MiR-455-5p upregulation in umbilical cord mesenchymal stem cells attenuates endometrial injury and promotes repair of damaged endometrium via Janus kinase/signal transducer and activator of transcription 3 signaling

Abstract

Umbilical cord mesenchymal stem cells (UCMSCs) are regarded as an ideal source for clinical use. Increasing evidence has suggested that microRNAs (miRNAs) work as a crucial regulator in the development of plentiful diseases, including intrauterine adhesions (IUA). Herein, we investigated the specific impacts of UCMSCs overexpressing miR-455-5p in IUA. UCMSCs were cocultured with endometrial stromal cells (ESCs). Thirty-two female mice were divided into four different treated groups: sham, model, model + UCMSC-miR-NC and model + UCMSC-miR-455-5p. Mice in model groups were induced by uterine curettage. MiR-455-5p overexpressed UCMSCs facilitated the proliferation and cell cycle progression of ESCs according to 5-ethynyl-2′-deoxyuridine assay and flow cytometry analysis. Hematoxylin-eosin and Masson staining revealed that miR-455-5p upregulation in UCMSCs increased the number of endometrial glands and suppressed endometrial fibrosis in murine uterine tissues. Western blotting displayed that miR-455-5p overexpressed UCMSCs promoted the activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signaling in ESCs and murine uterine tissues. Mechanistically, miR-455-5p targeted 3’ untranslated region of suppressor of cytokine signaling 3 (SOCS3), which was confirmed by luciferase reporter assay. Reverse transcription quantitative polymerase chain reaction demonstrated that miR-455-5p was lowly expressed and SOCS3 was highly expressed in murine uterine tissues of IUA model. Moreover, Pearson correlation analysis showed that their expression was inversely correlated. Rescue assays suggested that inhibiting JAK/STAT3 signaling reversed effects of miR-455-5p on the behaviors of ESCs. The results indicated that miR-455-5p overexpression in UCMSCs helps to attenuate endometrial injury and repair damaged endometrium by activating SOCS3-mediated JAK/STAT3 signaling.

Role of noncoding RNA in the pathophysiology and treatment of intrauterine adhesion

“…This study revealed the interrelationship between miRNAs and mRNAs during endometrial injury and repair, and provided a new approach for MSCs to treat IUA. Sun et al (2021) found that miR-455-5p could promote the proliferation and cell cycle progression of ESCs co-cultured with UCMSCs, and in vivo experiments verified that high expression of miR-455-5p could improve the therapeutic effect of UCMSCs on endometrial fibrosis. Mechanically, this experiment explored that miR-455-5p in MSCs promotes the repair of damaged endometrium by directly targeting SOCS3 to regulate the JAK/STAT3 signaling pathway.…”

Identification and validation of long non-coding RNA associated ceRNAs in intrauterine adhesion

“…Nayan J Sarma found miRNA-107 was participated in HCV-induced liver fibrosis [ 32 ]. In addition, miRNA-455-5p and miRNA-223-3p were confirmed to attenuate endometrial injury and promote repair of damaged endometrium in IUA [ 33 , 34 ]. Collectively, ceRNAs network mainly controlled critical functions such as transmembrane transport, cAMP signaling pathway and cGMP-PKG signaling pathway.…”

Human Umbilical Cord-Based Therapeutics: Stem Cells and Blood Derivatives for Female Reproductive Medicine

“…While small non-coding RNAs are usually transported by EVs, they can also be secreted directly by the hUC-MSCs to modulate other signaling cascades [90][91][92][93][94]. Indeed, the upregulation of miR-455-5p and miR-330-5p in hUC-MSCs has been associated with different mechanisms that attenuate endometrial injury and promote repair of murine damaged endometrium.…”

“…Indeed, the upregulation of miR-455-5p and miR-330-5p in hUC-MSCs has been associated with different mechanisms that attenuate endometrial injury and promote repair of murine damaged endometrium. In particular, miR-455-5p regulates the suppressor of cytokine signaling 3 (SOCS3)-mediated Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway [90], whereas miR-330-5p stabilizes mitochondrial metabolism through pyruvate dehydrogenase kinase 2 (PDK2) signaling [93].…”