Exosomes derived from mesenchymal stem cells reverse EMT via TGF-β1/Smad pathway and promote repair of damaged endometrium

Yao, Yuan; Chen, Ran; Wang, Guowu; Zhang, Yu; Liu, Fang

doi:10.1186/s13287-019-1332-8

Cited by 181 publications

(132 citation statements)

References 44 publications

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“…13,[128][129][130] Previous studies revealed that exosomes could function by regulating the TGF-β signal of their targeted cells. [131][132][133] In addition, Cai et al reported that exosomes from TGF-β1 genemodified dendritic cells delayed the development of inflammatory bowel disease by increasing CD4 + Foxp3 + Tregs and inhibiting Th17 in a dextran sodium sulfate (DSS)-induced mouse model. 134 The effects of exosomes on the signaling pathway of subchondral bone cells, including TGF-β signaling, and their potential roles in OA progression deserve further attention.…”

Section: Exosomes In Oamentioning

confidence: 99%

Exosomes: roles and therapeutic potential in osteoarthritis

Ni¹,

et al. 2020

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Exosomes participate in many physiological and pathological processes by regulating cell-cell communication, which are involved in numerous diseases, including osteoarthritis (OA). Exosomes are detectable in the human articular cavity and were observed to change with OA progression. Several joint cells, including chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and secrete exosomes that influence the biological effects of targeted cells. In addition, exosomes from stem cells can protect the OA joint from damage by promoting cartilage repair, inhibiting synovitis, and mediating subchondral bone remodeling. This review summarizes the roles and therapeutic potential of exosomes in OA and discusses the perspectives and challenges related to exosome-based treatment for OA patients in the future.

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Section: Exosomes In Oamentioning

confidence: 99%

Exosomes: roles and therapeutic potential in osteoarthritis

Ni¹,

et al. 2020

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“…Subsequently, EVs were purified and found to be capable of mediating a reduction in infarct size [27]. Since then, EVs from hMSCs have been explored for the treatment of a wide variety of conditions [28][29][30][31][32][33][34][35][36][37][38][39]. However, few subsequent studies have explicitly re-demonstrated that depleting EVs from hMSC-conditioned medium removes the therapeutic effect; rather, the majority of studies have focused on the use of EVs after their isolation from conditioned medium.…”

Section: Introductionmentioning

confidence: 99%

Experimental artefacts can lead to misattribution of bioactivity from soluble mesenchymal stem cell paracrine factors to extracellular vesicles

Whittaker

Nagelkerke

Nele

et al. 2020

J of Extracellular Vesicle

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It has been demonstrated that some commonly used Extracellular Vesicle (EV) isolation techniques can lead to substantial contamination with non-EV factors. Whilst it has been established that this impacts the identification of biomarkers, the impact on apparent EV bioactivity has not been explored. Extracellular vesicles have been implicated as critical mediators of therapeutic human mesenchymal stem cell (hMSC) paracrine signalling. Isolated hMSC-EVs have been used to treat multiple in vitro and in vivo models of tissue damage. However, the relative contributions of EVs and non-EV factors have not been directly compared. The dependence of hMSC paracrine signalling on EVs was first established by ultrafiltration of hMSC-conditioned medium to deplete EVs, which led to a loss of signalling activity. Here, we show that this method also causes depletion of non-EV factors, and that when this is prevented proangiogenic signalling activity is fully restored in vitro. Subsequently, we used size-exclusion chromatography (SEC) to separate EVs and soluble proteins to directly and quantitatively compare their relative contributions to signalling. Non-EV factors were found to be necessary and sufficient for the stimulation of angiogenesis and wound healing in vitro. EVs in isolation were found to be capable of potentiating signalling only when isolated by a low-purity method, or when used at comparatively high concentrations. These results indicate a potential for contaminating soluble factors to artefactually increase the apparent bioactivity of EV isolates and could have implications for future studies on the biological roles of EVs.

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“…MFs, which exhibit characteristics of smooth muscle cells and FBs, are generally considered the key source of ECM production during tissue brosis [12][13][14]. It has been con rmed that TGF-β1 induces the epithelial-mesenchymal transition (EMT) and causes ECM to be excessively deposited as collagen [15][16][17]. According to recent studies, Wnt/β-catenin signalling and TGF-β1 are the most powerful mediators that promote EMT; both increase the secretion of collagen and other ECM proteins by mesenchymal cells, inhibit ECM degradation and ultimately result in ECM deposition in damaged tissues and organs [11,18,19].…”

Section: Introductionmentioning

confidence: 99%

si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway

Liu

Chen

et al. 2020

Preprint

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Background: Intrauterine adhesions (IUAs) are manifestations of endometrial fibrosis characterized by inflammation and fibrinogen aggregation in the extracellular matrix (ECM). The available therapeutic interventions for IUA are insufficiently effective in the clinical setting for postoperative adhesion recurrence and infertility problems. In this study, we investigated whether si-SNHG5-FOXF2 can serve as a molecular mechanism for the inhibition of IUA fibrosis ex vivo.Methods: FOXF2, TGF-β1 and collagen expression levels were measured by microarray sequencing analysis in three normal endometrium groups and six IUA patients. We induced primary human endometrial stromal cells (HESCs) into myofibroblasts (MFs) to develop an IUA cell model with various concentrations of TGF-β1 at various times. Downstream target genes of FOXF2 were screened by chromatin immunoprecipitation combined with whole-genome high-throughput sequencing (ChIP-seq). We investigated ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related proteins in primary HESCs with FOXF2 downregulation by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting (WB), immunohistochemistry (IHC), flow cytometry, ethylenediurea (EdU) and CCK8 assays. We identified lncRNA SNHG5 as the upstream regulatory gene of FOXF2 through RNA immunoprecipitation (RIP), RNA pulldown and fluorescence in situ hybridization (FISH). Finally, we examined FOXF2 expression, ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related proteins in primary HESCs upon FOXF2 downregulation.Results: FOXF2 was highly expressed in the endometrium of patients with IUA. Treatment of primary HESCs with 10 ng/ml TGF-β1 for 72 h was found to be most effective for developing an IUA cell model. FOXF2 regulated multiple downstream target genes, including collagen, vimentin (VIM) and cyclin D2/DK4, by ChIP-seq and ChIP-PCR. FOXF2 downregulation inhibited TGF-β1-mediated primary HESC fibrosis, including ECM formation, cell proliferation and Wnt/β-catenin signalling pathway-related protein expression. We identified lncRNA SNHG5 as an upstream gene that directly regulates FOXF2 by RIP-seq, qRT-PCR, WB, and FISH. SNHG5 downregulation suppressed FOXF2 expression in the IUA cell model, resulting in synergistic repression of the Wnt/β-catenin pathway, thereby altering TGF-β1-mediated ECM aggregation in endometrial stromal cells ex vivo. Conclusions: Regulation of the Wnt/β-catenin signalling pathway and ECM formation by si-SNHG5-FOXF2 effectively inhibited the profibrotic effect of TGF-β1 on primary HESCs. This finding can provide a molecular basis for antagonizing TGF-β1-mediated fibrosis in primary HESCs.

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Exosomes derived from mesenchymal stem cells reverse EMT via TGF-β1/Smad pathway and promote repair of damaged endometrium

Cited by 181 publications

References 44 publications

Exosomes: roles and therapeutic potential in osteoarthritis

Exosomes: roles and therapeutic potential in osteoarthritis

Experimental artefacts can lead to misattribution of bioactivity from soluble mesenchymal stem cell paracrine factors to extracellular vesicles

si-SNHG5-FOXF2 inhibits TGF-β1-induced fibrosis in human primary endometrial stromal cells by the Wnt/β-catenin signalling pathway

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