Episomal Induced Pluripotent Stem Cells Promote Functional Recovery of Transected Murine Peripheral Nerve
Traumatic peripheral nerve neurotmesis occurs frequently and functional recovery is often slow and impaired. Induced pluripotent stem cells (iPSCs) have shown much promise in recent years due to its regenerative properties similar to that of embryonic stem cells. However, the potential of iPSCs in p...
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description | Traumatic peripheral nerve neurotmesis occurs frequently and functional recovery is often slow and impaired. Induced pluripotent stem cells (iPSCs) have shown much promise in recent years due to its regenerative properties similar to that of embryonic stem cells. However, the potential of iPSCs in promoting the functional recovery of a transected peripheral nerve is largely unknown. This study is the first to investigate in vivo effects of episomal iPSCs (EiPSCs) on peripheral nerve regeneration in a murine sciatic nerve transection model. Episomal iPSCs refer to iPSCs that are generated via Oct3/4-Klf4-Sox2 plasmid reprogramming instead of the conventional viral insertion techniques. It represents a relatively safer form of iPSC production without permanent transgene integration which may raise questions regarding risks of genomic mutation. A minimal number of EiPSCs were added directly to the transected nerve. Functional recovery of the EiPSC group was significantly improved compared to the negative control group when assessed via serial five-toe spread measurement and gait analysis of ankle angles. EiPSC promotion of nerve regeneration was also evident on stereographic analysis of axon density, myelin thickness, and axonal cross-sectional surface area. Most importantly, the results observed in EiPSCs are similar to that of the embryonic stem cell group. A roughly ten-fold increase in neurotrophin-3 levels was seen in EiPSCs which could have contributed to peripheral nerve regeneration and recovery. No abnormal masses or adverse effects were noted with EiPSC administration after one year of follow-up. We have hence shown that functional recovery of the transected peripheral nerve can be improved with the use of EiPSC therapy, which holds promise for the future of nerve regeneration. |
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Induced pluripotent stem cells (iPSCs) have shown much promise in recent years due to its regenerative properties similar to that of embryonic stem cells. However, the potential of iPSCs in promoting the functional recovery of a transected peripheral nerve is largely unknown. This study is the first to investigate in vivo effects of episomal iPSCs (EiPSCs) on peripheral nerve regeneration in a murine sciatic nerve transection model. Episomal iPSCs refer to iPSCs that are generated via Oct3/4-Klf4-Sox2 plasmid reprogramming instead of the conventional viral insertion techniques. It represents a relatively safer form of iPSC production without permanent transgene integration which may raise questions regarding risks of genomic mutation. A minimal number of EiPSCs were added directly to the transected nerve. Functional recovery of the EiPSC group was significantly improved compared to the negative control group when assessed via serial five-toe spread measurement and gait analysis of ankle angles. EiPSC promotion of nerve regeneration was also evident on stereographic analysis of axon density, myelin thickness, and axonal cross-sectional surface area. Most importantly, the results observed in EiPSCs are similar to that of the embryonic stem cell group. A roughly ten-fold increase in neurotrophin-3 levels was seen in EiPSCs which could have contributed to peripheral nerve regeneration and recovery. No abnormal masses or adverse effects were noted with EiPSC administration after one year of follow-up. We have hence shown that functional recovery of the transected peripheral nerve can be improved with the use of EiPSC therapy, which holds promise for the future of nerve regeneration.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0164696</identifier><identifier>PMID: 27736950</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amyotrophic lateral sclerosis ; Analysis ; Animals ; Ankle ; Axons - physiology ; Biology and Life Sciences ; Cellular Reprogramming ; Embryo cells ; Embryonic stem cells ; Female ; Fibroblasts - cytology ; Gait ; Genomes ; Hospitals ; Immunohistochemistry ; In vivo methods and tests ; Induced Pluripotent Stem Cells - cytology ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - transplantation ; Inhibitory postsynaptic potentials ; Injuries ; Insertion ; Kinesin - genetics ; Kinesin - metabolism ; KLF4 protein ; Laboratory animals ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Models, Animal ; Mutation ; Myelin ; Nerve Growth Factors - metabolism ; Nerve Regeneration ; Nervous system ; Neurotrophin 3 ; Oct-4 protein ; Octamer Transcription Factor-3 - genetics ; Octamer Transcription Factor-3 - metabolism ; Plasmids ; Plastic surgery ; Pluripotency ; Recovery ; Recovery (Medical) ; Recovery of Function ; Regeneration ; Sciatic nerve ; Sciatic Nerve - physiology ; Sciatic Nerve - surgery ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Stem cell transplantation ; Stem cells ; Transplants & implants</subject><ispartof>PloS one, 2016-10, Vol.11 (10), p.e0164696-e0164696</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Loh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Loh et al 2016 Loh et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c725t-33a965f60672b737945d982c8cb305406437b38e9da6bd39aaca52de5c65a1763</citedby><cites>FETCH-LOGICAL-c725t-33a965f60672b737945d982c8cb305406437b38e9da6bd39aaca52de5c65a1763</cites><orcidid>0000-0003-1609-1237</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063300/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063300/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27736950$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cooney, Austin John</contributor><creatorcontrib>Loh, Charles Yuen Yung</creatorcontrib><creatorcontrib>Wang, Aline Yen Ling</creatorcontrib><creatorcontrib>Kao, Huang-Kai</creatorcontrib><creatorcontrib>Cardona, Esteban</creatorcontrib><creatorcontrib>Chuang, Sheng-Hao</creatorcontrib><creatorcontrib>Wei, Fu-Chan</creatorcontrib><title>Episomal Induced Pluripotent Stem Cells Promote Functional Recovery of Transected Murine Peripheral Nerve</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Traumatic peripheral nerve neurotmesis occurs frequently and functional recovery is often slow and impaired. Induced pluripotent stem cells (iPSCs) have shown much promise in recent years due to its regenerative properties similar to that of embryonic stem cells. However, the potential of iPSCs in promoting the functional recovery of a transected peripheral nerve is largely unknown. This study is the first to investigate in vivo effects of episomal iPSCs (EiPSCs) on peripheral nerve regeneration in a murine sciatic nerve transection model. Episomal iPSCs refer to iPSCs that are generated via Oct3/4-Klf4-Sox2 plasmid reprogramming instead of the conventional viral insertion techniques. It represents a relatively safer form of iPSC production without permanent transgene integration which may raise questions regarding risks of genomic mutation. A minimal number of EiPSCs were added directly to the transected nerve. Functional recovery of the EiPSC group was significantly improved compared to the negative control group when assessed via serial five-toe spread measurement and gait analysis of ankle angles. EiPSC promotion of nerve regeneration was also evident on stereographic analysis of axon density, myelin thickness, and axonal cross-sectional surface area. Most importantly, the results observed in EiPSCs are similar to that of the embryonic stem cell group. A roughly ten-fold increase in neurotrophin-3 levels was seen in EiPSCs which could have contributed to peripheral nerve regeneration and recovery. No abnormal masses or adverse effects were noted with EiPSC administration after one year of follow-up. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Loh, Charles Yuen Yung</au><au>Wang, Aline Yen Ling</au><au>Kao, Huang-Kai</au><au>Cardona, Esteban</au><au>Chuang, Sheng-Hao</au><au>Wei, Fu-Chan</au><au>Cooney, Austin John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Episomal Induced Pluripotent Stem Cells Promote Functional Recovery of Transected Murine Peripheral Nerve</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-10-13</date><risdate>2016</risdate><volume>11</volume><issue>10</issue><spage>e0164696</spage><epage>e0164696</epage><pages>e0164696-e0164696</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Traumatic peripheral nerve neurotmesis occurs frequently and functional recovery is often slow and impaired. Induced pluripotent stem cells (iPSCs) have shown much promise in recent years due to its regenerative properties similar to that of embryonic stem cells. However, the potential of iPSCs in promoting the functional recovery of a transected peripheral nerve is largely unknown. This study is the first to investigate in vivo effects of episomal iPSCs (EiPSCs) on peripheral nerve regeneration in a murine sciatic nerve transection model. Episomal iPSCs refer to iPSCs that are generated via Oct3/4-Klf4-Sox2 plasmid reprogramming instead of the conventional viral insertion techniques. It represents a relatively safer form of iPSC production without permanent transgene integration which may raise questions regarding risks of genomic mutation. A minimal number of EiPSCs were added directly to the transected nerve. Functional recovery of the EiPSC group was significantly improved compared to the negative control group when assessed via serial five-toe spread measurement and gait analysis of ankle angles. EiPSC promotion of nerve regeneration was also evident on stereographic analysis of axon density, myelin thickness, and axonal cross-sectional surface area. Most importantly, the results observed in EiPSCs are similar to that of the embryonic stem cell group. A roughly ten-fold increase in neurotrophin-3 levels was seen in EiPSCs which could have contributed to peripheral nerve regeneration and recovery. No abnormal masses or adverse effects were noted with EiPSC administration after one year of follow-up. We have hence shown that functional recovery of the transected peripheral nerve can be improved with the use of EiPSC therapy, which holds promise for the future of nerve regeneration.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27736950</pmid><doi>10.1371/journal.pone.0164696</doi><tpages>e0164696</tpages><orcidid>https://orcid.org/0000-0003-1609-1237</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Amyotrophic lateral sclerosis Analysis Animals Ankle Axons - physiology Biology and Life Sciences Cellular Reprogramming Embryo cells Embryonic stem cells Female Fibroblasts - cytology Gait Genomes Hospitals Immunohistochemistry In vivo methods and tests Induced Pluripotent Stem Cells - cytology Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - transplantation Inhibitory postsynaptic potentials Injuries Insertion Kinesin - genetics Kinesin - metabolism KLF4 protein Laboratory animals Medicine and Health Sciences Mice Mice, Inbred C57BL Models, Animal Mutation Myelin Nerve Growth Factors - metabolism Nerve Regeneration Nervous system Neurotrophin 3 Oct-4 protein Octamer Transcription Factor-3 - genetics Octamer Transcription Factor-3 - metabolism Plasmids Plastic surgery Pluripotency Recovery Recovery (Medical) Recovery of Function Regeneration Sciatic nerve Sciatic Nerve - physiology Sciatic Nerve - surgery SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Stem cell transplantation Stem cells Transplants & implants |
title | Episomal Induced Pluripotent Stem Cells Promote Functional Recovery of Transected Murine Peripheral Nerve |
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