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Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury

There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration...

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Autores principales: Skop, Nolan B., Singh, Sweta, Antikainen, Henri, Saqcena, Chaitali, Calderon, Frances, Rothbard, Deborah E., Cho, Cheul H., Gandhi, Chirag D., Levison, Steven W., Dobrowolski, Radek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399762/
https://www.ncbi.nlm.nih.gov/pubmed/30818968
http://dx.doi.org/10.1177/1759091419830186
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author Skop, Nolan B.
Singh, Sweta
Antikainen, Henri
Saqcena, Chaitali
Calderon, Frances
Rothbard, Deborah E.
Cho, Cheul H.
Gandhi, Chirag D.
Levison, Steven W.
Dobrowolski, Radek
author_facet Skop, Nolan B.
Singh, Sweta
Antikainen, Henri
Saqcena, Chaitali
Calderon, Frances
Rothbard, Deborah E.
Cho, Cheul H.
Gandhi, Chirag D.
Levison, Steven W.
Dobrowolski, Radek
author_sort Skop, Nolan B.
collection PubMed
description There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration. In this study, we have compared neural progenitors (NPs) from the fetal ventricular zone (VZ), the postnatal subventricular zone, and an immortalized radial glia (RG) cell line engineered to conditionally secrete the trophic factor insulin-like growth factor 1 (IGF-1). Upon differentiation in vitro, the VZ cells were able to generate a greater number of neurons than subventricular zone cells. Furthermore, differentiated VZ cells generated pyramidal neurons. In vitro, doxycycline-driven secretion of IGF-1 strongly promoted neuronal differentiation of cells with hippocampal, interneuron and cortical specificity. Accordingly, VZ and engineered RG-IGF-1-hemagglutinin (HA) cells were selected for subsequent in vivo experiments. To increase cell survival, we delivered the NPs attached to a multifunctional chitosan-based scaffold. The microspheres containing adherent NPs were injected subacutely into the lesion cavity of adult rat brains that had sustained controlled cortical impact injury. At 2 weeks posttransplantation, the exogenously introduced cells showed a reduction in stem cell or progenitor markers and acquired mature neuronal and glial markers. In beam walking tests assessing sensorimotor recovery, transplanted RG cells secreting IGF-1 contributed significantly to functional improvement while native VZ or RG cells did not promote significant recovery. Altogether, these results support the therapeutic potential of chitosan-based multifunctional microsphere scaffolds seeded with genetically modified NPs expressing IGF-1 to promote repair and functional recovery after traumatic brain injuries.
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spelling pubmed-63997622019-03-08 Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury Skop, Nolan B. Singh, Sweta Antikainen, Henri Saqcena, Chaitali Calderon, Frances Rothbard, Deborah E. Cho, Cheul H. Gandhi, Chirag D. Levison, Steven W. Dobrowolski, Radek ASN Neuro Special Collection on Concussion There is intense interest and effort toward regenerating the brain after severe injury. Stem cell transplantation after insult to the central nervous system has been regarded as the most promising approach for repair; however, engrafting cells alone might not be sufficient for effective regeneration. In this study, we have compared neural progenitors (NPs) from the fetal ventricular zone (VZ), the postnatal subventricular zone, and an immortalized radial glia (RG) cell line engineered to conditionally secrete the trophic factor insulin-like growth factor 1 (IGF-1). Upon differentiation in vitro, the VZ cells were able to generate a greater number of neurons than subventricular zone cells. Furthermore, differentiated VZ cells generated pyramidal neurons. In vitro, doxycycline-driven secretion of IGF-1 strongly promoted neuronal differentiation of cells with hippocampal, interneuron and cortical specificity. Accordingly, VZ and engineered RG-IGF-1-hemagglutinin (HA) cells were selected for subsequent in vivo experiments. To increase cell survival, we delivered the NPs attached to a multifunctional chitosan-based scaffold. The microspheres containing adherent NPs were injected subacutely into the lesion cavity of adult rat brains that had sustained controlled cortical impact injury. At 2 weeks posttransplantation, the exogenously introduced cells showed a reduction in stem cell or progenitor markers and acquired mature neuronal and glial markers. In beam walking tests assessing sensorimotor recovery, transplanted RG cells secreting IGF-1 contributed significantly to functional improvement while native VZ or RG cells did not promote significant recovery. Altogether, these results support the therapeutic potential of chitosan-based multifunctional microsphere scaffolds seeded with genetically modified NPs expressing IGF-1 to promote repair and functional recovery after traumatic brain injuries. SAGE Publications 2019-02-28 /pmc/articles/PMC6399762/ /pubmed/30818968 http://dx.doi.org/10.1177/1759091419830186 Text en © The Author(s) 2019 http://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Special Collection on Concussion
Skop, Nolan B.
Singh, Sweta
Antikainen, Henri
Saqcena, Chaitali
Calderon, Frances
Rothbard, Deborah E.
Cho, Cheul H.
Gandhi, Chirag D.
Levison, Steven W.
Dobrowolski, Radek
Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title_full Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title_fullStr Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title_full_unstemmed Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title_short Subacute Transplantation of Native and Genetically Engineered Neural Progenitors Seeded on Microsphere Scaffolds Promote Repair and Functional Recovery After Traumatic Brain Injury
title_sort subacute transplantation of native and genetically engineered neural progenitors seeded on microsphere scaffolds promote repair and functional recovery after traumatic brain injury
topic Special Collection on Concussion
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6399762/
https://www.ncbi.nlm.nih.gov/pubmed/30818968
http://dx.doi.org/10.1177/1759091419830186
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