MicroRNAs (miR), as important epigenetic control factors, reportedly regulate wound repair. However, our insufficient knowledge of clinically relevant miRs hinders their potential therapeutic use. For this, we performed paired small RNA and long RNA sequencing and integrative omics analysis in human tissue samples, including matched skin and acute wounds collected at each healing stage and chronic non-healing venous ulcers (VU). On the basis of the findings, we developed a compendium (https://www.xulandenlab.com/humanwounds-mirna-mrna), which will be an open, comprehensive resource to broadly aid wound healing research. With this first clinical, wound-centric resource of miRs and mRNAs, we identified 17 pathologically relevant miRs that exhibited abnormal VU expression and displayed their targets enriched explicitly in the VU gene signature. Intermeshing regulatory networks controlled by these miRs revealed their high cooperativity in contributing to chronic wound pathology characterized by persistent inflammation and proliferative phase initiation failure. Furthermore, we demonstrated that miR-34a, miR-424, and miR-516, upregulated in VU, cooperatively suppressed keratinocyte migration and growth while promoting inflammatory response. By combining miR expression patterns with their specific target gene expression context, we identified miRs highly relevant to VU pathology. Our study opens the possibility of developing innovative wound treatment that targets pathologically relevant cooperating miRs to attain higher therapeutic efficacy and specificity.

中文翻译：

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人类愈合和不愈合伤口的综合小和长 RNA 组学分析发现合作的 microRNA 作为治疗靶点

据报道，作为重要的表观遗传控制因子，MicroRNAs (miR) 调节伤口修复。然而，我们对临床相关 miR 的了解不足阻碍了它们的潜在治疗用途。为此，我们在人体组织样本中进行了配对的小 RNA 和长 RNA 测序和综合组学分析，包括在每个愈合阶段收集的匹配皮肤和急性伤口以及慢性非愈合性静脉溃疡 (VU)。在研究结果的基础上，我们制定了一份纲要 (https://www.xulandenlab.com/humanwounds-mirna-mrna)，这将是一个开放的综合资源，可广泛帮助伤口愈合研究。凭借第一个临床、以伤口为中心的 miR 和 mRNA 资源，我们确定了 17 个病理相关的 miR，它们表现出异常的 VU 表达，并显示出在 VU 基因特征中明确富集的靶标。由这些 miR 控制的相互啮合的调节网络揭示了它们在促进以持续炎症和增殖期启动失败为特征的慢性伤口病理学方面的高度协同性。此外，我们证明了在 VU 中上调的 miR-34a、miR-424 和 miR-516 协同抑制角质形成细胞迁移和生长，同时促进炎症反应。通过将 miR 表达模式与其特定靶基因表达背景相结合，我们确定了与 VU 病理学高度相关的 miR。我们的研究开启了开发创新伤口治疗的可能性，该治疗针对病理相关的合作 miR，以获得更高的治疗功效和特异性。