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组织外泌体的转录组学研究 miR-195-5p 通过 YAP-Smad7 通路改善子宫内膜纤维化：一项动物研究。

Transcriptomics of tissue exosomes to investigate miR-195-5p's amelioration of endometrial fibrosis via the YAP-Smad7 pathway: an animal study.

机构信息

Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China.

Department of Reproductive Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, Fujian Province, China.

出版信息

J Transl Med. 2024 Nov 21;22(1):1050. doi: 10.1186/s12967-024-05871-8.

DOI:10.1186/s12967-024-05871-8

PMID:39574130

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11580480/

Abstract

BACKGROUND

A significant research gap exists regarding the role of tissue exosomes in intrauterine adhesions (IUAs). This study aims to investigate the involvement of miR-195-5p and its regulatory network in IUAs through the analysis of tissue exosomes.

METHODS

Exosomes from rat uterine tissue with intrauterine adhesions were analyzed via transcriptomics to identify downstream target genes of miR-195-5p, cross-referencing with the human endometrial transcriptomics database GSE224093. Dual luciferase labeling confirmed miRNA-target gene interactions. The therapeutic efficacy of a miR-195-5p agonist was assessed in vivo through HE staining, Masson staining, and mating tests. The mechanisms underlying extracellular matrix (ECM) deposition and myofibroblast transdifferentiation in endometrial fibrosis were investigated both in vitro and in vivo using RT-PCR, Western Blot, immunofluorescence, and immunohistochemistry. Migration ability of endometrial stromal cells was evaluated using CCK8, scratch tests, and Transwell assays. Finally, the clinical potential of miR-195-5p was compared with autologous adipose-derived mesenchymal stem cells.

RESULTS

The expression of miR-195-5p in uterine tissue exosomes from intrauterine adhesions was found to be decreased. Treatment with a miR-195-5p agonist resulted in improved endometrial health, reduced fibrosis, increased glandular density, and enhanced birth rates in rats. Both in vivo and in vitro experiments confirmed that miR-195-5p decreased ECM deposition, reduced myofibroblast transdifferentiation, and inhibited the migration of endometrial stromal cells. This was achieved through the downregulation of YAP expression in the Hippo pathway and the upregulation of Smad7. Notably, the therapeutic efficacy of miR-195-5p agonists was comparable to that of stem cell therapy, offering promising avenues for clinical application.

CONCLUSIONS

Differential expression of miR-195-5p in tissue exosomes can reduce ECM deposition and myofibroblast transdifferentiation, improving endometrial fibrosis by regulating the YAP-Smad7 pathway in the Hippo signaling cascade.

摘要

背景

组织外泌体在宫腔粘连（IUAs）中的作用存在显著的研究空白。本研究旨在通过分析组织外泌体，研究 miR-195-5p 及其调控网络在 IUAs 中的作用。

方法

通过转录组学分析大鼠宫腔粘连组织中外泌体，鉴定 miR-195-5p 的下游靶基因，并与人类子宫内膜转录组学数据库 GSE224093 进行交叉参考。双荧光素酶报告基因验证 miRNA-靶基因相互作用。通过 HE 染色、Masson 染色和交配试验评估 miR-195-5p 激动剂在体内的治疗效果。通过 RT-PCR、Western Blot、免疫荧光和免疫组化，在体外和体内研究细胞外基质（ECM）沉积和肌成纤维细胞转分化在子宫内膜纤维化中的机制。使用 CCK8、划痕试验和 Transwell 试验评估子宫内膜基质细胞的迁移能力。最后，将 miR-195-5p 的临床潜力与自体脂肪来源间充质干细胞进行比较。

结果

发现宫腔粘连组织中外泌体 miR-195-5p 的表达降低。用 miR-195-5p 激动剂治疗可改善子宫内膜健康，减少纤维化，增加腺体密度，提高大鼠出生率。体内和体外实验均证实，miR-195-5p 可减少 ECM 沉积，减少肌成纤维细胞转分化，抑制子宫内膜基质细胞迁移。这是通过 Hippo 通路中 YAP 表达的下调和 Smad7 的上调来实现的。值得注意的是，miR-195-5p 激动剂的治疗效果可与干细胞治疗相媲美，为临床应用提供了有前途的途径。