Abstract
BackgroundAccumulating 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.MethodsHere, 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.ResultsWJ-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.ConclusionsOur 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.
Highlights
Accumulating evidence indicates that mesenchymal stem cells (MSCs) exert tissue repair effects and therapeutic angiogenesis through their noncoding RNAs
Our results showed the abundance and regulation profiles of Noncoding RNA (ncRNA) of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) during repair of damaged endometrial stromal cells (ESCs) and, for the first time, clarified the underlying mechanism by which circ6401 promotes endometrial repair by WJ-MSCs; demonstrating that circ6401 may serve as a potential therapeutic target
The results showed that mifepristone treatment inhibited the expression of VEGFA, VEGFR1, VEGFR2, and RAP1B, while coculture with WJ-MSCs reversed the regulatory effects of mifepristone treatment on these vascular angiogenesis markers (Fig. 1g, h)
Summary
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. Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) exist in the Wharton’s jelly and perivascular area of the human umbilical cord and hold promise for the field of regenerative medicine because of their strong capacity to regenerate injured tissues indirectly through growth factor secretion and immunomodulation. Our previous studies showed that WJ-MSCs can ameliorate damaged human endometrial stromal cells (ESCs) [6, 7], indicating that it is possible to use WJ-MSCs to repair endometrial damage. To improve the efficiency of WJ-MSC treatment, it is necessary to further study the regulatory mechanism by which WJ-MSCs repair ESCs
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