Introduction: The role of Adipose-derived mesenchymal stem cells (AD-MSCs) in skin wound healing remains to be fully characterized. This study aims to evaluate the regenerative potential of autologous AD-MSCs in a non-healing porcine wound model, in addition to elucidate key miRNA-mediated epigenetic regulations that underlie the regenerative potential of AD-MSCs in wounds.Methods: The regenerative potential of autologous AD-MSCs was evaluated in porcine model using histopathology and spatial frequency domain imaging. Then, the correlations between miRNAs and proteins of AD-MSCs were evaluated using an integration analysis in primary human AD-MSCs in comparison to primary human keratinocytes. Transfection study of AD-MSCs was conducted to validate the bioinformatics data.Results: Autologous porcine AD-MSCs improved wound epithelialization and skin properties in comparison to control wounds. We identified 26 proteins upregulated in human AD-MSCs, including growth and angiogenic factors, chemokines and inflammatory cytokines. Pathway enrichment analysis highlighted cell signalling-associated pathways and immunomodulatory pathways. miRNA-target modelling revealed regulations related to genes encoding for 16 upregulated proteins. miR-155-5p was predicted to regulate Fibroblast growth factor 2 and 7, C-C motif chemokine ligand 2 and Vascular cell adhesion molecule 1. Transfecting human AD-MSCs cell line with anti-miR-155 showed transient gene silencing of the four proteins at 24 h post-transfection.Discussion: This study proposes a positive miR-155-mediated gene regulation of key factors involved in wound healing. The study represents a promising approach for miRNA-based and cell-free regenerative treatment for difficult-to-heal wounds. The therapeutic potential of miR-155 and its identified targets should be further explored in-vivo.

中文翻译：

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MicroRNA-155介导与人类脂肪间充质干细胞在皮肤再生中的作用相关的多个基因调控

简介：脂肪间充质干细胞 (AD-MSC) 在皮肤伤口愈合中的作用仍有待充分表征。本研究旨在评估自体 AD-MSC 在非愈合猪伤口模型中的再生潜力，并阐明 miRNA 介导的表观遗传调控，这些调控是 AD-MSC 在伤口中再生潜力的基础。使用组织病理学和空间频域成像在猪模型中评估自体 AD-MSC。然后，使用原代人 AD-MSC 与原代人角质形成细胞的整合分析来评估 miRNA 和 AD-MSC 蛋白质之间的相关性。进行 AD-MSC 的转染研究以验证生物信息学数据。结果：与对照伤口相比，自体猪 AD-MSC 改善了伤口上皮化和皮肤特性。我们鉴定出人类 AD-MSC 中 26 种上调的蛋白质，包括生长因子和血管生成因子、趋化因子和炎症细胞因子。通路富集分析强调了细胞信号传导相关通路和免疫调节通路。 miRNA 目标模型揭示了与编码 16 种上调蛋白质的基因相关的调控。 miR-155-5p 预计可调节成纤维细胞生长因子 2 和 7、CC 基序趋化因子配体 2 和血管细胞粘附分子 1。用抗 miR-155 转染人 AD-MSC 细胞系，结果显示四种蛋白在转染后 24 小时。讨论：本研究提出了 miR-155 介导的对伤口愈合关键因素的正向基因调控。这项研究代表了一种基于 miRNA 的无细胞再生治疗难以愈合伤口的有前途的方法。应进一步探索 miR-155 及其已确定靶点的治疗潜力体内。