Single cell transcriptomic landscape of diabetic foot ulcers

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.

MiR-21 regulating PVT1/PTEN/IL-17 axis towards the treatment of infectious diabetic wound healing by modified GO-derived biomaterial in mouse models

“…The formation of a diabetic foot ulcer (DFU) is a leading cause of morbidity and death in patients with poorly managed diabetes [ 1 – 4 ], with an estimated 25% of diabetes patients suffering from chronic infectious wounds that fail to properly heal and are associated with a risk of amputation, and the 5-year survival rate with such non-resolving wounds is estimated to be only 32% [ 5 ]. By preventing infection, eliminating injured tissue, and secreting cytokines that stimulate fibroblast migration, angiogenesis, collagen deposition, and wound closure, wound healing could be restored and facilitated [ 6 , 7 ].…”

Single‐cell transcriptomics in human skin research: available technologies, technical considerations and disease applications

“…69 A substantial increase of the sample size in a subsequent report allowed the comprehensive mapping of the diabetic wound healing ecosystem and comparison between patients who healed and those who did not heal their ulcers. 70 A subtype of fibroblasts that was uniquely present in the wounds of healers was identified and corroborated with spatial transcriptomics and immunostaining. These cells were enriched for extracellular matrix and inflammation-associated genes, including CHI3L1, MMP1, MMP3 and IL-6.…”

“…In addition, healing ulcers also contained elevated numbers of classically activated or M1 Mφs, highlighting the importance of mounting an acute inflammatory response to successfully heal and suggesting potential interplay between healing fibroblasts and Mφs. 70 Moreover, Li et al…”

Single cell Transcriptome and T cell Repertoire Mapping of the Mechanistic Signatures and T cell Trajectories Contributing to Vascular and Dermal Manifestations of Behcet’s Disease

“…To further evaluate this hypothesis, we then performed enrichment comparisons against macrophages and B cells derived from healthy controls in a publicly available dataset 35 . Consistent with our expectations, circulating macrophages from BD patients had increased enrichment for pathways associated with interferon signaling, TLR signaling, as well as chemotaxis (Fig3E).…”