Potential Role of CD99 Signaling Pathway in Schwann Cell Dysfunction in Diabetic Foot Ulcers Based on Single‐Cell Transcriptome Analysis

<b>Background:</b> Schwann cell (SC) dysfunction contributes to the delayed healing of diabetic foot ulcers (DFUs). However, the underlying molecular mechanism regarding the unregulated SC function is poorly understood. Thus, we examined the single-cell transcriptome data from different DFU states focusing on SC characteristics. <b>Methods:</b> The single-cell RNA sequencing (scRNA-seq) data of DFU was obtained from the Gene Expression Omnibus (GEO) database, covering foot skin samples from nondiabetic patients, diabetic patients without DFU, DFU healers, and DFU nonhealers. After scRNA-seq data processing, downscaling, and cell cluster identification, cell communication analysis was performed by the CellChat package. Furthermore, we subclustered SC populations and ran the trajectory inference and pseudotime analysis to investigate the dynamic changes in SC. Finally, the significant pathways were validated with a <i>db/db</i> mouse wound model. <b>Results:</b> scRNA-seq analysis revealed different SC percentages and gene markers across the DFU groups. We identified that the CD99 signaling pathway was upregulated in the DFU nonhealer group. In the <i>db/db</i> mouse wound model, we observed that CD99 was highly expressed in the demyelinated area of the peripheral nerve fibers. <b>Conclusion:</b> Our study elucidated that the CD99 pathway activation may play a crucial role in SC dysfunction of DFU, providing insights into the peripheral glia regulation mechanism and potential therapeutic target of DFU.