Human Single Cell Transcriptional Profiling Identifies Epigenetically Altered PGE2 Pathway that Modulates Diabetic Macrophage Phenotype and Wound Repair
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE154557 | GEO | 2020/10/07
REPOSITORIES: GEO
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Project description:RNA-sequencing techniques to profile the transcriptomes of lesional skin of diabetic patients
2020-10-07 | GSE154556 | GEO
Project description:Human Single Cell Transcriptional Profiling Identifies Epigenetically Altered PGE2 Pathway that Modulates Diabetic Macrophage Phenotype and Wound Repair
| PRJNA646693 | ENA
Project description:Macrophages are a primary immune cell involved in inflammation, and their cell plasticity allows for transition from an inflammatory to a reparative phenotype and is critical for normal tissue repair following injury. Evidence suggests that epigenetic alterations play a critical role in establishing macrophage phenotype and function during normal and pathologic wound repair. Here, we find in human and murine wound macrophages that cyclooxygenase 2/prostaglandin E2 (COX-2/PGE2) is elevated in diabetes and regulates downstream macrophage-mediated inflammation and host defense. Using single-cell RNA sequencing of human wound tissue, we identify increased NF-κB-mediated inflammation in diabetic wounds and show increased COX-2/PGE2 in diabetic macrophages. Further, we identify that COX-2/PGE2 production in wound macrophages requires epigenetic regulation of 2 key enzymes in the cytosolic phospholipase A2/COX-2/PGE2 (cPLA2/COX-2/PGE2) pathway. We demonstrate that TGF-β-induced miRNA29b increases COX-2/PGE2 production via inhibition of DNA methyltransferase 3b-mediated hypermethylation of the Cox-2 promoter. Further, we find mixed-lineage leukemia 1 (MLL1) upregulates cPLA2 expression and drives COX-2/PGE2. Inhibition of the COX-2/PGE2 pathway genetically (Cox2fl/fl Lyz2Cre+) or with a macrophage-specific nanotherapy targeting COX-2 in tissue macrophages reverses the inflammatory macrophage phenotype and improves diabetic tissue repair. Our results indicate the epigenetically regulated PGE2 pathway controls wound macrophage function, and cell-targeted manipulation of this pathway is feasible to improve diabetic wound repair.
| S-EPMC7526451 | biostudies-literature
Project description:Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus, which causes great health damage and economic burden to patients. The pathogenesis of DFU is not fully understood.We screened wound healing-related genes using bioinformatics analysis, and full-thickness skin injury mice model and cellular assays were used to explore the role of target genes in diabetic wound healing. SFRP2 was identified as a wound healing-related gene, and the expression of SFRP2 is associated with immune cell infiltration in DFU. In vivo study showed that suppression of SFRP2 delayed the wound healing process of diabetic mice, impeded angiogenesis and matrix remodeling, and increased macrophage infiltration in wound tissues. In addition, suppression of SFRP2 enhanced M1 polarization in both the early and later stage of wound healing, and decreased M2 polarization in the later stage, which impeded the transition of M1 to M2 polarization of wound healing. Moreover, suppression of SFRP2 affected the transcriptome signatures-related to inflammatory response and energy metabolism at the early stage of wound healing. Extracellular flux analysis (EFA) showed that suppression of SFRP2 decreased mitochondrial energy metabolism and increased glycolysis in injury-related macrophages. Furthermore, suppression of SFRP2 inhibited transcriptome signaturesrelated to carbohydrate metabolism, lipid metabolism and amino acid metabolism, which consists the three main components of energy metabolism of macrophages. In conclusions, SFRP2 may function as a wound healing-related gene in DFU, and suppression of SFRP2 impaired diabetic wound healing by compromising the M1-to-M2 transition of macrophages and modulating the balance between mitochondrial energy metabolism and glycolysis.
2024-10-04 | GSE268760 | GEO
Project description:Macrophage plasticity is critical for normal tissue repair to ensure transition from the inflammatory to the proliferative phase of healing. We examined macrophages isolated from wounds of patients afflicted with diabetes and of healthy controls and found differential expression of the methyltransferase Setdb2. Myeloid-specific deletion of Setdb2 impaired the transition of macrophages from an inflammatory phenotype to a reparative one in normal wound healing. Mechanistically, Setdb2 trimethylated histone 3 at NF-κB binding sites on inflammatory cytokine gene promoters to suppress transcription. Setdb2 expression in wound macrophages was regulated by interferon (IFN) β, and under diabetic conditions, this IFNβ-Setdb2 axis was impaired, leading to a persistent inflammatory macrophage phenotype in diabetic wounds. Setdb2 regulated the expression of xanthine oxidase and thereby the uric acid (UA) pathway of purine catabolism in macrophages, and pharmacologic targeting of Setdb2 or the UA pathway improved healing. Thus, Setdb2 regulates macrophage plasticity during normal and pathologic wound repair and is a target for therapeutic manipulation.
| S-EPMC6703945 | biostudies-literature
Project description:Diabetic foot ulcer (DFU) is a serious complication of diabetes mellitus, which causes great health damage and economic burden to patients. The pathogenesis of DFU is not fully understood.We screened wound healing-related genes using bioinformatics analysis, and full-thickness skin injury mice model and cellular assays were used to explore the role of target genes in diabetic wound healing. SFRP2 was identified as a wound healing-related gene, and the expression of SFRP2 is associated with immune cell infiltration in DFU. In vivo study showed that suppression of SFRP2 delayed the wound healing process of diabetic mice, impeded angiogenesis and matrix remodeling, and increased macrophage infiltration in wound tissues. In addition, suppression of SFRP2 enhanced M1 polarization in both the early and later stage of wound healing, and decreased M2 polarization in the later stage, which impeded the transition of M1 to M2 polarization of wound healing. Moreover, suppression of SFRP2 affected the transcriptome signatures-related to inflammatory response and energy metabolism at the early stage of wound healing. Extracellular flux analysis (EFA) showed that suppression of SFRP2 decreased mitochondrial energy metabolism and increased glycolysis in injury-related macrophages. Furthermore, suppression of SFRP2 inhibited transcriptome signaturesrelated to carbohydrate metabolism, lipid metabolism and amino acid metabolism, which consists the three main components of energy metabolism of macrophages. In conclusions, SFRP2 may function as a wound healing-related gene in DFU, and suppression of SFRP2 impaired diabetic wound healing by compromising the M1-to-M2 transition of macrophages and modulating the balance between mitochondrial energy metabolism and glycolysis.
2024-10-04 | GSE268759 | GEO
Project description:Keloids are benign dermal tumors that form during wound healing in genetically susceptible individuals. The mechanism(s) of keloid formation is unknown and there is no satisfactory treatment. We have reported differences between fibroblasts cultured from normal scars and keloids that include a pattern of glucocorticoid resistance and altered regulation of genes in several signaling pathways associated with fibrosis, including Wnt and IGF/IGF-binding protein 5 (IGFBP5). As previously reported for glucocorticoid resistance, decreased expression of the Wnt inhibitor secreted frizzled-related protein 1 (SFRP1), matrix metalloproteinase 3 (MMP3), and dermatopontin (DPT), and increased expression of IGFBP5 and jagged 1 (JAG1) are seen only in fibroblasts cultured from the keloid nodule. In vivo, decreased expression of SFRP1 and SFRP2 and increased expression of IGFBP5 proteins are observed only in proliferative keloid tissue. There is no consistent difference in the replicative life span of normal and keloid fibroblasts, and the altered response to hydrocortisone (HC) and differential regulation of a subset of genes in standard culture medium are maintained throughout at least 80% of the culture lifetime. Preliminary studies using ChIP-chip analysis, Trichostatin A, and 5-aza-2'-deoxycytidine further support an epigenetically altered program in keloid fibroblasts that includes an altered pattern of DNA methylation and histone acetylation.
| S-EPMC2939920 | biostudies-literature
Project description:Macrophages are critical for the initiation and resolution of the inflammatory phase of wound healing. In diabetes, macrophages display a prolonged inflammatory phenotype preventing tissue repair. TLRs, particularly TLR4, have been shown to regulate myeloid-mediated inflammation in wounds. We examined macrophages isolated from wounds of patients afflicted with diabetes and healthy controls as well as a murine diabetic model demonstrating dynamic expression of TLR4 results in altered metabolic pathways in diabetic macrophages. Further, using a myeloid-specific mixed-lineage leukemia 1 (MLL1) knockout (Mll1f/fLyz2Cre+ ), we determined that MLL1 drives Tlr4 expression in diabetic macrophages by regulating levels of histone H3 lysine 4 trimethylation on the Tlr4 promoter. Mechanistically, MLL1-mediated epigenetic alterations influence diabetic macrophage responsiveness to TLR4 stimulation and inhibit tissue repair. Pharmacological inhibition of the TLR4 pathway using a small molecule inhibitor (TAK-242) as well as genetic depletion of either Tlr4 (Tlr4-/- ) or myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) resulted in improved diabetic wound healing. These results define an important role for MLL1-mediated epigenetic regulation of TLR4 in pathologic diabetic wound repair and suggest a target for therapeutic manipulation.
| S-EPMC7443363 | biostudies-literature
Project description:SFRP2 modulates functional phenotype transition and energy metabolism of macrophages during diabetic wound healing [Skin wound]
| PRJNA1118699 | ENA
Project description:Epigenetic modification of the COX-2/PGE2 pathway modulates macrophage phenotype and cell-targeted manipulation improves diabetic tissue repair
| PRJNA646694 | ENA