Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insu...

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Autores principales:	Anissa Elahi, Jacen Emerson, Jacob Rudlong, Jeffrey W. Keillor, Garrick Salois, Adam Visca, Peter Girardi, Gail V.W. Johnson, Christoph Pröschel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	transglutaminase 2 spinal cord injury astrocytes regeneration GFAP SOX9 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/cc4664977ba6406abc8546d4e98a1f5b
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spelling	oai:doaj.org-article:cc4664977ba6406abc8546d4e98a1f5b2021-11-25T17:09:28ZDeletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury10.3390/cells101129422073-4409https://doaj.org/article/cc4664977ba6406abc8546d4e98a1f5b2021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2942https://doaj.org/toc/2073-4409Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (<i>Gfap</i>-Cre+/− <i>TG2</i>fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.Anissa ElahiJacen EmersonJacob RudlongJeffrey W. KeillorGarrick SaloisAdam ViscaPeter GirardiGail V.W. JohnsonChristoph PröschelMDPI AGarticletransglutaminase 2spinal cord injuryastrocytesregenerationGFAPSOX9Biology (General)QH301-705.5ENCells, Vol 10, Iss 2942, p 2942 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	transglutaminase 2 spinal cord injury astrocytes regeneration GFAP SOX9 Biology (General) QH301-705.5
spellingShingle	transglutaminase 2 spinal cord injury astrocytes regeneration GFAP SOX9 Biology (General) QH301-705.5 Anissa Elahi Jacen Emerson Jacob Rudlong Jeffrey W. Keillor Garrick Salois Adam Visca Peter Girardi Gail V.W. Johnson Christoph Pröschel Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
description	Following CNS injury, astrocytes become “reactive” and exhibit pro-regenerative or harmful properties. However, the molecular mechanisms that cause astrocytes to adopt either phenotype are not well understood. Transglutaminase 2 (TG2) plays a key role in regulating the response of astrocytes to insults. Here, we used mice in which TG2 was specifically deleted in astrocytes (<i>Gfap</i>-Cre+/− <i>TG2</i>fl/fl, referred to here as TG2-A-cKO) in a spinal cord contusion injury (SCI) model. Deletion of TG2 from astrocytes resulted in a significant improvement in motor function following SCI. GFAP and NG2 immunoreactivity, as well as number of SOX9 positive cells, were significantly reduced in TG2-A-cKO mice. RNA-seq analysis of spinal cords from TG2-A-cKO and control mice 3 days post-injury identified thirty-seven differentially expressed genes, all of which were increased in TG2-A-cKO mice. Pathway analysis revealed a prevalence for fatty acid metabolism, lipid storage and energy pathways, which play essential roles in neuron–astrocyte metabolic coupling. Excitingly, treatment of wild type mice with the selective TG2 inhibitor VA4 significantly improved functional recovery after SCI, similar to what was observed using the genetic model. These findings indicate the use of TG2 inhibitors as a novel strategy for the treatment of SCI and other CNS injuries.
format	article
author	Anissa Elahi Jacen Emerson Jacob Rudlong Jeffrey W. Keillor Garrick Salois Adam Visca Peter Girardi Gail V.W. Johnson Christoph Pröschel
author_facet	Anissa Elahi Jacen Emerson Jacob Rudlong Jeffrey W. Keillor Garrick Salois Adam Visca Peter Girardi Gail V.W. Johnson Christoph Pröschel
author_sort	Anissa Elahi
title	Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
title_short	Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
title_full	Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
title_fullStr	Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
title_full_unstemmed	Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury
title_sort	deletion or inhibition of astrocytic transglutaminase 2 promotes functional recovery after spinal cord injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cc4664977ba6406abc8546d4e98a1f5b
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Deletion or Inhibition of Astrocytic Transglutaminase 2 Promotes Functional Recovery after Spinal Cord Injury

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