SCI often causes long-term motor and sensory deficits because the injured 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 injury microenvironment. During the acute phase, scar formation limits inflammation and maintains structural stability, but sustained fibroblast activation and ECM deposition later forms a physical and biochemical barrier to regeneration. Current clinical approaches, such as decompressive surgery and anti-inflammatory treatments, are primarily aimed at reducing secondary damage rather than reshaping the scar itself. Based on these challenges, deeper studies on the molecular mechanisms controlling pathological scar formation after SCI are needed.
A research team from the Second Affiliated Hospital of Nantong University Naval Medical College, the Second Affiliated Hospital of Nantong University, the Second Affiliated Hospital of Dongzhou University, and the Shanghai Ninth People’s Hospital of Shanghai Jiao Tong University Medical College published the study in 2016 (DOI: 10.1093/burnst/tkag020). burns and trauma The paper with this title reports that a CD36-enriched fibroblast subpopulation accumulates in lesional scars and can be modulated therapeutically to improve the repair environment.
The researchers first used scRNA-seq and spatial transcriptome profiling to map CD36 expression after SCI. They found that CD36 was mainly concentrated in lesion scars and was preferentially increased in specific fibroblast subclusters associated with fibrosis progression. To test whether this pathway could be targeted, the researchers used the CD36 inhibitor salvianolic acid B (SAB) and the activator protein 1 (AP-1)/c-Jun inhibitor T5224 in a mouse SCI model. SAB reduced the accumulation of P4HB-positive fibroblasts, reduced fibrotic deposits, enhanced CD31-labeled angiogenesis, supported axonal regrowth, and improved hindlimb functional recovery. T5224 also reduced CD36 expression, reduced fibroblast aggregation and ECM deposition, promoted vascular remodeling, and improved early motor recovery. Mechanistically, this study showed that c-Jun activates Irf8, which then promotes the transcription of CD36, establishing the c-Jun-Irf8-CD36 signaling cascade. CUT&Tag and dual-luciferase reporter assays confirmed this regulatory relevance. Moreover, multiomic analysis showed that T5224 selectively suppressed the aberrant expansion of CD36-positive fibroblast subclusters and shifted their transcriptional state toward a less fibrotic and more repair-permissive phenotype.
The authors said the findings suggest a more accurate way to think about spinal cord scarring. Rather than trying to completely remove scar tissue, they say, the goal may be to condition the scar to the appropriate stage and maintain its initial protective function while preventing fibroblasts from building a long-lasting fibrous wall. They said that identifying c-Jun, Irf8, and CD36 as connected control points provides a clearer path to developing treatments that reshape the injury microenvironment and give regenerating axons a better chance to reconnect.
These findings may support new phase-adapted strategies for SCI treatment, particularly those targeting scar biology early after injury. Because both CD36 and c-Jun can be targeted pharmacologically, this study provides a foundation for testing local drug delivery, combination therapies, or precision approaches that act on pathogenic fibroblast subtypes while maintaining tissue stability. This study also shows that single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics can reveal not only which cells are present at the site of injury, but also where they act and how they change after treatment. Further validation in larger animal models and preclinical systems will be required before application to human SCI treatment.
sauce:
Chinese Academy of Sciences
Reference magazines:
Fenn, M. Others. (2026). Targeting the c-Jun-Irf8-CD36 axis reduces fibrotic scar formation and promotes functional recovery after spinal cord injury. burns and trauma. DOI: 10.1093/burnst/tkag020. https://academic.oup.com/burnstrauma/advance-article/doi/10.1093/burnst/tkag020/8516470
