Decoding CNS regeneration: Insights from single-cell RNA sequencing in SCI and TBI across multiple species

Spinal cord injury and traumatic brain injury result in significant functional loss and neurological deficits. Since the central nervous system in mammals has limited regeneration ability, treatment options are limited. To advance understanding of the molecular and cellular mechanisms underlying CNS injury and repair, this review synthesizes findings from studies employing single-cell RNA sequencing (scRNA-seq), a powerful tool enabling high-resolution profiling of individual cell states and trajectories. A systematic literature search was conducted in PubMed and Google Scholar for peer-reviewed studies published between 2010 and 2025 that applied scRNA-seq to SCI or TBI models in mammals, frogs, and zebrafish. By integrating insights across species and injury models, this review highlights key cellular responses, regenerative mechanisms, and transcriptomic signatures with potential relevance for future therapies. The single-cell resolution of scRNA-seq uncovers subtle cellular dynamics and intercellular signaling networks often masked in bulk analyses, offering a transformative perspective on CNS regeneration. Our comparative analyses identified shared activation of cell cycle pathways, immune responses, extracellular matrix remodeling, and stress responses, underscoring conserved mechanisms of CNS repair following both TBI and SCI. Notably, we observed a restricted yet significant regenerative capacity in specific mammalian cell populations, including subventricular zone (svz) progenitors and neurons expressing regeneration-associated genes (RAG). Temporal comparisons across major cell types revealed that cell cycle activity was consistently upregulated during the acute phase of both injuries. In addition, overlapping enrichment of chemotaxis during the acute and subacute phases highlights the central role of immune responses in shaping post-injury dynamics.