Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats
Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2018
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| Online Access: | http://hdl.handle.net/20.500.11937/96902 |
| _version_ | 1848766208349831168 |
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| author | Hodgetts, S.I. Yoon, J.H. Fogliani, A. Akinpelu, E.A. Baron-Heeris, D. Houwers, I.G.J. Wheeler, L.P.G. Majda, Bernadette T. Santhakumar, S. Lovett, S.J. Duce, E. Pollett, M.A. Wiseman, T.M. Fehily, B. Harvey, A.R. |
| author_facet | Hodgetts, S.I. Yoon, J.H. Fogliani, A. Akinpelu, E.A. Baron-Heeris, D. Houwers, I.G.J. Wheeler, L.P.G. Majda, Bernadette T. Santhakumar, S. Lovett, S.J. Duce, E. Pollett, M.A. Wiseman, T.M. Fehily, B. Harvey, A.R. |
| author_sort | Hodgetts, S.I. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| description | Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations. |
| first_indexed | 2025-11-14T11:47:29Z |
| format | Journal Article |
| id | curtin-20.500.11937-96902 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| language | eng |
| last_indexed | 2025-11-14T11:47:29Z |
| publishDate | 2018 |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-969022025-02-18T02:21:11Z Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats Hodgetts, S.I. Yoon, J.H. Fogliani, A. Akinpelu, E.A. Baron-Heeris, D. Houwers, I.G.J. Wheeler, L.P.G. Majda, Bernadette T. Santhakumar, S. Lovett, S.J. Duce, E. Pollett, M.A. Wiseman, T.M. Fehily, B. Harvey, A.R. Animals Ciliary Neurotrophic Factor Combined Modality Therapy Dependovirus Female Genetic Therapy Genetic Vectors Mesenchymal Stem Cell Transplantation Nerve Regeneration Rats Rats, Inbred F344 Recovery of Function Spinal Cord Injuries Treatment Outcome Animals Rats, Inbred F344 Rats Dependovirus Spinal Cord Injuries Ciliary Neurotrophic Factor Treatment Outcome Combined Modality Therapy Mesenchymal Stem Cell Transplantation Recovery of Function Nerve Regeneration Genetic Vectors Female Genetic Therapy Ciliary neurotrophic factor (CNTF) promotes survival and enhances long-distance regeneration of injured axons in parts of the adult CNS. Here we tested whether CNTF gene therapy targeting corticospinal neurons (CSN) in motor-related regions of the cerebral cortex promotes plasticity and regrowth of axons projecting into the female adult F344 rat spinal cord after moderate thoracic (T10) contusion injury (SCI). Cortical neurons were transduced with a bicistronic adeno-associated viral vector (AAV1) expressing a secretory form of CNTF coupled to mCHERRY (AAV-CNTFmCherry) or with control AAV only (AAV-GFP) two weeks prior to SCI. In some animals, viable or nonviable F344 rat mesenchymal precursor cells (rMPCs) were injected into the lesion site two weeks after SCI to modulate the inhibitory environment. Treatment with AAV-CNTFmCherry, as well as with AAV-CNTFmCherry combined with rMPCs, yielded functional improvements over AAV-GFP alone, as assessed by open-field and Ladderwalk analyses. Cyst size was significantly reduced in the AAV-CNTFmCherry plus viable rMPC treatment group. Cortical injections of biotinylated dextran amine (BDA) revealed more BDA-stained axons rostral and alongside cysts in the AAV-CNTFmCherry versus AAV-GFP groups. After AAV-CNTFmCherry treatments, many sprouting mCherry-immunopositive axons were seen rostral to the SCI, and axons were also occasionally found caudal to the injury site. These data suggest that CNTF has the potential to enhance corticospinal repair by transducing parent CNS populations. 2018 Journal Article http://hdl.handle.net/20.500.11937/96902 10.1155/2018/9828725 eng http://creativecommons.org/licenses/by/4.0/ fulltext |
| spellingShingle | Animals Ciliary Neurotrophic Factor Combined Modality Therapy Dependovirus Female Genetic Therapy Genetic Vectors Mesenchymal Stem Cell Transplantation Nerve Regeneration Rats Rats, Inbred F344 Recovery of Function Spinal Cord Injuries Treatment Outcome Animals Rats, Inbred F344 Rats Dependovirus Spinal Cord Injuries Ciliary Neurotrophic Factor Treatment Outcome Combined Modality Therapy Mesenchymal Stem Cell Transplantation Recovery of Function Nerve Regeneration Genetic Vectors Female Genetic Therapy Hodgetts, S.I. Yoon, J.H. Fogliani, A. Akinpelu, E.A. Baron-Heeris, D. Houwers, I.G.J. Wheeler, L.P.G. Majda, Bernadette T. Santhakumar, S. Lovett, S.J. Duce, E. Pollett, M.A. Wiseman, T.M. Fehily, B. Harvey, A.R. Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title | Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title_full | Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title_fullStr | Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title_full_unstemmed | Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title_short | Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats |
| title_sort | cortical aav-cntf gene therapy combined with intraspinal mesenchymal precursor cell transplantation promotes functional and morphological outcomes after spinal cord injury in adult rats |
| topic | Animals Ciliary Neurotrophic Factor Combined Modality Therapy Dependovirus Female Genetic Therapy Genetic Vectors Mesenchymal Stem Cell Transplantation Nerve Regeneration Rats Rats, Inbred F344 Recovery of Function Spinal Cord Injuries Treatment Outcome Animals Rats, Inbred F344 Rats Dependovirus Spinal Cord Injuries Ciliary Neurotrophic Factor Treatment Outcome Combined Modality Therapy Mesenchymal Stem Cell Transplantation Recovery of Function Nerve Regeneration Genetic Vectors Female Genetic Therapy |
| url | http://hdl.handle.net/20.500.11937/96902 |