Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6
BackgroundInflammatory bowel disease (IBD), characterized by chronic intestinal inflammation and epithelial barrier dysfunction, remains a therapeutic challenge due to the limitations of current treatments, including drug resistance and invasive surgical risks. Emerging evidence implicates intestina...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601591/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849426801934204928 |
|---|---|
| author | Bihua Wu Shuangyan Su Xianyu Wang Yuwei Li Zhenghao Mei Fenglin Lou Le Guo |
| author_facet | Bihua Wu Shuangyan Su Xianyu Wang Yuwei Li Zhenghao Mei Fenglin Lou Le Guo |
| author_sort | Bihua Wu |
| collection | DOAJ |
| description | BackgroundInflammatory bowel disease (IBD), characterized by chronic intestinal inflammation and epithelial barrier dysfunction, remains a therapeutic challenge due to the limitations of current treatments, including drug resistance and invasive surgical risks. Emerging evidence implicates intestinal epithelial cells (IECs) pyroptosis as a key contributor to IBD progression. Bone marrow mesenchymal stem cell exosomes (BMSCs-Exo) exhibit anti-inflammatory and tissue-reparative potential, yet the role of tumor necrosis factor-stimulated gene 6 (TSG-6), a critical anti-inflammatory mediator in BMSCs-Exo, in modulating pyroptosis and intestinal barrier integrity remains unexplored. This study investigates the role of TSG-6 contained in mesenchymal stem cell-derived exosomes (MSCs-Exo) in alleviating IBD by modulating the pyroptosis signaling pathway in IECs.ResultsIn this study, TSG-6-enriched BMSCs-Exo significantly alleviated intestinal inflammation and pyroptosis in murine IBD models. BMSCs-Exo administration reduced NLRP3 inflammasome activation, suppressed Caspase-1-mediated Gasdermin D (GSDMD) cleavage, and decreased pro-inflammatory cytokine release (IL-1β, IL-18). Notably, TSG-6 knockdown in BMSCs-Exo abolished these protective effects, confirming its essential role in blocking the NLRP3/Caspase-1/GSDMD axis. Furthermore, BMSCs-Exo restored intestinal barrier integrity by upregulating tight junction proteins (e.g., ZO-1, occludin) and reducing epithelial permeability. In vitro experiments revealed that BMSCs-Exo directly inhibited pyroptosis in IECs, attenuating cell membrane rupture and inflammatory cascade amplification.ConclusionThis study identifies TSG-6 as a pivotal mediator in BMSCs-Exo that disrupts pyroptosis-driven IBD pathogenesis by targeting NLRP3 inflammasome activation. The findings highlight BMSCs-Exo as a cell-free therapeutic strategy to mitigate intestinal inflammation and barrier damage, offering advantages over traditional MSCs-based therapies in safety and specificity. By elucidating the TSG-6/NLRP3 regulatory axis, this work provides a novel framework for developing exosome-engineered treatments for IBD and other pyroptosis-related inflammatory disorders. |
| format | Article |
| id | doaj-art-43f998d0705c48edbea03ebebf5cea2b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-43f998d0705c48edbea03ebebf5cea2b2025-08-20T03:29:15ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-06-011610.3389/fimmu.2025.16015911601591Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6Bihua Wu0Shuangyan Su1Xianyu Wang2Yuwei Li3Zhenghao Mei4Fenglin Lou5Le Guo6Department of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaDepartment of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaDepartment of General Surgery, School of Clinical Medicine, Dali University, Dali, Yunnan, ChinaDepartment of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaDepartment of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaDepartment of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaDepartment of Medical Microbiology and Immunology, School of Basic Medical Sciences, Dali University, Dali, Yunnan, ChinaBackgroundInflammatory bowel disease (IBD), characterized by chronic intestinal inflammation and epithelial barrier dysfunction, remains a therapeutic challenge due to the limitations of current treatments, including drug resistance and invasive surgical risks. Emerging evidence implicates intestinal epithelial cells (IECs) pyroptosis as a key contributor to IBD progression. Bone marrow mesenchymal stem cell exosomes (BMSCs-Exo) exhibit anti-inflammatory and tissue-reparative potential, yet the role of tumor necrosis factor-stimulated gene 6 (TSG-6), a critical anti-inflammatory mediator in BMSCs-Exo, in modulating pyroptosis and intestinal barrier integrity remains unexplored. This study investigates the role of TSG-6 contained in mesenchymal stem cell-derived exosomes (MSCs-Exo) in alleviating IBD by modulating the pyroptosis signaling pathway in IECs.ResultsIn this study, TSG-6-enriched BMSCs-Exo significantly alleviated intestinal inflammation and pyroptosis in murine IBD models. BMSCs-Exo administration reduced NLRP3 inflammasome activation, suppressed Caspase-1-mediated Gasdermin D (GSDMD) cleavage, and decreased pro-inflammatory cytokine release (IL-1β, IL-18). Notably, TSG-6 knockdown in BMSCs-Exo abolished these protective effects, confirming its essential role in blocking the NLRP3/Caspase-1/GSDMD axis. Furthermore, BMSCs-Exo restored intestinal barrier integrity by upregulating tight junction proteins (e.g., ZO-1, occludin) and reducing epithelial permeability. In vitro experiments revealed that BMSCs-Exo directly inhibited pyroptosis in IECs, attenuating cell membrane rupture and inflammatory cascade amplification.ConclusionThis study identifies TSG-6 as a pivotal mediator in BMSCs-Exo that disrupts pyroptosis-driven IBD pathogenesis by targeting NLRP3 inflammasome activation. The findings highlight BMSCs-Exo as a cell-free therapeutic strategy to mitigate intestinal inflammation and barrier damage, offering advantages over traditional MSCs-based therapies in safety and specificity. By elucidating the TSG-6/NLRP3 regulatory axis, this work provides a novel framework for developing exosome-engineered treatments for IBD and other pyroptosis-related inflammatory disorders.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601591/fullinflammatory bowel diseasebone marrow mesenchymal stem cellsexosomespyroptosisintestinal epithelial cellsTSG-6 |
| spellingShingle | Bihua Wu Shuangyan Su Xianyu Wang Yuwei Li Zhenghao Mei Fenglin Lou Le Guo Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 Frontiers in Immunology inflammatory bowel disease bone marrow mesenchymal stem cells exosomes pyroptosis intestinal epithelial cells TSG-6 |
| title | Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 |
| title_full | Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 |
| title_fullStr | Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 |
| title_full_unstemmed | Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 |
| title_short | Bone marrow mesenchymal stem cell-derived exosomes alleviate DSS-induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of TSG-6 |
| title_sort | bone marrow mesenchymal stem cell derived exosomes alleviate dss induced inflammatory bowel disease in mice through inhibiting intestinal epithelial cell pyroptosis via delivery of tsg 6 |
| topic | inflammatory bowel disease bone marrow mesenchymal stem cells exosomes pyroptosis intestinal epithelial cells TSG-6 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1601591/full |
| work_keys_str_mv | AT bihuawu bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT shuangyansu bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT xianyuwang bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT yuweili bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT zhenghaomei bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT fenglinlou bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 AT leguo bonemarrowmesenchymalstemcellderivedexosomesalleviatedssinducedinflammatoryboweldiseaseinmicethroughinhibitingintestinalepithelialcellpyroptosisviadeliveryoftsg6 |