Single cell transcriptomic landscape of diabetic foot ulcers

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 uniqu...

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Published in:	Nature communications Vol. 13; no. 1; p. 181
Main Authors:	Theocharidis, Georgios, Thomas, Beena E., Sarkar, Debasree, Mumme, Hope L., Pilcher, William J. R., Dwivedi, Bhakti, Sandoval-Schaefer, Teresa, Sîrbulescu, Ruxandra F., Kafanas, Antonios, Mezghani, Ikram, Wang, Peng, Lobao, Antonio, Vlachos, Ioannis S., Dash, Biraja, Hsia, Henry C., Horsley, Valerie, Bhasin, Swati S., Veves, Aristidis, Bhasin, Manoj
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 10-01-2022 Nature Publishing Group Nature Portfolio
Subjects:	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
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-021-27801-8