Comparative Transcriptomics of Rat and Axolotl After Spinal Cord Injury Dissects Differences and Similarities in Inflammatory and Matrix Remodeling Gene Expression Patterns.

Jure Tica,Athanasios Didangelos

doi:10.3389/fnins.2018.00808

Jure Tica, Athanasios Didangelos

Open Access

https://doi.org/10.3389/fnins.2018.00808

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Abstract

Following spinal cord injury in mammals, maladaptive inflammation, and matrix deposition drive tissue scarring and permanent loss of function. In contrast, axolotls regenerate their spinal cord after severe injury fully and without scarring. To explore previously unappreciated molecules and pathways that drive tissue responses after spinal cord injury, we performed a 4-way intersection of rat and axolotl transcriptomics datasets and isolated shared genes with similar or differential expression at days 1, 3, and 7 after spinal cord injury in both species. Systems-wide differences and similarities between the two species are described in detail using public-domain computational tools and key differentially regulated genes are highlighted. Amongst persistent differential expression in matching neuronal genes (upregulated in axolotls but downregulated in rats) and nucleic acid metabolism genes (downregulated in axolotls but upregulated in rats), we found multiple extracellular matrix genes that were upregulated in both species after spinal cord injury and all time-points (days 1, 3, and 7), indicating the importance of extracellular matrix remodeling in wound healing. Moreover, the archetypal transcription factor SP1, which was consistently upregulated in rats but was unchanged in axolotls, was predicted as a potential transcriptional regulator of classic inflammatory response genes in rats most of which were not regulated in regenerating axolotls. This analysis offers an extensive comparative platform between a non-regenerating mammal and a regenerating urodele after spinal cord injury. To better understand regeneration vs. scarring mechanisms it is important to understand consistent molecular differences as well as similarities after experimental spinal cord injury.

Highlights

Following spinal cord injury (SCI) in mammals, inflammation and reactive gliosis drive neuronal loss and irreversible tissue scarring (Fitch and Silver, 2008)
To identify molecular differences and similarities between rats and axolotls we performed an intersection of differentially regulated genes identified in rat clip-impact compression SCI microarray performed by Chamankhah et al (2013) at 3 time-points after injury with orthologous differentially regulated genes identified in a microarray dataset of axolotl SCI performed by Sabin et al (2015) at 1, 3, and 7 days post-injury
Detailed quantitative cross-species and temporal comparison is summarized in Supplemental Figures 1A,B

Summary

Introduction

Following spinal cord injury (SCI) in mammals, inflammation and reactive gliosis drive neuronal loss and irreversible tissue scarring (Fitch and Silver, 2008). Tissue remodeling mechanisms are not well understood and there are no therapies that promote functional repair in mammals. Urodela such as axolotls and newts have the ability to fully regenerate most tissues including the spinal cord (Echeverri and Tanaka, 2002; Diaz Quiroz et al, 2014; Rodrigo Albors et al, 2015; Sabin et al, 2015). While the mechanisms behind this ability are not fully understood, older and recent work point toward the molecular effect of progenitors, excellent spatiotemporal patterning and matrix remodeling, and an effective immune response (Echeverri and Tanaka, 2002; Monaghan et al, 2007; Godwin et al, 2013). Mammalian SCI has not been compared extensively to axolotls, yet such comparisons have shown the potential to identify molecules and mechanisms with pathological or regenerative function in SCI (Monaghan et al, 2007; Diaz Quiroz et al, 2014)

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Conclusion