{"paper_id":"854f9fb1-874b-41b5-92b9-35d08f3edeab","body_text":"Abstract\nIntroduction: Endometriosis is a chronic disorder characterized by abnormal endometrial tissue growth. This study evaluates a novel combination immunomodulatory treatment involving etanercept (ETN) and exosomes derived from human Wharton's jelly mesenchymal stem cells (hWJMSC-Exo) as a promising alternative to conventional therapies for modulating inflammation in endometriosis.\nMethods: Endometrial stromal cells were isolated by enzymatic digestion of eutopic (EuESCs, N = 6) and ectopic (EESCs, N = 6) tissues of endometriosis patients and non-endometriotic controls (CESCs, N = 6). hWJMSC-Exo were confirmed by flow cytometry, SEM, and DLS tests. Cells were treated with varying concentrations of ETN (0-40 μg/ml), hWJMSC-Exo (0-15 μg/ml), and their combination (E+E). IC50 values were determined using the MTT assay at 24, 48, and 72 hours. Protein levels of TNF- α, VEGF-A, and IL-10, and gene expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 were measured using ELISA and RT-PCR, respectively.\nResults: The combination of ETN (10 μg/ml) and hWJMSC-Exo (10 μg/ml) at 24 and 48 hours, respectively, reduced protein expression of TNF-α, VEGF-A, and IL-10 in EESCs, EuESCs, and CESCs compared with untreated groups (P < 0.001). Additionally, E+E treatment significantly reduced mRNA expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 in all three groups compared to untreated groups.\nDiscussion: This combination therapy improves inflammation, angiogenesis, tissue remodeling, and immune regulation in endometriosis. However, clinical validation and long-term safety require further in vivo studies with larger sample sizes.\nConclusion: E+E treatment synergistically reduced key cytokines and enzymes in endometriosis. This approach is a promising means of regulating inflammation.\nKeywords: Combination therapy, endometriosis, etanercept, exosome, inflammation, mesenchymal stem cell, wharton jelly.\n[http://dx.doi.org/10.2174/0115665240311438241011052341] [PMID: 39501947]\n[PMID: 38375785]\n[http://dx.doi.org/10.3389/fendo.2022.858176] [PMID: 35784569] [PMCID: PMC9245568]\n[http://dx.doi.org/10.1016/j.yexcr.2025.114553] [PMID: 40216010]\n[http://dx.doi.org/10.3390/biom11111739] [PMID: 34827737]\n[http://dx.doi.org/10.3389/fonc.2019.01370] [PMID: 31921634]\n[http://dx.doi.org/10.1038/srep16859] [PMID: 26577912]\n[http://dx.doi.org/10.1093/humrep/dex067] [PMID: 28383711]\n[http://dx.doi.org/10.5603/gpl.103148] [PMID: 39878755]\n[PMID: 8923461]\n[PMID: 24966899]\n[http://dx.doi.org/10.1016/j.jri.2022.103515] [PMID: 35381481]\n[http://dx.doi.org/10.1016/j.ejogrb.2016.07.513] [PMID: 27544308]\n[http://dx.doi.org/10.3390/ph17070827] [PMID: 39065678]\n[http://dx.doi.org/10.1080/14712598.2024.2436094] [PMID: 39663567]\n[http://dx.doi.org/10.1016/j.jri.2024.104415] [PMID: 39700679]\n[http://dx.doi.org/10.1007/s00404-010-1543-9] [PMID: 20544212]\n[http://dx.doi.org/10.1016/j.ejogrb.2011.06.029] [PMID: 21741153]\n[http://dx.doi.org/10.1007/s00404-010-1434-0] [PMID: 20333392]\n[http://dx.doi.org/10.1016/j.cellimm.2024.104813] [PMID: 38364454]\n[http://dx.doi.org/10.1016/j.intimp.2023.110405] [PMID: 37270928]\n[http://dx.doi.org/10.1186/s12964-022-00853-z] [PMID: 35414084]\n[http://dx.doi.org/10.1038/ncomms8321] [PMID: 26084661]\n[http://dx.doi.org/10.2217/rme-2021-0169] [PMID: 35938412]\n[http://dx.doi.org/10.1007/s11356-021-18401-6] [PMID: 34993805]\n[http://dx.doi.org/10.34172/apb.2024.027] [PMID: 39206409]\n[http://dx.doi.org/10.1016/j.jri.2022.103638] [PMID: 35588629]\n[http://dx.doi.org/10.1186/s13287-021-02244-6] [PMID: 33761997]\n[http://dx.doi.org/10.1186/s13287-022-03079-5] [PMID: 35897039]\n[http://dx.doi.org/10.1016/j.intimp.2023.110294] [PMID: 37167639]\n[http://dx.doi.org/10.1016/S0015-0282(97)81391-X] [PMID: 9130884]\n[http://dx.doi.org/10.1373/clinchem.2008.112797] [PMID: 19246619]\n[http://dx.doi.org/10.1002/cpt.1827] [PMID: 32153014]\n[http://dx.doi.org/10.1186/s12348-023-00375-w] [PMID: 38017191]\n[http://dx.doi.org/10.3389/fimmu.2020.00312] [PMID: 32174918]\n[http://dx.doi.org/10.1007/s00404-003-0591-9] [PMID: 14745563]\n[http://dx.doi.org/10.1177/22840265241231722]\n[http://dx.doi.org/10.3390/ijms25094802] [PMID: 38732021]\n[PMID: 39717957]\n[http://dx.doi.org/10.1016/j.fertnstert.2003.09.034 ] [PMID: 15019808]\n[http://dx.doi.org/10.3389/fimmu.2023.1128301] [PMID: 37138868]\n[http://dx.doi.org/10.1016/j.genrep.2021.101298]\n[http://dx.doi.org/10.1016/j.ebiom.2016.04.030] [PMID: 27428420]\n[http://dx.doi.org/10.1007/s10815-019-01687-4] [PMID: 31938932]\n[http://dx.doi.org/10.3892/mmr.2024.13167] [PMID: 38240108]\n[http://dx.doi.org/10.1016/j.jri.2021.103340] [PMID: 34139652]\n[http://dx.doi.org/10.18240/ijo.2024.07.07] [PMID: 39026907]\n[http://dx.doi.org/10.1080/09513590.2017.1409717] [PMID: 29308924]\n[http://dx.doi.org/10.1038/cddis.2014.414] [PMID: 25275597]\n[http://dx.doi.org/10.1038/cddis.2017.95] [PMID: 28300844]\n[http://dx.doi.org/10.3389/fimmu.2019.00003] [PMID: 30713533]\n[http://dx.doi.org/10.1093/humrep/deac248] [PMID: 36413036]\n[http://dx.doi.org/10.1002/path.5339] [PMID: 31418859]\n[http://dx.doi.org/10.25122/jml-2020-0117] [PMID: 33072202]\n[http://dx.doi.org/10.1016/j.pupt.2012.02.006] [PMID: 22724137]\n[http://dx.doi.org/10.1186/s13018-020-1553-7] [PMID: 32054483]\n[http://dx.doi.org/10.3389/fimmu.2020.610963] [PMID: 33381124]\n[http://dx.doi.org/10.1016/j.jdermsci.2017.12.008] [PMID: 29279286]\n[http://dx.doi.org/10.1124/mol.107.042176] [PMID: 18252806]\n[http://dx.doi.org/10.1016/j.fertnstert.2007.12.067] [PMID: 18314120]\n[http://dx.doi.org/10.1186/s12905-021-01560-6] [PMID: 34930225]\n[http://dx.doi.org/10.3109/s10165-009-0175-z] [PMID: 19458908]\n[http://dx.doi.org/10.18632/aging.205034] [PMID: 37724890]\n[PMID: 39306730]\n[http://dx.doi.org/10.2174/1566524023666220819122948] [PMID: 35986537]\n[http://dx.doi.org/10.1016/j.fertnstert.2005.08.017] [PMID: 16595205]\n[http://dx.doi.org/10.5301/JE.2012.9070]\n[http://dx.doi.org/10.21873/invivo.11970] [PMID: 32606145] [PMCID: PMC7439897]\n[http://dx.doi.org/10.1210/en.2008-0352] [PMID: 18703630]\n[http://dx.doi.org/10.2147/OTT.S493643] [PMID: 39989503]\n[PMID: 35875336]\n[http://dx.doi.org/10.1093/humupd/dmx016] [PMID: 28903471]\n[http://dx.doi.org/10.1165/rcmb.2004-0288OC] [PMID: 15653932]\n[http://dx.doi.org/10.1111/j.1582-4934.2008.00647.x] [PMID: 20141610]\n[http://dx.doi.org/10.1016/j.yexmp.2020.104468] [PMID: 32445750]\n[http://dx.doi.org/10.1530/REP-19-0597] [PMID: 32155128]\n[http://dx.doi.org/10.3389/fonc.2018.00592] [PMID: 30581772]","source_license":"CC0","license_restricted":false}