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...
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| Format: | Article |
| Language: | English |
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Wiley
2018-01-01
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| Series: | Neural Plasticity |
| Online Access: | http://dx.doi.org/10.1155/2018/9828725 |
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| author | Stuart I. Hodgetts Jun Han Yoon Alysia Fogliani Emmanuel A. Akinpelu Danii Baron-Heeris Imke G. J. Houwers Lachlan P. G. Wheeler Bernadette T. Majda Sreya Santhakumar Sarah J. Lovett Emma Duce Margaret A. Pollett Tylie M. Wiseman Brooke Fehily Alan R. Harvey |
| author_facet | Stuart I. Hodgetts Jun Han Yoon Alysia Fogliani Emmanuel A. Akinpelu Danii Baron-Heeris Imke G. J. Houwers Lachlan P. G. Wheeler Bernadette T. Majda Sreya Santhakumar Sarah J. Lovett Emma Duce Margaret A. Pollett Tylie M. Wiseman Brooke Fehily Alan R. Harvey |
| author_sort | Stuart I. Hodgetts |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-1a8b0e65624940cbb9fcbfda79c855ba |
| institution | Kabale University |
| issn | 2090-5904 1687-5443 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Neural Plasticity |
| spelling | doaj-art-1a8b0e65624940cbb9fcbfda79c855ba2025-02-03T00:59:35ZengWileyNeural Plasticity2090-59041687-54432018-01-01201810.1155/2018/98287259828725Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult RatsStuart I. Hodgetts0Jun Han Yoon1Alysia Fogliani2Emmanuel A. Akinpelu3Danii Baron-Heeris4Imke G. J. Houwers5Lachlan P. G. Wheeler6Bernadette T. Majda7Sreya Santhakumar8Sarah J. Lovett9Emma Duce10Margaret A. Pollett11Tylie M. Wiseman12Brooke Fehily13Alan R. Harvey14School of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaUniversity of Notre Dame Australia, Fremantle, WA 6959, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaSchool of Human Sciences, The University of Western Australia (UWA), Perth, WA 6009, AustraliaCiliary 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.http://dx.doi.org/10.1155/2018/9828725 |
| spellingShingle | Stuart I. Hodgetts Jun Han Yoon Alysia Fogliani Emmanuel A. Akinpelu Danii Baron-Heeris Imke G. J. Houwers Lachlan P. G. Wheeler Bernadette T. Majda Sreya Santhakumar Sarah J. Lovett Emma Duce Margaret A. Pollett Tylie M. Wiseman Brooke Fehily Alan R. Harvey Cortical AAV-CNTF Gene Therapy Combined with Intraspinal Mesenchymal Precursor Cell Transplantation Promotes Functional and Morphological Outcomes after Spinal Cord Injury in Adult Rats Neural Plasticity |
| 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 |
| url | http://dx.doi.org/10.1155/2018/9828725 |
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