Identification of regenerative processes in neonatal spinal cord injury in the opossum (Monodelphis domestica): A transcriptomic study

Abstract

This study investigates the response to spinal cord injury in the gray short‐tailed opossum (Monodelphis domestica). In opossums spinal injury early in development results in spontaneous axon growth through the injury, but this regenerative potential diminishes with maturity until it is lost entirely. The mechanisms underlying this regeneration remain unknown. RNA sequencing was used to identify differential gene expression in regenerating (SCI at postnatal Day 7, P7SCI) and nonregenerating (SCI at Day 28, P28SCI) cords +1d, +3d, and +7d after complete spinal transection, compared to age‐matched controls. Genes showing significant differential expression (log2FC ≥ 1, Padj ≤ 0.05) were used for downstream analysis. Across all time‐points 233 genes altered expression after P7SCI, and 472 genes altered expression after P28SCI. One hundred and forty‐seven genes altered expression in both injury ages (63% of P7SCI data set). The majority of changes were gene upregulations. Gene ontology overrepresentation analysis in P7SCI gene‐sets showed significant overrepresentations only in immune‐associated categories, while P28SCI gene‐sets showed overrepresentations in these same immune categories, along with other categories such as “cell proliferation,” “cell adhesion,” and “apoptosis.” Cell‐type–association analysis suggested that, regardless of injury age, injury‐associated gene transcripts were most strongly associated with microglia and endothelial cells, with strikingly fewer astrocyte, oligodendrocyte and neuron‐related genes, the notable exception being a cluster of mostly downregulated oligodendrocyte‐associated genes in the P7SCI + 7d gene‐set. Our findings demonstrate a more complex transcriptomic response in nonregenerating cords, suggesting a strong influence of non‐neuronal cells in the outcome after injury and providing the largest survey yet of the transcriptomic changes occurring after SCI in this model.

Multi-omics in Spinal Cord Injury: Diagnosis, Prognosis, and Treatment

“…MSCs-Evs pre-treated with melatonin was found to promote better recovery after SCI (67), and after proteomic analysis was conducted, Ubiquitin-specific protease 29 expression was significantly elevated, allowing further research to establish its probable mechanism of action, in order to formulate more valuable methods for the treatment of SCI. Unlike mammals, some animals have the ability to repair and regenerate nerves in close association with age (68)(69)(70)(71)(72) and this can provide insight into ways to improve recovery from SCI. When Xenopus regenerative and non-regenerative SCI models of laevis were quantitatively detected by proteome (73), 172 were in the regenerative phase and 240 in the nonregenerative phase.…”

Epigenetic clock and methylation studies in marsupials: opossums, Tasmanian devils, kangaroos, and wallabies

“…Researchers have taken advantage of these traits to study development of the lung [ 7 ], neural crest [ 8 ], brain [ 9 – 11 ], limb [ 12 , 13 ], reproductive [ 14 , 15 ], and other systems. Because of their early developmental state at birth, newborn opossums are also capable of totally regenerating their spinal cord even after it has been completely severed, and therefore provide an ideal model for spinal cord regeneration [ 9 , 16 – 18 ]. Opossums are also one of the only mammals besides humans that develop UV-induced melanoma, making them a good model for melanoma research [ 19 – 21 ].…”

Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica

“…Marsupials are also valuable for investigating major epigenetic processes such as X-chromosome inactivation ( Hornecker et al 2007 ; Grant et al 2012 ; Rodriguez-Delgado et al 2014 ; Wang et al 2014 ; Waters et al 2018 ; Mahadevaiah et al 2020 ) and genomic imprinting ( Weidman et al 2006 ; Lawton et al 2008 ; Das et al 2012 ; Douglas et al 2014 ; Suzuki et al 2018 ). Monodelphis domestica has been used in many medical and disease studies, such as gene expression during neural development ( Dooley et al 2012 ; Sears et al 2012 ; Pavan et al 2014 ; Wheaton et al 2021 ), hypercholesterolemia and steatohepatitis ( Chan et al 2010 , 2012 ; Chan and VandeBerg 2011 ), cancer therapy and prevention ( Nair and VandeBerg 2012 ; Nair et al 2014 ), immunogenomics ( Parra et al 2008 ; Morrissey et al 2021 ; Schraven et al 2021 ), viral pathogenesis ( Thomas et al 2019 ), and influence of biological sex on social behavior, individual recognition, and associative learning ( Gil et al 2019 ).…”