Journal Article

Single cell transcriptomic landscape of diabetic foot ulcers

Mezghani, Ikram, Wang, Peng, Hsia, Henry C., Pilcher, William J. R., Sandoval-Schaefer, Teresa, Bhasin, Manoj, Theocharidis, Georgios, Thomas, Beena E., Bhasin, Swati S., Dash, Biraja, Kafanas, Antonios, Horsley, Valerie, Mumme, Hope L., Veves, Aristidis, Lobao, Antonio, Vlachos, Ioannis S., Sarkar, Debasree, Dwivedi, Bhakti, Sîrbulescu, Ruxandra F.

2022

Overview

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. Diabetic foot ulcers (DFUs) remain a complication of diabetes that are difficult to heal and lead to disability. Here the authors use single-cell RNA-sequencing and spatial transcriptomics to characterize the DFU cellular landscape and identify a population of fibroblasts that is associated with successful wound closure.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/51 / 49/39 / 49/91 / 631/1647/48 / 631/208/212/2019 / 692/699/2743/137/138 / Biomarkers - metabolism / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - metabolism / Chitinase-3-Like Protein 1 - genetics / Chitinase-3-Like Protein 1 - metabolism / Diabetes / Diabetes mellitus / Diabetes Mellitus - genetics / Diabetes Mellitus - metabolism / Diabetes Mellitus - pathology / Diabetic Foot - genetics / Diabetic Foot - metabolism / Diabetic Foot - pathology / Endothelial Cells - metabolism / Endothelial Cells - pathology / Exome Sequencing / Feet / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Foot diseases / Forearm / Gene Expression Regulation / Gene sequencing / High-Throughput Nucleotide Sequencing / Humanities and Social Sciences / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - genetics / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Keratinocytes - metabolism / Keratinocytes - pathology / Leg ulcers / Leukocytes (mononuclear) / Leukocytes - metabolism / Leukocytes - pathology / Localization / Macrophages / Macrophages - metabolism / Macrophages - pathology / Matrix Metalloproteinase 1 - genetics / Matrix Metalloproteinase 1 - metabolism / Matrix Metalloproteinase 11 - genetics / Matrix Metalloproteinase 11 - metabolism / Matrix Metalloproteinase 3 - genetics / Matrix Metalloproteinase 3 - metabolism / Microenvironments / multidisciplinary / Pathogenesis / Patients / Peripheral blood mononuclear cells / Science / Science (multidisciplinary) / Single-Cell Analysis - methods / Skin - metabolism / Skin - pathology / Transcriptome / Transcriptomics / Ulcers / Wound healing / Wound Healing - genetics