ArticleFrontiers in cellular and infection microbiology2026
Single-cell reanalysis identifies macrophage-associated transcriptional and intercellular communication features in diabetic foot ulcers.
Article in Frontiers in cellular and infection microbiology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Diabetic foot ulcers (DFUs) are devastating diabetic complications characterized by an extremely high non-healing rate and elevated risk of life-threatening outcomes. To characterize the cellular landscape and macrophage-associated alterations between DFU tissue and diabetic non-ulcer foot (DNFU) skin, we performed a comprehensive reanalysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets. Methods: A fully reproducible R-based analytical pipeline was used to process public scRNA-seq count matrices (GSE165816) from 5 DFU and 8 DNFU skin samples. A total of 27,844 cells (16,579 from DFU and 11,265 from DNFU skin) passed stringent quality control filters. Data normalization, integration, dimensionality reduction, unsupervised clustering, and marker-based cell type annotation were performed using the Seurat and Harmony packages. Sample-level comparisons included cell fraction analysis and UCell pathway scoring. Macrophages were further investigated through subclustering analysis, edgeR-based pseudobulk differential expression analysis, volcano plot visualization, GO over-representation analysis, enrichment analysis, and CellChat ligand-receptor interaction inference. Results: The integrated single-cell atlas resolved 10 major cell compartments including epithelial, stromal, endothelial, lymphatic endothelial, smooth muscle/pericyte, lymphoid, myeloid, mast cell, plasma cell, and melanocyte/Schwann cells. Sample-level cell fraction analysis revealed a nominal reduction in lymphatic endothelial cells in DFU; however, no cell type proportion differences remained statistically significant after false discovery rate (FDR) correction. Similarly, no significant differences were observed in macrophage UCell pathway scores for glycolysis, lactate metabolism, combined glycolysis-lactate metabolism, TNF-NF-κB signaling, or insulin/IGF signaling between DFU and DNFU skin following FDR correction. Macrophage subclustering identified DFU-enriched subpopulations, and macrophage pseudobulk analysis prioritized multiple DFU-associated genes. Notably, sex-linked genes including XIST, RPS4Y1, and DDX3Y reached statistical significance after FDR correction, indicating that a portion of the observed transcriptional signal may be attributed to demographic imbalance between groups. Exploratory enrichment analysis of nominal and ranked macrophage differentially expressed genes highlighted DFU-directional enrichment of translation, oxidative phosphorylation, electron transport, and antigen presentation terms, while DNFU-directional genes were enriched for transcriptional regulation and rhythmic process terms. CellChat analysis prioritized macrophage-associated CD99-CD99 and MIF-CD74/CXCR4 ligand-receptor pairs as key DFU-associated intercellular communication hypotheses. Conclusion: This single-cell reanalysis comparing DFU and DNFU skin identifies putative ligand-receptor interaction hypotheses, transcriptomic alterations, and macrophage subpopulation shifts that require definitive validation in larger, clinically well-characterized, and spatially resolved patient cohorts.
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