NPC transplantation rescues sci-driven cAMP/EPAC2 alterations, leading to neuroprotection and microglial modulation.
EPAC2
NPC transplantation
Spinal cord injury
Transcriptomic analysis
cAMP
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
29 Jul 2022
29 Jul 2022
Historique:
received:
05
06
2022
accepted:
17
07
2022
revised:
07
07
2022
entrez:
29
7
2022
pubmed:
30
7
2022
medline:
3
8
2022
Statut:
epublish
Résumé
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 affects nearly 20,000 genes in total tissue extracts. Functional analysis of this dysregulated transcriptome reveals the significant 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 significant transcriptional impact in spinal tissue, as evidenced by the normalized expression of a large proportion of SCI-affected 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 significant 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 inflammatory 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 inflammation and provides a more neuropermissive environment through an EPAC2-dependent mechanism.
Identifiants
pubmed: 35904607
doi: 10.1007/s00018-022-04494-w
pii: 10.1007/s00018-022-04494-w
pmc: PMC9338125
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
455Subventions
Organisme : Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación
ID : RTI2018-095872-B-C21/ERDF
Organisme : Conselleria de Innovación, Universidades, Ciencia y Sociedad Digital, Generalitat Valenciana
ID : ACIF/2019/120
Organisme : H2020 European Research Council
ID : 964562 (RISEUP)
Informations de copyright
© 2022. The Author(s).
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