology, Tokyo Dental CollegeDepartment of Clinical Regenerative Medicine, Fujita Medical Innovation Center, Fujita Health UniversityOral Health Science Center, Tokyo Dental CollegeDivision of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental SciencesDivision of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental SciencesDivision of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental SciencesDepartment of Physiology, Keio University School of MedicineDivision of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental SciencesDivision of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental SciencesDepartment of Physiology, Keio University School of MedicineDepartment of Orthopaedic Surgery, Keio University School of MedicineDepartment of Orthopaedic Surgery, Keio University School of MedicineDepartment of Physiology, Keio University School of MedicineDepartment of Orthopaedic Surgery, Keio University School of MedicineAbstract Background Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected. Methods Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing. Result After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system’s role in recovery. Conclusion The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application.https://doi.org/10.1186/s41232-024-00319-4Peripheral nerve injuryArtificial nerveNeurite bundlehiPSC |
| spellingShingle | Takayuki Nishijima Kentaro Okuyama Shinsuke Shibata Hiroo Kimura Munehisa Shinozaki Takehito Ouchi Yo Mabuchi Tatsukuni Ohno Junpei Nakayama Manabu Hayatsu Keiko Uchiyama Tomoko Shindo Eri Niiyama Sayaka Toita Jiro Kawada Takuji Iwamoto Masaya Nakamura Hideyuki Okano Narihito Nagoshi Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury Inflammation and Regeneration Peripheral nerve injury Artificial nerve Neurite bundle hiPSC |
| title | Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| title_full | Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| title_fullStr | Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| title_full_unstemmed | Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| title_short | Novel artificial nerve transplantation of human iPSC-derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| title_sort | novel artificial nerve transplantation of human ipsc derived neurite bundles enhanced nerve regeneration after peripheral nerve injury |
| topic | Peripheral nerve injury Artificial nerve Neurite bundle hiPSC |
| url | https://doi.org/10.1186/s41232-024-00319-4 |
| work_keys_str_mv | AT takayukinishijima novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT kentarookuyama novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT shinsukeshibata novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT hirookimura novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT munehisashinozaki novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT takehitoouchi novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT yomabuchi novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT tatsukuniohno novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT junpeinakayama novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT manabuhayatsu novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT keikouchiyama novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT tomokoshindo novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT eriniiyama novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT sayakatoita novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT jirokawada novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT takujiiwamoto novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT masayanakamura novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT hideyukiokano novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury AT narihitonagoshi novelartificialnervetransplantationofhumanipscderivedneuritebundlesenhancednerveregenerationafterperipheralnerveinjury |