Regional Molecular Diversity in Chronic Spinal Cord Injury.

The development of next generation cellular and acellular therapies for regenerative repair of the injured spinal cord will benefit from a greater understanding of microenvironment heterogeneity. To address this need, we used genome wide RNA sequencing to illuminate gene expression changes in the spinal cord injury (SCI) epicenter, and in regions above and below, 30 days after contusion-compression (8 g Fejota clip) of the lumbar spinal cord (L1/L3) in adult female C57BL7J mice. Across injury zones, there were more upregulated versus downregulated genes, with the most dynamic changes occurring in the epicenter, followed by the below and above regions. The expression of 52.9% of genes was uniquely changed in epicenter, 6.6% in the below region, and 2.8% in the above region, while 18.3% of differentially expressed genes (DEGs) overlapped across regions. Ingenuity Pathway analysis of epicenter DEGs showed 49 unique pathways, including Type II Diabetes Mellitus, P2Y Purinergic Receptor, Amyotrophic Lateral Sclerosis, JAK family kinases, and pathways related to GABA and Glutamate function. Thyroid Hormone Metabolism II, Serotonin degradation, and Myc-Mediated Apoptosis were enriched in the zone above the epicenter, while the Chondroitin sulfate degradation, the Superpathway of Geranylgeranylipidphosphate and Zymosterol Biosynthesis, and Regulation of Cellular Mechanics by Calpain Proteases were enriched below. There were 100 pathways shared across regions emphasizing fundamental roles for Apoptosis, Cytoskeletal organization, Chemokines, Complement, Prothrombin Activation pathways, Type I Diabetes Mellitus Signaling, and RXR signaling. These findings provide a rich resource of candidate mechanisms for additional validation and the design of targeted therapies to improve recovery after spinal cord injury. GRAPHICAL ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10571-026-01694-x.