Cargando…

Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model

Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes, which affect the potency of the functional recovery after spinal cord injury (SCI). Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodelin...

Descripción completa

Detalles Bibliográficos
Autores principales: Davleeva, Maria Aleksandrovna, Garifulin, Ravil Rasimovich, Bashirov, Farid Vagizovich, Izmailov, Andrei Aleksandrovich, Nurullin, Leniz Faritovich, Salafutdinov, Ilnur Ildusovich, Gatina, Dilara Zilbarovna, Shcherbinin, Dmitrij Nikolaevich, Lysenko, Andrei Aleksandrovich, Tutykhina, Irina Leonidovna, Shmarov, Maksim Mikhailovich, Islamov, Rustem Robertovich
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Wolters Kluwer - Medknow 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075125/
https://www.ncbi.nlm.nih.gov/pubmed/36571355
http://dx.doi.org/10.4103/1673-5374.360241
_version_ 1785019855670345728
author Davleeva, Maria Aleksandrovna
Garifulin, Ravil Rasimovich
Bashirov, Farid Vagizovich
Izmailov, Andrei Aleksandrovich
Nurullin, Leniz Faritovich
Salafutdinov, Ilnur Ildusovich
Gatina, Dilara Zilbarovna
Shcherbinin, Dmitrij Nikolaevich
Lysenko, Andrei Aleksandrovich
Tutykhina, Irina Leonidovna
Shmarov, Maksim Mikhailovich
Islamov, Rustem Robertovich
author_facet Davleeva, Maria Aleksandrovna
Garifulin, Ravil Rasimovich
Bashirov, Farid Vagizovich
Izmailov, Andrei Aleksandrovich
Nurullin, Leniz Faritovich
Salafutdinov, Ilnur Ildusovich
Gatina, Dilara Zilbarovna
Shcherbinin, Dmitrij Nikolaevich
Lysenko, Andrei Aleksandrovich
Tutykhina, Irina Leonidovna
Shmarov, Maksim Mikhailovich
Islamov, Rustem Robertovich
author_sort Davleeva, Maria Aleksandrovna
collection PubMed
description Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes, which affect the potency of the functional recovery after spinal cord injury (SCI). Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue. In our previous studies for delivering the therapeutic genes at the site of spinal cord injury, we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses (Ad5/35) carrying recombinant cDNA. In the present study, the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury. Experimental animals were randomly divided into two groups of 4 pigs each: the therapeutic (infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35-VEGF165, Ad5/35-GDNF, and Ad5/35-NCAM1) and control groups (infused with intact leucoconcentrate). The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed: (1) higher sparing of the grey matter and increased survivability of the spinal cord cells (lower number of Caspase-3-positive cells and decreased expression of Hsp27); (2) recovery of synaptophysin expression; (3) prevention of astrogliosis (lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells); (4) higher growth rates of regenerating βIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region. These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF, GDNF, and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury. Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.
format Online
Article
Text
id pubmed-10075125
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Wolters Kluwer - Medknow
record_format MEDLINE/PubMed
spelling pubmed-100751252023-04-06 Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model Davleeva, Maria Aleksandrovna Garifulin, Ravil Rasimovich Bashirov, Farid Vagizovich Izmailov, Andrei Aleksandrovich Nurullin, Leniz Faritovich Salafutdinov, Ilnur Ildusovich Gatina, Dilara Zilbarovna Shcherbinin, Dmitrij Nikolaevich Lysenko, Andrei Aleksandrovich Tutykhina, Irina Leonidovna Shmarov, Maksim Mikhailovich Islamov, Rustem Robertovich Neural Regen Res Research Article Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes, which affect the potency of the functional recovery after spinal cord injury (SCI). Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue. In our previous studies for delivering the therapeutic genes at the site of spinal cord injury, we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses (Ad5/35) carrying recombinant cDNA. In the present study, the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor (VEGF), glial cell line-derived neurotrophic factor (GDNF), and neural cell adhesion molecule (NCAM) was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury. Experimental animals were randomly divided into two groups of 4 pigs each: the therapeutic (infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35-VEGF165, Ad5/35-GDNF, and Ad5/35-NCAM1) and control groups (infused with intact leucoconcentrate). The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed: (1) higher sparing of the grey matter and increased survivability of the spinal cord cells (lower number of Caspase-3-positive cells and decreased expression of Hsp27); (2) recovery of synaptophysin expression; (3) prevention of astrogliosis (lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells); (4) higher growth rates of regenerating βIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region. These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF, GDNF, and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury. Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology. Wolters Kluwer - Medknow 2022-11-09 /pmc/articles/PMC10075125/ /pubmed/36571355 http://dx.doi.org/10.4103/1673-5374.360241 Text en Copyright: © Neural Regeneration Research https://creativecommons.org/licenses/by-nc-sa/4.0/This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
spellingShingle Research Article
Davleeva, Maria Aleksandrovna
Garifulin, Ravil Rasimovich
Bashirov, Farid Vagizovich
Izmailov, Andrei Aleksandrovich
Nurullin, Leniz Faritovich
Salafutdinov, Ilnur Ildusovich
Gatina, Dilara Zilbarovna
Shcherbinin, Dmitrij Nikolaevich
Lysenko, Andrei Aleksandrovich
Tutykhina, Irina Leonidovna
Shmarov, Maksim Mikhailovich
Islamov, Rustem Robertovich
Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title_full Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title_fullStr Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title_full_unstemmed Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title_short Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
title_sort molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10075125/
https://www.ncbi.nlm.nih.gov/pubmed/36571355
http://dx.doi.org/10.4103/1673-5374.360241
work_keys_str_mv AT davleevamariaaleksandrovna molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT garifulinravilrasimovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT bashirovfaridvagizovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT izmailovandreialeksandrovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT nurullinlenizfaritovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT salafutdinovilnurildusovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT gatinadilarazilbarovna molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT shcherbinindmitrijnikolaevich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT lysenkoandreialeksandrovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT tutykhinairinaleonidovna molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT shmarovmaksimmikhailovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel
AT islamovrustemrobertovich molecularandcellularchangesintheposttraumaticspinalcordremodelingafterautoinfusionofageneticallyenrichedleucoconcentrateinaminipigmodel