Mesenchymal Stem Cell-Derived Exosomes Laden Scaffold for Promoting Endometrium Regeneration and Fertility Restoration Through Macrophage Immunomodulation

Xin, Liaobing; Lin, Xiaona; Wang, Xiufen; Yu, Huaying; Pan, Y. B.; Fei, Haiyi; Ma, Lie

doi:10.2139/ssrn.3563935

Cited by 19 publications

(30 citation statements)

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“…Exosomes serve as carriers that transport functional proteins, mRNAs and miRNAs to various cells, where these factors act as mediators of intercellular communication and signaling pathway [38,39]. Studies proved that MSC-EXO microRNAs possess the abilities to promote cell proliferation, accelerate injured tissues' repairment, and inhibit brotic diseases [16,[40][41][42]. In this study, we further demonstrated that there was a series of miRNAs of the BMSC-EXOs, which contributed to the alleviation of SSc through regulating related signaling pathways.…”

Section: Discussionmentioning

confidence: 99%

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

Jin

Wang

et al. 2021

Preprint

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BackgroundSystemic sclerosis (SSc) is a disease with severe fibrosis of the skin without effective therapy. While bone marrow mesenchymal stem cell (BMSC) derived exosome was a potential stem cell-based candidate in treatment of SSc.MethodsBMSCs were isolated from the bone marrow of mouse and identified with the surface markers and multi-lineage differentiation. The exosomes were isolated from the BMSCs culture medium with ultracentrifugation and identified with NTA, TEM and western blot. The miRNAs of the BMSC-derived exosomes (BMSC-EXOs) were studied via miRNA sequencing and bioinformatic analysis. The SSc model was established in mice by bleomycin (BLM) subcutaneous injection and the mice were treated with BMSCs or BMSC-derived exosomes. The skin tissues were dissociated and analyzed with H&E staining, RNA sequencing and immunohistochemical staining.ResultsEvident pathological changes like fibrosis and inflammation induced in the skin of BLM-treated mice. Both BMSCs and BMSC-EXOs effectively intervened such pathological manifestations and disease process, in a very similar way. The effects of the BMSC-EXOs were tracked to their microRNAs, which were proved to be involved in regulating the proliferation and differentiation of multiple cell types and in multiple biological processes when the EXOs functioned. Furthermore, the TGF-β1 positive cells and α-SMA positive myofibroblasts were significantly increased in the scleroderma skin of BLM-treated mice, but evidently reduced in the EXO-treated SSc group. Meanwhile, the number of mast cells as well as the infiltrated macrophages and lymphocytes were evidently increased in the skins of the BLM-treated mice, but significantly reduced by the EXO treatment. Such observations were confirmed by the data of the detected inflammatory cytokines that significantly higher mRNA levels of Il6, Il10 and Tnf-α were found in SSc mice, but reduced following the EXO treatment. Through bioinformatics analysis, TGFβ and WNT signaling pathways were revealed to be closely involved in the pathogenic changes in mouse SSc and could be the main targets for treating the disease.ConclusionsBMSC-derived exosomes could be developed as a potential therapy for treating the dysfunction of the skin in SSc, especially for its similar efficacy with BMSCs but less regulated as compared to cell therapy. Its mechanisms are involved in its microRNAs which alleviate the SSc pathogenic changes through regulating WNT and TGFβ signaling pathways.

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Section: Discussionmentioning

confidence: 99%

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

Jin

Wang

et al. 2021

Preprint

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“…In the past few years, the endometrial therapeutic effects of MSCs derived from different tissues such as bone marrow [17], umbilical cord [18,19], human decidual [20], and uterus [21] have been investigated intensively, thus, providing new approaches to restore the endometrium to its normal morphology and function. In particular, the umbilical cord Wharton's jelly was reported to be an ideal source of stem cells for clinical treatment and scientific research applications because of its highest concentration of allogeneic MSCs compared to that of other tissues [22].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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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.

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“…In the past few years, the endometrial therapeutic effects of MSCs derived from different tissues such as bone marrow [17] , umbilical cord [18,19] , human decidual [20] , and uterus [21] have been investigated intensively, thus, providing new approaches to restore the endometrium to its normal morphology and function. In particular, the umbilical cord Wharton's jelly was reported to be an ideal source of stem cells for clinical treatment and scienti c research applications because of its highest concentration of allogeneic MSCs compared to that of other tissues [22] .…”

Section: Discussionmentioning

confidence: 99%

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

Sun

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

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Mesenchymal Stem Cell-Derived Exosomes Laden Scaffold for Promoting Endometrium Regeneration and Fertility Restoration Through Macrophage Immunomodulation

Cited by 19 publications

References 0 publications

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

BMSC-Derived Exosomes Intervened the Pathogenic Changes of Scleroderma in Mouse Through Its microRNAs

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

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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