NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation

[EN] Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, whi...

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Autores: Martinez-Rojas, Beatriz, Grillo-Risco, Rubén, Hidalgo, Marta R., López-Mocholi, Eric, Alastrue-Agudo, Ana, Garcia-Garcia, Francisco, Moreno-Manzano, Victoria, Giraldo, Esther|||0000-0001-5488-3011
Tipo de recurso: artículo
Fecha de publicación:2022
País:España
Institución:Universitat Politècnica de València (UPV)
Repositorio:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
Idioma:inglés
OAI Identifier:oai:riunet.upv.es:10251/208644
Acceso en línea:https://riunet.upv.es/handle/10251/208644
Access Level:acceso abierto
Palabra clave:NPC transplantation
EPAC2
CAMP signalling
Spinal cord injury
BIOLOGIA CELULAR
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oai_identifier_str oai:riunet.upv.es:10251/208644
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
title NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
spellingShingle NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
Martinez-Rojas, Beatriz
NPC transplantation
EPAC2
CAMP signalling
Spinal cord injury
BIOLOGIA CELULAR
title_short NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
title_full NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
title_fullStr NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
title_full_unstemmed NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
title_sort NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation
dc.creator.none.fl_str_mv Martinez-Rojas, Beatriz
Grillo-Risco, Rubén
Hidalgo, Marta R.
López-Mocholi, Eric
Alastrue-Agudo, Ana
Garcia-Garcia, Francisco
Moreno-Manzano, Victoria
Giraldo, Esther|||0000-0001-5488-3011
author Martinez-Rojas, Beatriz
author_facet Martinez-Rojas, Beatriz
Grillo-Risco, Rubén
Hidalgo, Marta R.
López-Mocholi, Eric
Alastrue-Agudo, Ana
Garcia-Garcia, Francisco
Moreno-Manzano, Victoria
Giraldo, Esther|||0000-0001-5488-3011
author_role author
author2 Grillo-Risco, Rubén
Hidalgo, Marta R.
López-Mocholi, Eric
Alastrue-Agudo, Ana
Garcia-Garcia, Francisco
Moreno-Manzano, Victoria
Giraldo, Esther|||0000-0001-5488-3011
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Departamento de Biotecnología
Centro Avanzado de Microbiología Aplicada
Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural
European Commission
Generalitat Valenciana
European Regional Development Fund
Ministerio de Ciencia e Innovación
Repositorio Institucional de la Universitat Politècnica de València Riunet
dc.subject.none.fl_str_mv NPC transplantation
EPAC2
CAMP signalling
Spinal cord injury
BIOLOGIA CELULAR
topic NPC transplantation
EPAC2
CAMP signalling
Spinal cord injury
BIOLOGIA CELULAR
description [EN] Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and afects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the signifcant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a signifcant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-afected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a signifcant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs+ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an infammatory phenotype, and increases the magnitude of the gap between NeuN+cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces infammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022-08-01
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://riunet.upv.es/handle/10251/208644
url https://riunet.upv.es/handle/10251/208644
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Agencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-095872-B-C21 NUEVO BIOMATERIAL BIO-ACTIVO PARA LA REGENERACION DE LESIONES MEDULARES
European Commission https://doi.org/10.13039/501100000780 H2020 964562 Regeneration of Injured Spinal cord by Electro pUlsed bio-hybrid imPlant
Generalitat Valenciana https://doi.org/10.13039/501100003359 ACIF%2F2019%2F120
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento (by)
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Reconocimiento (by)
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer-Verlag
publisher.none.fl_str_mv Springer-Verlag
dc.source.none.fl_str_mv reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
instname:Universitat Politècnica de València (UPV)
instname_str Universitat Politècnica de València (UPV)
reponame_str RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
collection RiuNet. Repositorio Institucional de la Universitat Politécnica de Valéncia
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulationMartinez-Rojas, BeatrizGrillo-Risco, RubénHidalgo, Marta R.López-Mocholi, EricAlastrue-Agudo, AnaGarcia-Garcia, FranciscoMoreno-Manzano, VictoriaGiraldo, Esther|||0000-0001-5488-3011NPC transplantationEPAC2CAMP signallingSpinal cord injuryBIOLOGIA CELULAR[EN] Neural progenitor cell (NPC) transplantation represents a promising treatment strategy for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We demonstrate that severe spinal contusion in adult rats causes transcriptional dysregulation, which persists from early subacute to chronic stages of SCI and afects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the signifcant downregulation of cAMP signalling components immediately after SCI, involving genes such as EPAC2 (exchange protein directly activated by cAMP), PKA, BDNF, and CAMKK2. The ectopic transplantation of spinal cord-derived NPCs at acute or subacute stages of SCI induces a signifcant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-afected genes. The transcriptional modulation pattern driven by NPC transplantation includes the rescued expression of cAMP signalling genes, including EPAC2. We also explore how the sustained in vivo inhibition of EPAC2 downstream signalling via the intrathecal administration of ESI-05 for 1 week impacts therapeutic mechanisms involved in the NPC-mediated treatment of SCI. NPC transplantation in SCI rats in the presence and absence of ESI-05 administration prompts increased rostral cAMP levels; however, NPC and ESI-05 treated animals exhibit a signifcant reduction in EPAC2 mRNA levels compared to animals receiving only NPCs treatment. Compared with transplanted animals, NPCs+ESI-05 treatment increases the scar area (as shown by GFAP staining), polarizes microglia into an infammatory phenotype, and increases the magnitude of the gap between NeuN+cells across the lesion. Overall, our results indicate that the NPC-associated therapeutic mechanisms in the context of SCI involve the cAMP pathway, which reduces infammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism.This research was funded by FEDER/Ministerio de Ciencia e Innovacion - Agencia Estatal de Investigacion [RTI2018-095872-B-C21/ERDF] and RISEUP EU grant (Ref. 964562) from FetOpen H2020 program. Part of the equipment employed in this work was funded by Generalitat Valenciana and cofinanced with ERDF funds (OP ERDF of Comunitat Valenciana 2014-2020) and the UE; Fondo Europeo de Desarrollo Regional (FEDER) incluido en el Programa Operativo FEDER de la Comunidad Valenciana 2014-2020. B. Martinez-Rojas was supported by a grant from the Conselleria de Educacion, Investigacion, Cultura y Deporte de la Generalitat Valenciana and the European Social Fundation ACIF/2019/120.Springer-VerlagDepartamento de BiotecnologíaCentro Avanzado de Microbiología AplicadaEscuela Técnica Superior de Ingeniería Agronómica y del Medio NaturalEuropean CommissionGeneralitat ValencianaEuropean Regional Development FundMinisterio de Ciencia e InnovaciónRepositorio Institucional de la Universitat Politècnica de València Riunet20222022-08-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://riunet.upv.es/handle/10251/208644reponame:RiuNet. Repositorio Institucional de la Universitat Politécnica de Valénciainstname:Universitat Politècnica de València (UPV)InglésengAgencia Estatal de Investigación http://dx.doi.org/10.13039/501100011033 Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020 RTI2018-095872-B-C21 NUEVO BIOMATERIAL BIO-ACTIVO PARA LA REGENERACION DE LESIONES MEDULARESEuropean Commission https://doi.org/10.13039/501100000780 H2020 964562 Regeneration of Injured Spinal cord by Electro pUlsed bio-hybrid imPlantGeneralitat Valenciana https://doi.org/10.13039/501100003359 ACIF%2F2019%2F120open accesshttp://purl.org/coar/access_right/c_abf2Reconocimiento (by)http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:riunet.upv.es:10251/2086442026-06-13T07:49:27Z
score 15.811543

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