Abstract
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 (Gfap-Cre+/− TG2fl/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.
Highlights
Astrocytes are the most abundant cell type in the central nervous system (CNS) and play an essential role in supporting neuron homeostasis and function [1]
We demonstrate that astrocytic-specific transglutaminase 2 (TG2) deletion results in a significant improvement in functional recovery in a mouse thoracic 9 (T9) spinal cord contusion injury model
In the injured CNS, astroglial response is a highly regulated process that is characterized by changes in astrocyte gene expression, morphology, proliferative state and mobility, and is dependent upon numerous factors such as location, severity and time after insult [1]
Summary
Astrocytes are the most abundant cell type in the central nervous system (CNS) and play an essential role in supporting neuron homeostasis and function [1]. We have demonstrated that mice with astrocyte-specific TG2 deletion (glial fibrillary acidic protein (Gfap)-Cre+/−/TG2fl/fl, referred to here as TG2A-cKO) exhibited significantly less astrocytic scarring in an in vivo model of a contusion spinal cord injury (SCI) when compared to TG2fl/fl mice expressing normal levels of astrocytic TG2 [7]. We further extend these findings and demonstrate that expression of both the transcription factor SOX9 and the chondroitin sulfate proteoglycan (CSPG) NG2 (Cspg4) are significantly decreased in TG2-A-cKO spinal cord compared to TG2fl/fl mice at 3 and 7 days after injury These are exciting findings as NG2 is part of the astroglial scar and may block successful CNS regeneration [14], while deletion of SOX9 improves outcomes after CNS injury [15,16,17]. The results of our studies demonstrate that removal of astrocytic TG2 or inhibition of TG2 significantly improves outcomes after CNS injury and strongly suggest that the use of TG2 inhibitors may be a therapeutic strategy for treating acute SCI
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