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Circ6401, a novel circular RNA, is implicated in repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells through regulation of the miR-29b-1-5p/RAP1B axis.

ABSTRACT: Background:Accumulating evidence indicates that mesenchymal stem cells (MSCs) exert tissue repair effects and therapeutic angiogenesis through their noncoding RNAs (ncRNAs). Our previous studies showed that MSCs derived from Wharton's jelly (WJ-MSCs) can ameliorate damaged human endometrium by promoting angiogenesis. There is limited information on the functions and mechanism of ncRNAs in MSC-induced endometrial repair, and additional studies are needed for more insights.

Methods:Here, WJ-MSCs were cocultured with or without endometrial stromal cells (ESCs) damaged by mifepristone (cocultured group versus non-cocultured group). TUNEL staining assays, EdU proliferation assays, flow cytometry apoptosis assays, and western blot assays were performed to observe the reparative effect of WJ-MSCs on damaged ESCs. Subsequently, circular RNA (circRNA) and microRNA microarrays were performed between the two groups. A subset of top upregulated circRNAs was validated by qRT-PCR. The functions of circ6401 (hsa_circ_0006401) in WJ-MSCs were investigated using lentivirus-mediated circRNA overexpression assays. The subcellular localization of circ6401 and miR-29b-1-5p in WJ-MSCs was identified by double RNA fluorescence in situ hybridization. Dual-luciferase reporter assays and western blot assays were performed to elucidate the regulatory mechanisms among circ6401, miR-29b-1-5p, and RAP1B.

Results:WJ-MSCs significantly improved ESC proliferation and upregulated the expression of vascular angiogenesis markers. Circ6401 was upregulated in WJ-MSCs cocultured with damaged ESCs, while miR-29b-1-5p was significantly downregulated. Furthermore, circ6401 was found to bind to miR-29b-1-5p and prevent it from decreasing the level of RAP1B, a crucial protein involved in the VEGF signaling pathway, which promoted angiogenesis and stimulated the proliferation of ESCs.

Conclusions:Our results showed the abundance and regulation profiles of ncRNAs of WJ-MSCs during repair of damaged ESCs and, for the first time, clarified the underlying mechanism by which circ6401 promotes endometrial repair by WJ-MSCs; thus, demonstrating that circ6401 may serve as a potential therapeutic target.

SUBMITTER: Shi Q

PROVIDER: S-EPMC7708228 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Circ6401, a novel circular RNA, is implicated in repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells through regulation of the miR-29b-1-5p/RAP1B axis.

Shi Qin Q Sun Baolan B Wang Di D Zhu Yi Y Zhao Xinxin X Yang Xiaoqing X Zhang Yuquan Y

Stem cell research & therapy 20201201 1

<h4>Background</h4>Accumulating evidence indicates that mesenchymal stem cells (MSCs) exert tissue repair effects and therapeutic angiogenesis through their noncoding RNAs (ncRNAs). Our previous studies showed that MSCs derived from Wharton's jelly (WJ-MSCs) can ameliorate damaged human endometrium by promoting angiogenesis. There is limited information on the functions and mechanism of ncRNAs in MSC-induced endometrial repair, and additional studies are needed for more insights.<h4>Methods</h4> ...[more]

PMID: 33261656

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Project description:BackgroundWharton's jelly-derived mesenchymal stem cells (WJ-MSCs) exhibit strong and powerful potential in repairing different diseases. The expression profile of circular RNA (circRNA) provides valuable insight for regulation of the repair process and exploration of reparative effect mechanisms.MethodsHuman endometrial stromal cells (ESCs) were cultured with mifepristone to obtain damaged ESCs, which were then cocultured with or without WJ-MSCs (cocultured group versus non-cocultured group) to observe the reparative effect upon damaged ESCs by WJ-MSCs. CircRNA microarray was performed between the two groups. Based on the transcriptomics data, the differential gene expression profiles of the two groups were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and network analysis methods. Screening of a circRNA database was performed, and the results were confirmed by quantitative polymerase chain reaction (qPCR).ResultsWJ-MSCs exerted a reparative effect upon damaged ESCs in the cocultured group such as improved cell morphology, higher proliferative ability, and lower apoptosis rate. CircRNA array showed that 7757 circRNAs were differentially expressed in ESCs from the cocultured group. Mitotic cell cycle, cell cycle process, and nuclear division ranked top in the GO upregulated list of the two groups, while DNA replication and cell cycle ranked top in the KEGG pathway analysis upregulated list of the two groups. The nine most aberrantly expressed circRNAs were selected for further verification in the same cohort of samples by microarray analysis. Seven of the nine most aberrantly circRNAs were confirmed to be significantly upregulated in the cocultured group. And four of the seven circRNAs (hsa_circ_0015825, hsa-circRNA4049-38, hsa-circRNA5028-15, and hsa_circ_0111659) expression both in ESCs and WJ-MSCs tended to decrease with time by qPCR. The levels of the remaining three circRNAs (hsa-circRNA8881-21, hsa_circ_0020492 and hsa_circ_ 0026141) did not change significantly over time in either ESCs or WJ-MSCs. Moreover, we focused on hsa_circRNA_0111659 and predicted its miRNAs and targeted mRNA. The association of circRNA-miRNA-mRNA is likely to be involved in regulating the repair of endometrial damage.ConclusionsOur results presented the abundant and upregulated circRNAs profile during repair of the damaged endometrium by WJ-MSCs and provided a novel perspective for circRNAs in the regulation of WJ-MSCs for endometrial repair.

Dataset Information

Circ6401, a novel circular RNA, is implicated in repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells through regulation of the miR-29b-1-5p/RAP1B axis.

Publications

Circ6401, a novel circular RNA, is implicated in repair of the damaged endometrium by Wharton's jelly-derived mesenchymal stem cells through regulation of the miR-29b-1-5p/RAP1B axis.

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