Transcriptome Profiling after Early Spinal Cord Injury in the Axolotl and Its Comparison with Rodent Animal Models through RNA-Seq Data Analysis

Abstract

Background: Traumatic spinal cord injury (SCI) is a disabling condition that affects millions of people around the world. Currently, no clinical treatment can restore spinal cord function. Comparison of molecular responses in regenerating to non-regenerating vertebrates can shed light on neural restoration. The axolotl (Ambystoma mexicanum) is an amphibian that regenerates regions of the brain or spinal cord after damage. Methods: In this study, we compared the transcriptomes after SCI at acute (1–2 days after SCI) and sub-acute (6–7 days post-SCI) periods through the analysis of RNA-seq public datasets from axolotl and non-regenerating rodents. Results: Genes related to wound healing and immune responses were upregulated in axolotls, rats, and mice after SCI; however, the immune-related processes were more prevalent in rodents. In the acute phase of SCI in the axolotl, the molecular pathways and genes associated with early development were upregulated, while processes related to neuronal function were downregulated. Importantly, the downregulation of processes related to sensorial and motor functions was observed only in rodents. This analysis also revealed that genes related to pluripotency, cytoskeleton rearrangement, and transposable elements (e.g., Sox2, Krt5, and LOC100130764) were among the most upregulated in the axolotl. Finally, gene regulatory networks in axolotls revealed the early activation of genes related to neurogenesis, including Atf3/4 and Foxa2. Conclusions: Immune-related processes are upregulated shortly after SCI in axolotls and rodents; however, a strong immune response is more noticeable in rodents. Genes related to early development and neurogenesis are upregulated beginning in the acute stage of SCI in axolotls, while the loss of motor and sensory functions is detected only in rodents during the sub-acute period of SCI. The approach employed in this study might be useful for designing and establishing regenerative therapies after SCI in mammals, including humans.

Regeneration in Mice of Injured Skin, Heart, and Spinal Cord by α-Gal Nanoparticles Recapitulates Regeneration in Amphibians

“…A recent study [ 106 ] analyzed activated genes during regeneration of injured spinal cord in axolotl in comparison to activated genes in spinal cord injuries of adult mice that led to fibrosis and scar formation. This study demonstrated much longer activity of some immune-associated genes in the axolotl than similar genes in mice [ 106 ].…”

“…A recent study [ 106 ] analyzed activated genes during regeneration of injured spinal cord in axolotl in comparison to activated genes in spinal cord injuries of adult mice that led to fibrosis and scar formation. This study demonstrated much longer activity of some immune-associated genes in the axolotl than similar genes in mice [ 106 ]. Future comparisons between activated genes in macrophages orchestrating regeneration in injured organs in axolotl and in adult mice treated with α-gal nanoparticles vs. control mice, may enable identification of the regeneration-associated genes that are active in urodeles, suppressed in adult mammals, and reactivated following α-gal nanoparticle treatment.…”