Single cell transcriptomic landscape of diabetic foot ulcers

• DOI: 10.1038/s41467-021-27801-8
• Publication Date: 2022-01-10T11:02:59Z
• Authors: Georgios Theochar...; Beena E. Thomas; Debasree Sarkar; Hope L. Mumme; William J. R. Pil...; Bhakti Dwivedi; Teresa Sandoval-S...; Ruxandra F. Sîrbu...; Antonios Kafanas; Ikram Mezghani; Peng Wang; Antonio Lobao; Ioannis S. Vlachos; Biraja Dash; Henry C. Hsia; Valerie Horsley; Swati S. Bhasin; Aristidis Veves; Manoj Bhasin
• Keywords: Keratinocytes; Science; Article; 03 medical and health sciences; Matrix Metalloproteinase 11; Diabetes Mellitus; Leukocytes; Humans; Chitinase-3-Like Protein 1; Skin; 0303 health sciences; Macrophages; Q; Endothelial Cells; High-Throughput Nucleotide Sequencing; Fibroblasts; Hypoxia-Inducible Factor 1, alpha Subunit; Diabetic Foot; 3. Good health; Gene Expression Regulation; Matrix Metalloproteinase 3; Matrix Metalloproteinase 1; Single-Cell Analysis; Transcriptome; Cell Adhesion Molecules; Biomarkers

AbstractDiabetic foot ulceration (DFU) is a devastating complication of diabetes whose pathogenesis remains incompletely understood. Here, we profile 174,962 single cells from the foot, forearm, and peripheral blood mononuclear cells using single-cell RNA sequencing. Our analysis shows enrichment of a unique population of fibroblasts overexpressing MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 and increased M1 macrophage polarization in the DFU patients with healing wounds. Further, analysis of spatially separated samples from the same patient and spatial transcriptomics reveal preferential localization of these healing associated fibroblasts toward the wound bed as compared to the wound edge or unwounded skin. Spatial transcriptomics also validates our findings of higher abundance of M1 macrophages in healers and M2 macrophages in non-healers. Our analysis provides deep insights into the wound healing microenvironment, identifying cell types that could be critical in promoting DFU healing, and may inform novel therapeutic approaches for DFU treatment.