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Prospective, Randomized, and Controlled Study of a Human Umbilical Cord Mesenchymal Stem Cell Injection for Treating Diabetic Foot Ulcers
Published on: March 3, 2023
MicroRNA-122-5p is upregulated in diabetic foot ulcers and decelerates the transition from the inflammatory to the
Mei-Jie Yuan1, He-Chen Huang1, Hong-Shuo Shi1
1Department of Peripheral Vascular Surgery, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Background:
Shifting from the inflammatory to the proliferative phase represents a pivotal step during managing diabetic foot ulcers (DFUs); however, existing medical interventions remain insufficient. MicroRNAs (miRs) highlight notable capacity for accelerating the repair process of DFUs. Previous research has demonstrated which miR-122-5p regulates matrix metalloproteinases under diabetic conditions, thereby influencing extracellular matrix dynamics.
Aim:
To investigate the impact of miR-122-5p on the transition from the inflammatory to the proliferative stage in DFU.
Methods:
Analysis for miR-122-5p expression in skin tissues from diabetic ulcer patients and mice was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A diabetic wound healing model induced by streptozotocin was used, with mice receiving intradermal injections of adeno-associated virus -DJ encoding empty vector or miR-122. Skin tissues were retrieved at 3, 7, and 14 days after injury for gene expression analysis, histology, immunohistochemistry, and network studies. The study explored miR-122-5p's role in macrophage-fibroblast interactions and its effect on transitioning from inflammation to proliferation in DFU healing.
Results:
High-throughput sequencing revealed miR-122-5p as crucial for DFU healing. qRT-PCR showed significant upregulation of miR-122-5p within diabetic skin among DFU individuals and mice. Western blot, along with immunohistochemical and enzyme-linked immunosorbent assay, demonstrating the upregulation of inflammatory mediators (hypoxia inducible factor-1α, matrix metalloproteinase 9, tumor necrosis factor-α) and reduced fibrosis markers (fibronectin 1, α-smooth muscle actin) by targeting vascular endothelial growth factor. Fluorescence in situ hybridization indicated its expression localized to epidermal keratinocytes and fibroblasts in diabetic mice. Immunofluorescence revealed enhanced increased presence of M1 macrophages and reduced M2 polarization, highlighting its role in inflammation. MiR-122-5p elevated inflammatory cytokine levels while suppressing fibrotic activity from fibroblasts exposed to macrophage-derived media, highlighting its pivotal role in regulating DFU healing.
Conclusion:
MiR-122-5p impedes cutaneous healing of diabetic mice via enhancing inflammation and inhibiting fibrosis, offering insights into miR roles in human skin wound repair.
Insights
MicroRNA-122-5p (miR-122-5p) exacerbates diabetic foot ulcer (DFU) healing by increasing inflammation and reducing fibrosis. This finding provides crucial insights into the role of microRNAs in DFU pathogenesis and potential therapeutic targets.
Area of Science:
- Biomedical Science
- Molecular Biology
- Wound Healing Research
Background:
- Diabetic foot ulcers (DFUs) present a significant clinical challenge due to insufficient healing.
- MicroRNAs (miRs) show promise in accelerating DFU repair.
- miR-122-5p is known to regulate matrix metalloproteinases, impacting extracellular matrix dynamics in diabetes.
Purpose of the Study:
- To investigate the specific impact of miR-122-5p on the transition from the inflammatory to the proliferative phase in DFU healing.
- To elucidate the mechanisms by which miR-122-5p influences macrophage-fibroblast interactions during DFU repair.
Main Methods:
- Quantitative real-time polymerase chain reaction (qRT-PCR) to analyze miR-122-5p expression in DFU tissues.
- A diabetic wound healing mouse model induced by streptozotocin, with interventions using adeno-associated virus vectors.
- Histology, immunohistochemistry, and network studies to assess gene expression, cellular infiltration, and molecular pathways.
Main Results:
- miR-122-5p was significantly upregulated in diabetic skin tissues from DFU patients and mice.
- miR-122-5p promoted the expression of inflammatory mediators (e.g., HIF-1α, MMP-9, TNF-α) and reduced fibrosis markers (e.g., fibronectin 1, α-SMA).
- miR-122-5p enhanced M1 macrophage polarization and suppressed M2 polarization, increasing inflammatory cytokines and inhibiting fibroblast fibrotic activity.
Conclusions:
- miR-122-5p impedes cutaneous healing in diabetic mice by promoting inflammation and inhibiting fibrosis.
- These findings offer critical insights into the multifaceted roles of microRNAs in human skin wound repair, particularly in the context of diabetes.
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