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Diabetic foot ulcers debridement SCRNA-seq showed healing association with inflammatory fibroblasts in minorities

ABSTRACT: In this pilot study, we optimized diabetic foot ulcers (DFUs) single-cell profiling from debrided DFUs of underrepresented African American (AA) patients. The healing-DFUs were significantly enriched (P=0.03) with unique heterogenous Healing-associated Fibroblasts (HE-Fibro), expressing inflammation (CHI3L1), ECM-remodeling (MMP13, ASPN) and wound healing (NRG1, COL7A1) associated genes, validating our previous findings with surgically resected healer-DFUs. HE-Fibro/Fibro cells depicted significantly lower expression of key healing-associated CHIL3L1, and TIMP1 genes in AAs compared to Whites, signifying race-associated heterogeneity. Reparative M2 macrophages were enriched in Healing-DFUs (P=0.05), while inflammatory M1 macrophages displayed distinct transcriptome differences in Nonhealing-DFUs and Healing-DFUs. Cellular communication analysis revealed a pivotal role for HE-Fibro/Fibroblasts (signal-senders) and M1 (signal-receivers). HE-Fibro’s signaling significantly upregulated wound-resolving WNT, and ECM-remodeling CXCL pathways in Healing-DFUs, while M1 signaling upregulated healing-disruptive, and inflammation-associated, SPP1 pathways, in Nonhealing-DFUs. This study justifies using debrided tissues for single-cell assays and highlights the need for in-depth investigations into dysregulated wound healing microenvironments in AAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE231643 | GEO | 2025/07/10

REPOSITORIES: GEO

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Project description:While considerable progress has been made towards understanding the complex processes and pathways that regulate human wound healing, regenerative medicine has been unable to develop therapies that coax the natural wound environment to heal scar-free. The inability to induce perfect skin regeneration stems partly from our limited understanding of how scar-free healing occurs in a natural setting. Here we have investigated the wound repair process in adult axolotls and demonstrate that they are capable of perfectly repairing full thickness excisional wounds made on the flank. In the context of mammalian wound repair, our findings reveal a substantial reduction in hemostasis, reduced neutrophil infiltration and a relatively long delay in production of new extracellular matrix (ECM) during scar-free healing. Additionally, we test the hypothesis that metamorphosis leads to scarring and instead show that terrestrial axolotls also heal scar-free, albeit at a slower rate. Analysis of newly forming dermal ECM suggests that low levels of fibronectin and high levels of tenascin-C promote regeneration in lieu of scarring. Lastly, a genetic analysis during wound healing comparing epidermis between aquatic and terrestrial axolotls suggests that matrix metalloproteinases may regulate the fibrotic response. Our findings outline a blueprint to understand the cellular and molecular mechanisms coordinating scar-free healing that will be useful towards elucidating new regenerative therapies targeting fibrosis and wound repair. We used microarray analysis to determine the gene expression changes that take place during scar free wound healing in aquatic and terrestrial axolotl salamanders. Epidermal tissue was harvested using a 4mm biopsy punch. Two wounds were made along the flank and posterior to the forelimbs. Harvested epidermis was pooled for each animal. Four biological replicates were collected from uninjured epidermis (D0) and at 1, 3, and 7 days post injury.

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Diabetic foot ulcers debridement SCRNA-seq showed healing association with inflammatory fibroblasts in minorities

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