Using single-cell transcriptomics, researchers have mapped the cellular landscape in the diabetic foot ulcers of healers and non-healers.
Diabetic foot ulceration
Diabetic foot ulceration (DFU) is a major issue in diabetic patients. Estimates indicate that more than 15% of patients develop DFUs within their lifetime. It is characterised by an open wound or sore on the skin that is very slow to heal. DFUs impair quality of life, result in prolonged hospitalisations and can lead to amputation. Notably, over half of patients undergoing amputation die within 5 years. Diabetes Mellitus (DM) is expected to increase worldwide. As a result, the burden for health systems and costs on society will represent an even bigger burden.
Several cell types are involved in the wound healing process, including endothelial cells, fibroblasts, keratinocytes and immune cells. The role of these cells in impaired wound healing in DFU is less understood. Dissecting the roles of these cells in DFU patients whose ulcers heal versus those who develop chronic ulcers is important to understand DFU pathogenesis.
Cellular landscape using single cell analysis
In a recent study, published in Nature Communications, researchers used single-cell RNA-sequencing analysis to map the cellular landscape in the diabetic foot ulcers of healers and non-healers within 12 weeks. They specifically investigated the molecular changes of DFUs and forearm skin biopsies as well as peripheral blood mononuclear cells (PBMCs). They also performed these analyses on DM patients with no DFU and healthy non-DM patients for controls.
The team’s analysis showed an enrichment of a unique population of fibroblasts that overexpressed MMP1, MMP3, MMP11, HIF1A, CHI3L1, and TNFAIP6 in DFU patients with healing wounds. These patients also had increased M1 macrophages. Spatial transcriptomics also validated these findings by revealing a higher abundance of M1 macrophages in healers and M2 macrophages in non-healers.
The researchers also studied different sites of a chronic wound (wound site, wound periphery and healthy skin) using spatial transcriptomics. Here, they found preferential localisation of these healing associated fibroblasts in the wound bed compared to the wound periphery and healthy skin.
Altogether, this analysis provides important insights into the wound healing microenvironment. The study has identified cell types that are critical in promoting DFU healing, which may be important for novel therapeutic strategies.
Co-corresponding author, Aristidis Veves, said:
“We have now substantially expanded the number of cells sequenced and gained novel insights into diabetic foot ulcers. Our data suggests that specific fibroblast subtypes are key players in healing these ulcers and targeting these cells could be one therapeutic option. While further testing is needed, our dataset will be a valuable resource for diabetes, dermatology and wound healing research and can serve as the baseline for designing experiments for the assessment of therapeutic interventions.”
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