Spatial transcriptomics of healing and non-healing diabetic foot ulcers
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166120 | GEO | 2021/10/28
REPOSITORIES: GEO
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Project description:Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. In order to identify systemic and local factors associated with DFU healing, we examined the cellular landscape of DFUs by single-cell RNA-seq analysis of foot and forearm skin specimens, as well as PBMC samples, from 10 non-diabetic subjects, and 17 diabetic patients, 11 with, and 6 without DFU. Our analysis shows enrichment of a unique inflammatory fibroblast population in DFU patients with healing wounds. The patients with healing DFUs also depicted enrichment of macrophages with M1 polarization, as opposed to more M2 macrophages in non-healing wounds. These findings were verified using Immunohistochemistry and Spatial Transcriptomics.
2021-11-01 | GSE165816 | GEO
Project description:Diabetic foot ulcers (DFUs) and associated impaired healing, represent a major problem, that significantly impairs the quality of life of diabetic patients, leading to prolonged hospitalization and resulting in more than 70,000 lower extremity amputations per year in the USA alone. In the present study, we prospectively followed a large group of DFU patients for 12 weeks and aimed to identify systemic and local factors that are associated with DFU healing. We also studied healthy control subjects and diabetic patients without DFU and compared differences with the DFU patients. We first employed serum multiplex arrays to detect systemic cytokines, chemokines and growth factors, which correlate with DFU healing. In addition, we collected forearm biopsies for histology and bulk transcriptome analyses to establish whether DFU healing outcome was reflected at a non-ulcerative skin site. Bulk RNA-seq analysis revealed extracellular matrix (ECM) related genes up-regulated in Healers, including MMP2 as well as implication of IFNγ and IL13 as upstream regulators. According to transcriptome data analysis with a false discovery rate (FDR) <0.05 and log2 fold-change (log2FC) > 0.5, a total of 25 genes (3 up-regulated) were differentially expressed when comparing Non-Healers and Healers, 916 (530 up-regulated) in Healers compared to DM and 160 (89 up-regulated) in Non-Healers compared to DM. Genes of interest that were increased in Healers include inflammation associated molecules lymphoid chemokine ligand 19 (CCL19), complement component 6 (C6), lipoprotein lipase (LPL) and beta-defensin 124 (DEFB124), as well as extracellular matrix linked proteins pigment-epithelium derived factor (SERPINF1), tenascin X (TNXB), biglycan (BGN) and matrix metalloproteinase-2 (MMP2). For Non-Healers, up-regulated genes were cytochrome P450 family member (CYP1A1), prostaglandin transporter (SLCO2A1) and metabolism regulator G0/G1 switch gene 2 (G0S2).
2020-08-01 | GSE143735 | GEO
Project description:Diabetic foot ulcers (DFUs) are the leading cause of lower leg amputations in diabetic population. To better understand molecular pathophysiology of DFUs we used patients’ specimens and genomic profiling. We identified 3900 genes specifically regulated in DFUs. Moreover, we compared DFU to human skin acute wound (AW) profiles and found DNA repair mechanisms and regulation of gene expression among the processes specifically suppressed in DFUs, whereas essential wound healing-related processes, inflammatory/immune response or cell migration, were not activated properly. To identify potential regulators of DFU-specific genes, we used upstream target analysis. We found miR-15/16 family enriched in DFUs, but not in AW, which was confirmed by qPCR. We found that infection with the most common DFU colonizer, Staphylococcus aureus, triggers induction of miR-15-5p, which in turn, targets multiple DFU-specific genes, including genes involved in DNA repair (WEE1, MSH2 and RAD50) and the regulator of inflammatory pathway, IKBKB. Induction of miR-15b-5p, either by miR-mimic transfection in vitro or by S. aureus infection of acute wounds ex vivo, suppressed both WEE1 and IKBKB. Consequently, we detected an increase in DNA double strand breaks in DFUs. In summary, our data indicate that S. aureus infection, via induction of miR-15b-5p, may lead to suppression of DNA repair mechanisms and a sub-optimal inflammatory response, contributing to pathophysiology of DFU patients
2017-12-28 | GSE80178 | GEO
Project description:Infection in diabetic foot ulcers (DFU) are one of the major complications associated with diabetic patients. Staphylococcus aureus is the most common offending pathogen in patients with infected DFU. Previous studies have suggested application of species-specific antibodies against S. aureus for diagnosis and monitoring treatment response. Early and accurate identification of the main pathogen is critical for management of DFU infection. Understanding the host immune response against species-specific infection may facilitate diagnosis and suggest potential intervention options to promote healing infected DFUs. We sought to investigate evolving host transcriptome associated with surgical treatment of S. aureus infected DFU. This study compared the transcriptome profile of twenty-one patients with S. aureus infected DFU who underwent initial foot salvage therapy with irrigation and debridement followed by intravenous antibiotics therapy. Blood samples were collected at the recruitment (0-weeks) and 8-week after therapy to isolate peripheral blood mononuclear cells (PBMC). We analyzed the PBMCs expression of transcriptomes at two different time points (0 vs 8-week). Subjects were further divided into two groups at 8-week: healed (n=17, 80.95%) versus non-healed (n=4,19.05%) based on the wound healing status. DESeq2 differential gene analysis was performed. An increased expression of IGHG1, IGHG2, IGHG3 and IGLV3-21, IGLV6-57 were noted during active infection at 0-week compared to 8-week. Lysine and arginine-rich histones (HIST1H2AJ, HIST1H2AL, HIST1H2BM, HIST1H3B and HIST1H3G) were upregulated at the initial phase of active infection at 0-week. CD177 and RRM2 were also upregulated at the initial phase of active infection (0-week) compared to 8-week follow-up. Genes of heat shock protein members (HSPA1A, HSPE1, and HSP90B1) were high in not-healed compared to healed patients 8-week after therapy. The outcome of our study suggests that identification of genes evolution based on a transcriptomic profiling could be a useful tool for diagnosing infection, assessing severity and assess host-immune response to therapies.
2023-06-22 | GSE230426 | GEO
Project description:Circular RNA (circRNA) microarray analysis was performed to examine the expression profiles of circRNAs in diabetic foot ulcers (DFU) and in human excisional skin wounds 7 days after injury.
2019-10-01 | GSE114248 | GEO
Project description:Diabetic foot ulcers (DFUs) are one of the major complications of diabetes. Its molecular pathology remains poorly understood, impeding the development of effective treatments. Although it has been established that multiple cell types, including fibroblasts, keratinocytes, macrophages and endothelial cells, all contribute to inhibition of healing, less is known regarding individual contributions of each cell type. Thus, we generated primary fibroblasts from non-healing DFUs and evaluated their cellular and molecular properties in comparison to non-diabetic foot fibroblasts (NFFs). Specifically, we analyzed both micro-RNA and mRNA expression profiles of primary DFU fibroblasts. These paired genomic analyses identified a total of 331 reciprocal miRNA-mRNA pairs (21 miRNAs (FC>2.0) along with 239 predicted target genes (FC>1.5) that are significantly and differentially expressed. Of these, we focused on three miRNAs (miR-21-5p, miR-34a-5p, miR-145-5p) found to be induced in DFU fibroblasts as most differentially regulated. Their involvement in cellular functions important for wound healing was investigated by testing the expression of their downstream targets as well as by quantifying cellular behaviors in a prospectively collected and generated cell lines from 15 patients (7 DFUF and 8 NFF samples). We found large number of downstream targets of miR-21-5p, miR-34a-5p, miR-145-5p to be coordinately regulated in mRNA profiles, which was confirmed by qPCR. Genomic analysis of miR-21-5p, miR-34a-5p, miR-145-5p and their target genes indicates that these are contributing to the inhibition of cell movement and cell proliferation, together with increased cell differentiation and senescence in DFU fibroblasts, which was confirmed by cellular assays. We conclude that induction of miR-21-5p, miR-34a-5p, miR-145-5p in DFU dermal fibroblasts plays an important role in impairing multiple cellular functions, thus contributing to overall inhibition of healing in DFUs.
2016-10-01 | GSE84971 | GEO
Project description:Objective: This study aims to investigate the diversity of fibroblasts present in diabetic ulcers and their impact on the wound healing process, as well as to evaluate the effectiveness of Platelet-Rich Plasma (PRP) therapy in the management of diabetic ulcers. Methodology: The single-cell dataset GSE165816 from the GEO database was utilized to analyze DFU-healer and DFU-nonhealer samples in order to evaluate variations in fibroblasts. Functional characteristics of fibroblasts were investigated through analyses of cell communication, transcription factors, and pseudotime analysis. Additionally, a diabetic ulcer rat model was established to compare the therapeutic effects of PRP, followed by histological and transcriptomic sequencing analyses. Result: Single-cell sequencing analysis identified a greater abundance of fibroblasts in the group of diabetic foot ulcer (DFU) patients who exhibited healing. The findings from biological informatics analysis emphasized the critical role of fibroblasts in the wound healing process. Treatment with PRP notably enhanced wound healing in diabetic ulcers in rats, and transcriptomic analysis indicated that gene expression levels post-PRP treatment resembled those of the non-diabetic ulcer group, with a strong association to fibroblasts. Conclusion: Fibroblasts are essential in the process of healing diabetic ulcers, as certain transcription factors have the potential to facilitate wound closure. PRP therapy has been shown to enhance the healing process in diabetic ulcer rat models, possibly through the modulation of gene expression and the promotion of extracellular matrix arrangement. This research offers novel insights and potential therapeutic approaches for managing diabetic ulcers.
2024-11-11 | GSE280992 | GEO
Project description:We show that a combinatorial upregulation of SOX2 and hyperglycemia in cutaneous keratinocytes triggers a pro-healing signature and increased neutrophil chemoattraction, putatively by Ccr2, Ccr5, and Csf3r signaling. Neutrophil depletion and deregulation through the TREM1/FOXM1 pathway are directly implicated in diabetic foot ulcer (DFU) pathophysiology. Our results highlight the role of neutrophil recruitment in wound healing and can be used to explore potential therapeutic targets for DFUs in patients.
2024-07-22 | GSE266638 | GEO
Project description:To investigate the expression of miRNAs in C57 diabetic ulcer mice by Small RNA sequencing
2024-08-31 | GSE275847 | GEO
Project description:Spatial transcriptomics of healing and non-healing diabetic foot ulcers
| PRJNA699294 | ENA