Integrative small and long RNA omics analysis of human healing and nonhealing wounds discovers cooperating microRNAs as therapeutic targets

被引：14

作者：

Liu, Zhuang ^{[1
]}

Zhang, Letian ^{[1
]}

Toma, Maria A. ^{[1
]}

Li, Dongqing ^{[1
,2
,3
]}

Bian, Xiaowei ^{[1
]}

Pastar, Irena ^{[4
]}

Tomic-Canic, Marjana ^{[4
]}

Sommar, Pehr ^{[5
]}

Xu Landen, Ning ^{[1
,6
]}

机构：

[1] Karolinska Inst, Ctr Mol Med, Dept Med Solna, Dermatol & Venereol Div, Stockholm, Sweden

[2] Chinese Acad Med Sci, Key Lab Basic & Translat Res Immune Mediated Skin, Nanjing, Peoples R China

[3] Chinese Acad Med Sci & Peking Union Med Coll, Inst Dermatol, Jiangsu Key Lab Mol Biol Skin Dis & STIs, Nanjing, Peoples R China

[4] Univ Miami, Miller Sch Med, Dr Phillip Frost Dept Dermatol & Cutaneous Surg, Wound Healing & Regenerat Med Res Program, Miami, FL 33136 USA

[5] Karolinska Univ Hosp, Dept Plast & Reconstruct Surg, Stockholm, Sweden

[6] Karolinska Inst, Ming Wai Lau Ctr Reparat Med, Stockholm Node, Stockholm, Sweden

来源：

ELIFE | 2022年 / 11卷

基金：

瑞典研究理事会;

关键词：

microRNA; regulatory network; wound healing; chronic wound; venous ulcer; Human; TRANSCRIPTION FACTOR; NONCODING RNAS; GENOME-WIDE; EXPRESSION; PROLIFERATION; DEREGULATION; INFLAMMATION; TRANSITION; MANAGEMENT; MODELS;

D O I：

10.7554/eLife.80322

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 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 nonhealing venous ulcers (VUs). On the basis of the findings, we developed a compendium (), 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.

引用

页数：31