Single cell transcriptomic landscape of diabetic foot ulcers

• Authors: Georgios Theocharidis, Harvard Medical School; Beena E Thomas, Emory University; Debasree Sarkar, Emory University; Hope L Mumme, Emory University; William JR Pilcher, Emory University; Bhakti Dwivedi, Emory University; Teresa Sandoval-Schaefer, Yale University; Ruxandra F Sîrbulescu, Harvard Medical School; Antonios Kafanas, Lincoln County Hospital; Ikram Mezghani, Harvard Medical School; Peng Wang, Harvard Medical School; Aantonio Lobao, Harvard Medical School; Ioannis S Vlachos, Harvard Medical School; Biraja Dash, Yale School of Medicine; Henry C Hsia, Yale School of Medicine; Valerie Horsley, Yale University; Swati Bhasin, Emory University; Aristidis Veves, Harvard Medical School; Manoj Bhasin, Emory University
• Journal Title: Nature Communications
• Volume: Volume 13, Number 1
• Publisher: Springer Nature | 2022-12-01, Pages 181-181
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41467-021-27801-8
• Subjects: Health Sciences, Oncology; Health Sciences, Pathology
• Keywords: Biomarkers; Cell Adhesion Molecules; Chitinase-3-Like Protein 1; Diabetes Mellitus; Diabetic Foot; Endothelial Cells; Fibroblasts; Gene Expression Regulation; High-Throughput Nucleotide Sequencing; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Keratinocytes; Leukocytes; Macrophages; Matrix Metalloproteinase 1; Matrix Metalloproteinase 11; Matrix Metalloproteinase 3; Single-Cell Analysis; Skin; Transcriptome; Whole Exome Sequencing; Wound Healing

Abstract

Diabetic 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.