ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1591944
Single-cell atlas of human skin implicates APOE pro-inflammatory signaling in diabetic foot ulcers
Provisionally accepted
- Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Background: Diabetic foot ulcers (DFU) are a major global complication of diabetes mellitus, yet their underlying mechanisms remain incompletely understood. Fibroblasts are key regulators in the finely tuned process of wound healing. Methods: Single-cell RNA sequencing was performed on human skin tissues to delineate cellular composition and transcriptional profiles.Results: We identified a distinct fibroblast population overexpressing Apolipoprotein E (APOE) in DFU patients with non-healing wounds. APOE+ fibroblasts were predominantly enriched in DFU patients, and exhibited strong associations with fat cell differentiation and the regulation of epithelial cell proliferation. Metabolic pathway analysis indicated that APOE+ fibroblasts might play a role in the onset and progression of diabetes through the Drug Metabolism-Cytochrome P450 pathway. Pseudotime analysis suggested that APOE+ fibroblasts are in an intermediate differentiation state. CellChat analysis highlighted the significant role of the FGF signaling pathway in DFU. Immunohistochemical staining confirmed upregulated APOE expression in DFU tissues. Ex vivo experiments demonstrated that soluble APOE accelerated fibrosis and inflammation in human fibroblasts, suggesting its detrimental role. Furthermore, high glucose elevated APOE expression and induced a profibrotic and inflammatory phenotype in human fibroblasts.Conclusions: This study provides critical insights into the differences between healthy and DFU fibroblasts, identifying specific cell populations that may influence DFU healing. These findings may contribute to future therapeutic development for DFU.
Keywords: Single-cell RNA sequencing, Diabetic foot ulcers, Apolipoprotein E, Human fibroblasts, Inflammatory disease APOE: Apolipoprotein E, DFU: Diabetic foot ulcers, JAK: Janus kinase, STAT3: signal transducer and activator of transcription 3, NF-κB: nuclear factor kappa-B, ECM: extracellular matrix, TLR4:Toll-like receptor 4, TNFα: tumor necrosis factor-alpha
Received: 14 Mar 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Yin, Li, Liu and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Bin Wang, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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