Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer
Abstract Background Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in stroke outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umb...
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2025-03-01
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| Online Access: | https://doi.org/10.1186/s13287-025-04224-6 |
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| author | Shuna Chen Chao Han Zihan Shi Xin Guan Liyuan Cheng Liang Wang Wei Zou Jing Liu |
| author_facet | Shuna Chen Chao Han Zihan Shi Xin Guan Liyuan Cheng Liang Wang Wei Zou Jing Liu |
| author_sort | Shuna Chen |
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| description | Abstract Background Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in stroke outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umbilical mesenchymal stem cells (UMSCs) offer therapeutic potential due to their immunomodulatory properties. They can regulate immune responses and reduce neuroinflammation, potentially enhancing recovery by fostering a pro-regenerative peripheral immune environment. However, the effect of UMSCs on T-cell dynamics in AIS remains underexplored. This study investigates T-cell dynamics following AIS and examines how UMSCs may mitigate immune dysregulation to develop better treatment strategies. Methods AIS patients (NIHSS scores 0–15) were recruited within 72 h of stroke onset, with peripheral blood samples collected on Day 0 (enrollment) and Day 7. T-cell compartments were identified by flow cytometry, and plasma cytokine levels were quantified using a cytometric bead array (CBA). Mitochondria in UMSCs were labeled with MitoTracker. Peripheral blood mononuclear cells from patients were isolated, treated with lipopolysaccharide (LPS), and cocultured with UMSCs in both direct contact and Transwell systems. Flow cytometry, CBA, RT-qPCR, and immunofluorescence assays were used to detect T-cell compartments, gene expression markers for helper T (Th) cell differentiation, cytokine profiles, mitochondrial transfer, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Additionally, mitochondrial DNA in UMSCs was depleted. The effects of UMSCs and mitochondria-depleted UMSCs on ischemic stroke mice were compared through behavioral assessments and analysis of the peripheral immune microenvironment. Results In AIS, T-cell compartments underwent a phenotypic shift from naïve to effector or memory states, with a specific increase in Th17 cells and a decrease in regulatory T cells, leading to alterations in T-cell-mediated immune functions. In an ex vivo co-culture system, LPS stimulation further amplified these disparities, inducing mitochondrial dysfunction and oxidative stress in T cells. Notably, UMSCs restored mitochondrial function and reversed the shift in T-cell compartments through mitochondrial transfer. Critically, UMSC treatment significantly improved both neurological deficits and peripheral immune disorders in ischemic stroke mice, whereas mitochondria-depleted UMSCs failed to produce this effect. Conclusions Our comprehensive insights into the key attributes of T-cell compartments in acute ischemic stroke and the immune regulatory mechanisms of UMSCs provide a crucial theoretical foundation for understanding peripheral immune disorders in ischemic stroke and the therapeutic potential of UMSC treatment. Graphical abstract |
| format | Article |
| id | doaj-art-efdd1e4ae3d44970bc769f7fd99d75ea |
| institution | DOAJ |
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| spelling | doaj-art-efdd1e4ae3d44970bc769f7fd99d75ea2025-08-20T02:56:16ZengBMCStem Cell Research & Therapy1757-65122025-03-0116112410.1186/s13287-025-04224-6Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transferShuna Chen0Chao Han1Zihan Shi2Xin Guan3Liyuan Cheng4Liang Wang5Wei Zou6Jing Liu7Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityStem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian Innovation Institute of Stem Cell and Precision MedicineStem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityStem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityStem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityDalian Innovation Institute of Stem Cell and Precision MedicineStem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, The First Affiliated Hospital of Dalian Medical UniversityAbstract Background Acute ischemic stroke (AIS) initiates secondary injuries that worsen neurological damage and hinder recovery. While peripheral immune responses play a key role in stroke outcomes, clinical results from immunotherapy have been suboptimal, with limited focus on T-cell dynamics. Umbilical mesenchymal stem cells (UMSCs) offer therapeutic potential due to their immunomodulatory properties. They can regulate immune responses and reduce neuroinflammation, potentially enhancing recovery by fostering a pro-regenerative peripheral immune environment. However, the effect of UMSCs on T-cell dynamics in AIS remains underexplored. This study investigates T-cell dynamics following AIS and examines how UMSCs may mitigate immune dysregulation to develop better treatment strategies. Methods AIS patients (NIHSS scores 0–15) were recruited within 72 h of stroke onset, with peripheral blood samples collected on Day 0 (enrollment) and Day 7. T-cell compartments were identified by flow cytometry, and plasma cytokine levels were quantified using a cytometric bead array (CBA). Mitochondria in UMSCs were labeled with MitoTracker. Peripheral blood mononuclear cells from patients were isolated, treated with lipopolysaccharide (LPS), and cocultured with UMSCs in both direct contact and Transwell systems. Flow cytometry, CBA, RT-qPCR, and immunofluorescence assays were used to detect T-cell compartments, gene expression markers for helper T (Th) cell differentiation, cytokine profiles, mitochondrial transfer, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Additionally, mitochondrial DNA in UMSCs was depleted. The effects of UMSCs and mitochondria-depleted UMSCs on ischemic stroke mice were compared through behavioral assessments and analysis of the peripheral immune microenvironment. Results In AIS, T-cell compartments underwent a phenotypic shift from naïve to effector or memory states, with a specific increase in Th17 cells and a decrease in regulatory T cells, leading to alterations in T-cell-mediated immune functions. In an ex vivo co-culture system, LPS stimulation further amplified these disparities, inducing mitochondrial dysfunction and oxidative stress in T cells. Notably, UMSCs restored mitochondrial function and reversed the shift in T-cell compartments through mitochondrial transfer. Critically, UMSC treatment significantly improved both neurological deficits and peripheral immune disorders in ischemic stroke mice, whereas mitochondria-depleted UMSCs failed to produce this effect. Conclusions Our comprehensive insights into the key attributes of T-cell compartments in acute ischemic stroke and the immune regulatory mechanisms of UMSCs provide a crucial theoretical foundation for understanding peripheral immune disorders in ischemic stroke and the therapeutic potential of UMSC treatment. Graphical abstracthttps://doi.org/10.1186/s13287-025-04224-6Acute ischemic strokeUmbilical mesenchymal stem cellsTh17/Treg imbalanceT-cell compartmentMitochondrial transfer |
| spellingShingle | Shuna Chen Chao Han Zihan Shi Xin Guan Liyuan Cheng Liang Wang Wei Zou Jing Liu Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer Stem Cell Research & Therapy Acute ischemic stroke Umbilical mesenchymal stem cells Th17/Treg imbalance T-cell compartment Mitochondrial transfer |
| title | Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer |
| title_full | Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer |
| title_fullStr | Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer |
| title_full_unstemmed | Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer |
| title_short | Umbilical mesenchymal stem cells mitigate T-cell compartments shift and Th17/Treg imbalance in acute ischemic stroke via mitochondrial transfer |
| title_sort | umbilical mesenchymal stem cells mitigate t cell compartments shift and th17 treg imbalance in acute ischemic stroke via mitochondrial transfer |
| topic | Acute ischemic stroke Umbilical mesenchymal stem cells Th17/Treg imbalance T-cell compartment Mitochondrial transfer |
| url | https://doi.org/10.1186/s13287-025-04224-6 |
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