Modulating pathogenic scar cells promotes spinal cord regeneration

SCI often causes long-term motor and sensory deficits because the damaged tissue does not simply heal like many peripheral tissues. After injury, astrocytes, fibroblasts, immune cells, blood vessels, and extracellular matrix (ECM) components form a complex lesion microenvironment. In the acute stage, scar formation can limit inflammation and preserve structural stability, but persistent fibroblast activation and ECM deposition later create a physical and biochemical barrier to regeneration. Current clinical approaches, including decompression surgery and anti-inflammatory treatment, mainly aim to reduce secondary damage rather than reshape the scar itself. Based on these challenges, deeper investigation is needed into the molecular mechanisms that control pathological scar formation after SCI.

A research team from the Second Affiliated Hospital of Naval Medical University, Nantong University, the Second Affiliated Hospital of Nantong University, the Second Affiliated Hospital of Soochow University, and Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, published (DOI: 10.1093/burnst/tkag020) the study in Burns & Trauma on 12 March 2026. The article, titled reports that CD36-enriched fibroblast subpopulations accumulate in lesion scars and can be therapeutically modulated to improve the repair environment.

The researchers first used scRNA-seq and spatial transcriptomic profiling to map CD36 expression after SCI. They found that CD36 was mainly concentrated in lesion scars and preferentially increased in specific fibroblast subclusters associated with fibrotic progression. To test whether this pathway could be targeted, they used salvianolic acid B (SAB), a CD36 inhibitor, and T5224, an activator protein-1 (AP-1)/c-Jun inhibitor, in mouse SCI models. SAB reduced P4HB-positive fibroblast accumulation, decreased fibrotic deposition, enhanced CD31-marked angiogenesis, supported axonal regrowth, and improved hindlimb functional recovery. T5224 also lowered CD36 expression, reduced fibroblast aggregation and ECM deposition, promoted vascular remodeling, and improved early motor recovery. Mechanistically, the study showed that c-Jun activates Irf8, and Irf8 then promotes CD36 transcription, establishing a c-Jun-Irf8-CD36 signaling cascade. CUT&Tag and dual-luciferase reporter assays supported this regulatory connection. Multi-omic analyses further showed that T5224 selectively restrained the abnormal expansion of CD36-positive fibroblast subclusters and shifted their transcriptional state toward a less fibrotic, more repair-permissive phenotype.

The authors said the findings suggest a more precise way to think about spinal cord scars. Rather than trying to remove scar tissue completely, they said, the goal may be to tune the scar at the right stage—preserving its early protective role while preventing fibroblasts from building a long-lasting fibrotic wall. They said identifying c-Jun, Irf8, and CD36 as connected control points provides a clearer route for developing therapies that reshape the injury microenvironment and give regenerating axons a better chance to reconnect.

These findings may support new stage-adapted strategies for SCI treatment, especially therapies aimed at scar biology during the early post-injury window. Because both CD36 and c-Jun are pharmacologically targetable, the work provides a foundation for testing localized drug delivery, combination therapy, or precision approaches that act on pathogenic fibroblast subtypes while preserving tissue stability. The study also shows how single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics can reveal not only which cells are present in an injury site, but where they act and how they change after treatment. Further validation in larger animal models and preclinical systems will be needed before translation to human SCI therapy.