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Xie Y, Lv Z, Wang Y, Ma J, Wei X, Zheng G, Wu J. Study on the efficacy of IFN-γ- and sPD-1-overexpressing BMSCs in enhancing immune effects for the treatment of lung adenocarcinoma. Front Immunol 2025; 16:1554467. [PMID: 40181963 PMCID: PMC11965897 DOI: 10.3389/fimmu.2025.1554467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 02/25/2025] [Indexed: 04/05/2025] Open
Abstract
Background Soluble programmed cell death receptor-1 (sPD-1) blocks the PD-1/PD-L1 pathway, reverses tumor immune suppression, and inhibits tumor growth. However, clinical applications are limited by its poor tissue distribution and rapid dispersion. Bone marrow-derived mesenchymal stem cells (BMSCs) are favorable carriers for tumor immunotherapy due to their capacity for external gene introduction and targeted tumor homing. However, they may inadvertently promote tumor growth. Interferon-gamma (IFN-γ) inhibits BMSC-mediated tumor growth and stimulates antigen-presenting cells to activate T lymphocytes. This study utilizes BMSCs transfected with IFN-γ as carriers for sPD-1, enabling the targeted homing of sPD-1 to tumor tissues, thereby enhancing the efficacy and sustained stability of immunotherapy. Methods stable IFN-γ- and sPD-1-overexpressing BMSCs were successfully constructed by lentiviral transfection. A non-contact co-culture system was established with Lewis and A549 lung adenocarcinoma cells to observe changes in the lung cancer cells after co-culture, using assays including cell migration and invasion experiments, as well as cellular senescence detection. Additionally, a subcutaneous lung adenocarcinoma model was established in C57BL/6J mice for intervention studies. Tumor volume, cellular apoptosis in tumor tissue (assessed by TUNEL assay), peripheral Treg cells (analyzed by flow cytometry), and histopathological markers (evaluated by HE staining and immunohistochemistry) were analyzed. The expression levels of BAX, BCL-2, AKT, PI3K, and PD-L1 were assessed by quantitative PCR and Western Blot. Results IFN-γ- and sPD-1-overexpressing BMSCs exhibited high bioactivity and genetic stability, inhibiting lung adenocarcinoma cell proliferation, accelerating cellular senescence, and reducing migration and invasion. Furthermore, they upregulate Bax expression, downregulate Bcl-2, and promote apoptosis. Additionally, these cells alleviate inflammatory damage in lung tissue of tumor-bearing mice, lower Treg cell levels to inhibit tumor immune evasion, and reduce the expression of PI3K/AKT and PD-L1. Conclusion IFN-γ- and sPD-1-overexpressing BMSCs effectively inhibit lung adenocarcinoma cell growth and tumor progression. The primary mechanisms include suppression of cancer cell growth, migration, and invasion; promotion of apoptosis and senescence in cancer cells; modulation of Treg cells; and inhibition of the PI3K/AKT signaling pathway and PD-1/PD-L1 pathways.
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Affiliation(s)
- Yahui Xie
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Zhen Lv
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Yubin Wang
- Center for Laboratory Medicine, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jin Ma
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Xingmin Wei
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Guisen Zheng
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
| | - Jianjun Wu
- School of Public Health, Gansu University of Traditional Chinese Medicine, Lanzhou, China
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Ma J, Zhang Y, Li J, Dang Y, Hu D. Regulation of histone H3K27 methylation in inflammation and cancer. MOLECULAR BIOMEDICINE 2025; 6:14. [PMID: 40042761 PMCID: PMC11882493 DOI: 10.1186/s43556-025-00254-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 02/17/2025] [Accepted: 02/19/2025] [Indexed: 03/09/2025] Open
Abstract
Inflammation is a multifaceted defense mechanism of the immune system against infection. Chronic inflammation is intricately linked to all stages of tumorigenesis and is therefore associated with an elevated risk of developing serious cancers. Epigenetic mechanisms have the capacity to trigger inflammation as well as facilitate tumor development and transformation within an inflammatory context. They achieve this by dynamically modulating the expression of both pro-inflammatory and anti-inflammatory cytokines, which in turn sustains chronic inflammation. The aberrant epigenetic landscape reconfigures the transcriptional programs of inflammatory and oncogenic genes. This reconfiguration is pivotal in dictating the biological functions of both tumor cells and immune cells. Aberrant histone H3 lysine 27 site (H3K27) methylation has been shown to be involved in biological behaviors such as inflammation development, tumor progression, and immune response. The establishment and maintenance of this repressive epigenetic mark is dependent on the involvement of the responsible histone modifying enzymes enhancer of zeste homologue 2 (EZH2), jumonji domain containing 3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat gene X (UTX) as well as multiple cofactors. In addition, specific pharmacological agents have been shown to modulate H3K27 methylation levels, thereby modulating inflammation and carcinogenesis. This review comprehensively summarises the current characteristics and clinical significance of epigenetic regulation of H3K27 methylation in the context of inflammatory response and tumor progression.
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Affiliation(s)
- Jing Ma
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Yalin Zhang
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China
| | - Jingyuan Li
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China
| | - Yanqi Dang
- Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, (Shanghai University of Traditional Chinese Medicine), Shanghai, 200032, China.
| | - Dan Hu
- Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, No. 358 Datong Road, Pudong New Area, Shanghai, 200137, China.
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Li Y, Zhu M, Yang P, Chen D, Zhou D, Ren Y, Zhang Z, Ruan C, Da Y, Zhang R. Sp3 ameliorated experimental autoimmune encephalomyelitis by triggering Socs3 in Th17 cells. J Adv Res 2025:S2090-1232(25)00070-0. [PMID: 39884649 DOI: 10.1016/j.jare.2025.01.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 01/06/2025] [Accepted: 01/27/2025] [Indexed: 02/01/2025] Open
Abstract
INTRODUCTION Although it is believed that chronic inflammatory and degenerative diseases of the central nervous system are mediated by autoimmune Th17 cells, the underlying mechanisms remain largely unexplored. Recent studies and our research have revealed that Sp3 was blocked in multiple sclerosis (MS) patients and experimental autoimmune encephalomyelitis (EAE). However, it remained unclear why it is silent and how it regulates Th17 cell differentiation in MS. OBJECTIVES This study aimed to explore the impact of Sp3 on Th17 cell-mediated EAE and the underlying mechanism. METHODS The effect of Sp3 on the clinical symptoms of EAE was evaluated by scoring, histochemistry, and fast blue (FB) techniques, scRNA-seq data analysis, flow cytometry, ELISA, PCR, WB, immunofluorescence and reporter gene techniques were used to explore the molecular mechanism of Sp3 regulating Th17 cell differentiation. RESULTS Injection of overexpression Sp3 lentivirus could significantly ameliorate the EAE progress and clinical symptoms and prevent the polarization of Th1 and Th17 cells both in vivo and in vitro. We confirmed the occurrence of EAE in Sp3+/+CD4Cre mice and Sp3+/- knockout mice. Furthermore, we identified Sp3 as a target of miR-223, which is found to be upregulated in the blood of MS patients, as well as in EAE and Th17 cells. Moreover, knockdown of miR-223 led to a marked improvement in EAE symptoms and a suppression of Th1 and Th17 cell polarization in vivo and in vitro. Mechanistically, Sp3 significantly suppressed RORγt expression and the phosphorylation of Stat3 and Smad2/3 by directly upregulating Socs3. Interestingly, Socs3 was found to regulate Sp3 expression in response to TGF-β1 via a feedback loop. Moreover, Socs3 modulated phospho-Smad2/3 by binding to and degrading the transforming growth factor-β receptor II (TβRII). CONCLUSION Thus, our study suggests a novel mechanism involving miR-223/Sp3/Socs3/TGF-β signaling as a potential therapeutic strategy for targeting Th17 cells in immunotherapy.
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Affiliation(s)
- Yan Li
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Mengyi Zhu
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Penghui Yang
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Daoyang Chen
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Dongmei Zhou
- Department of Immunology, Tianjin Medical University, Tianjin 300070, China
| | - Yinghui Ren
- Department of Immunology, Tianjin Medical University, Tianjin 300070, China
| | - Zimu Zhang
- Department of Immunology, Tianjin Medical University, Tianjin 300070, China
| | - Chuangdong Ruan
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yurong Da
- Department of Immunology, Tianjin Medical University, Tianjin 300070, China
| | - Rongxin Zhang
- Department of Biotechnology, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Advanced Drug Delivery, Guangdong Provincial Engineering Center of Topical Precise Drug Delivery System, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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Chen Y, Liu W, Xu X, Zhen H, Pang B, Zhao Z, Zhao Y, Liu H. The Role of H3K27me3-Mediated Th17 Differentiation in Ankylosing Spondylitis. Inflammation 2024; 47:1685-1698. [PMID: 38517649 DOI: 10.1007/s10753-024-02002-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/29/2024] [Accepted: 03/02/2024] [Indexed: 03/24/2024]
Abstract
Ankylosing spondylitis (AS) is a common chronic progressive inflammatory autoimmune disease. T helper 17 (Th17) cells are the major effector cells mediating AS inflammation. Histone 3 Lys 27 trimethylation (H3K27me3) is an inhibitory histone modification that silences gene transcription and plays an important role in Th17 differentiation. The objective of this study was to investigate the expression of H3K27me3 in patients with AS and to explore its epigenetic regulation mechanism of Th17 differentiation during AS inflammation. We collected serum samples from 45 patients with AS at various stages and 10 healthy controls to measure their Interleukin-17 (IL-17) levels using ELISA. A quantitative polymerase chain reaction was used to quantify the mRNA levels of RORc and the signaling molecules of the JAK2/STAT3 pathway, JMJD3, and EZH2. Additionally, Western blot analysis was performed to quantify the protein levels of H3K27me3, RORγt, JAK2, STAT3, JMJD3, and EZH2 in cell protein extracts. The results showed that H3K27me3 expression in peripheral blood mononuclear cells (PBMCs) was significantly lower in patients with active AS compared to both the normal control groups and those with stable AS. Moreover, a significant negative correlation was observed between H3K27me3 expression and the characteristic transcription factor of Th17 differentiation, RORγt. We also discovered that patients with active AS exhibited significantly higher levels of JMJD3, an inhibitor of H3K27 demethylase, compared to the normal control group and patients with stable AS, while the expression of H3K27 methyltransferase (EZH2) was significantly lower. These findings suggest that H3K27me3 may be a dynamic and important epigenetic modification in AS inflammation, and JMJD3/EZH2 regulates the methylation level of H3K27me3, which may be one of the key regulatory factors in the pathogenesis of AS. These findings contribute to our understanding of the role of epigenetics in AS and may have implications for the development of novel therapeutic strategies for AS.
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Affiliation(s)
- Yuening Chen
- Department of Rheumatology, China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, 100053, China
| | - Wanlin Liu
- State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Beijing Proteome Research Center, Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xiaohan Xu
- Guang'anmen Hospital Jinan, China Academy of Chinese Medical Sciences, Jinan, 250012, China
| | - Hongying Zhen
- Department of Cell Biology, Basic Medical School, Peking University Health Science Center, Beijing, 100191, China
| | - Bo Pang
- Clinical Laboratory, China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, 100053, China
| | - Zhe Zhao
- Department of Rheumatology, China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, 100053, China
| | - Yanan Zhao
- Department of Rheumatology, China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, 100053, China
| | - Hongxiao Liu
- Department of Rheumatology, China Academy of Chinese Medical Sciences, Guang'anmen Hospital, Beijing, 100053, China.
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Dehnavi S, Sadeghi M, Tavakol Afshari J, Mohammadi M. Interactions of mesenchymal stromal/stem cells and immune cells following MSC-based therapeutic approaches in rheumatoid arthritis. Cell Immunol 2023; 393-394:104771. [PMID: 37783061 DOI: 10.1016/j.cellimm.2023.104771] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 09/21/2023] [Accepted: 09/21/2023] [Indexed: 10/04/2023]
Abstract
Rheumatoid arthritis (RA) is considered to be a degenerative and progressive autoimmune disorder. Although several medicinal regimens are used to treat RA, potential adverse events such as metabolic disorders and increased risk of infection, as well as drug resistance in some patients, make it essential to find an effective and safe therapeutic approach. Mesenchymal stromal/stem cells (MSCs) are a group of non-hematopoietic stromal cells with immunomodulatory and inhibitory potential. These cells exert their regulatory properties through direct cell-to-cell interactions and paracrine effects on various immune and non-immune cells. As conventional therapeutic approaches for RA are limited due to their side effects, and some patients became refractory to the treatment, MSCs are considered as a promising alternative treatment for RA. In this review, we introduced various experimental and clinical studies conducted to evaluate the therapeutic effects of MSCs on animal models of arthritis and RA patients. Then, possible modulatory and suppressive effects of MSCs on different innate and adaptive immune cells, including dendritic cells, neutrophils, macrophages, natural killer cells, B lymphocytes, and various subtypes of T cells, were categorized and summarized. Finally, limitations and future considerations for the efficient application of MSCs as a therapeutic approach in RA patients were presented.
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Affiliation(s)
- Sajad Dehnavi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahvash Sadeghi
- Department of Immunology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran; Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | | | - Mojgan Mohammadi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zolfaghari Baghbadorani P, Rayati Damavandi A, Moradi S, Ahmadi M, Bemani P, Aria H, Mottedayyen H, Rayati Damavandi A, Eskandari N, Fathi F. Current advances in stem cell therapy in the treatment of multiple sclerosis. Rev Neurosci 2023; 34:613-633. [PMID: 36496351 DOI: 10.1515/revneuro-2022-0102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 11/18/2022] [Indexed: 08/04/2023]
Abstract
Multiple sclerosis (MS) is an inflammatory disease related to the central nervous system (CNS) with a significant global burden. In this illness, the immune system plays an essential role in its pathophysiology and progression. The currently available treatments are not recognized as curable options and, at best, might slow the progression of MS injuries to the CNS. However, stem cell treatment has provided a new avenue for treating MS. Stem cells may enhance CNS healing and regulate immunological responses. Likewise, stem cells can come from various sources, including adipose, neuronal, bone marrow, and embryonic tissues. Choosing the optimal cell source for stem cell therapy is still a difficult verdict. A type of stem cell known as mesenchymal stem cells (MSCs) is obtainable from different sources and has a strong immunomodulatory impact on the immune system. According to mounting data, the umbilical cord and adipose tissue may serve as appropriate sources for the isolation of MSCs. Human amniotic epithelial cells (hAECs), as novel stem cell sources with immune-regulatory effects, regenerative properties, and decreased antigenicity, can also be thought of as a new upcoming contender for MS treatment. Overall, the administration of stem cells in different sets of animal and clinical trials has shown immunomodulatory and neuroprotective results. Therefore, this review aims to discuss the different types of stem cells by focusing on MSCs and their mechanisms, which can be used to treat and improve the outcomes of MS disease.
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Affiliation(s)
| | - Amirmasoud Rayati Damavandi
- Students' Scientific Research Center, Exceptional Talents Development Center, Tehran University of Medical Sciences, Keshavarz Blvrd, Vesal Shirazi St., Tehran 1417613151, Iran
| | - Samira Moradi
- School of Medicine, Hormozgan University of Medical Sciences Chamran Blvrd., Hormozgan 7919693116, Bandar Abbass, Iran
| | - Meysam Ahmadi
- School of Medicine, Shiraz University of Medical Sciences, Fars, Zand St., Shiraz 7134814336, Iran
| | - Peyman Bemani
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
| | - Hamid Aria
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fars, Ibn Sina Sq., Fasa 7461686688, Iran
| | - Hossein Mottedayyen
- Department of Immunology, School of Medicine, Kashan University of Medical Sciences, Ravandi Blvrd, Isfahan, Kashan 8715988141, Iran
| | - Amirhossein Rayati Damavandi
- Student's Research Committee, Pharmaceutical Sciences Branch, Islamic Azad University, Yakhchal St., Tehran 193951498, Iran
| | - Nahid Eskandari
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
| | - Farshid Fathi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Hezar Jerib St., Isfahan 8174673461, Iran
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Barzaghini B, Carelli S, Messa L, Rey F, Avanzini MA, Jacchetti E, Maghraby E, Berardo C, Zuccotti G, Raimondi MT, Cereda C, Calcaterra V, Pelizzo G. Bone Marrow Mesenchymal Stem Cells Expanded Inside the Nichoid Micro-Scaffold: a Focus on Anti-Inflammatory Response. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2023:1-12. [PMID: 37363698 PMCID: PMC10027280 DOI: 10.1007/s40883-023-00296-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 02/08/2023] [Accepted: 02/19/2023] [Indexed: 03/28/2023]
Abstract
Purpose Mesenchymal stem cells (MSCs) represent a promising source for stem cell therapies in numerous diseases, including pediatric respiratory system diseases. Characterized by low immunogenicity, high anti-inflammatory, and immunoregulatory features, MSCs demonstrated an excellent therapeutic profile in numerous in vitro and preclinical models. MSCs reside in a specialized physiologic microenvironment, characterized by a unique combination of biophysical, biochemical, and cellular properties. The exploitation of the 3D micro-scaffold Nichoid, which simulates the native niche, enhanced the anti-inflammatory potential of stem cells through mechanical stimulation only, overcoming the limitation of biochemical and xenogenic growth factors application. Materials and Methods In this work, we expanded pediatric bone marrow MSCs (BM-MSCs) inside the Nichoid and performed a complete cellular characterization with different approaches including viability assays, immunofluorescence analyses, RNA sequencing, and gene expression analysis. Results We demonstrated that BM-MSCs inside the scaffold remain in a stem cell quiescent state mimicking the condition of the in vivo environment. Moreover, the gene expression profile of these cells shows a significant up-regulation of genes involved in immune response when compared with the flat control. Conclusion The significant changes in the expression profile of anti-inflammatory genes could potentiate the therapeutic effect of BM-MSCs, encouraging the possible clinical translation for the treatment of pediatric congenital and acquired pulmonary disorders, including post-COVID lung manifestations. Lay Summary Regenerative medicine is the research field integrating medicine, biology, and biomedical engineering. In this context, stem cells, which are a fundamental cell source able to regenerate tissues and restore damage in the body, are the key component for a regenerative therapeutic approach. When expanded outside the body, stem cells tend to differentiate spontaneously and lose regenerative potential due to external stimuli. For this reason, we exploit the scaffold named Nichoid, which mimics the in vivo cell niche architecture. In this scaffold, mesenchymal stem cells "feel at home" due to the three-dimensional mechanical stimuli, and our findings could be considered as an innovative culture system for the in vitro expansion of stem cells for clinical translation. Future Perspective The increasing demand of safe and effective cell therapies projects our findings toward the possibility of improving cell therapies based on the use of BM-MSCs, particularly for their clinical translation in lung diseases. Graphical Abstract
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Affiliation(s)
- Bianca Barzaghini
- Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta,” Politecnico Di Milano, Milan, Italy
| | - Stephana Carelli
- Pediatric Research Center “Romeo Ed Enrica Invernizzi,” Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
| | - Letizia Messa
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
- Department of Electronic, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Federica Rey
- Pediatric Research Center “Romeo Ed Enrica Invernizzi,” Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
| | - Maria Antonietta Avanzini
- Immunology and Transplantation Laboratory, Cell Factory, Pediatric Hematology Oncology, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Emanuela Jacchetti
- Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta,” Politecnico Di Milano, Milan, Italy
| | - Erika Maghraby
- Pediatric Research Center “Romeo Ed Enrica Invernizzi,” Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Department of Biology and Biotechnology “L. Spallanzani”, University of Pavia, Pavia, Italy
| | - Clarissa Berardo
- Pediatric Research Center “Romeo Ed Enrica Invernizzi,” Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
| | - Gianvincenzo Zuccotti
- Pediatric Research Center “Romeo Ed Enrica Invernizzi,” Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy
- Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
| | - Manuela Teresa Raimondi
- Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta,” Politecnico Di Milano, Milan, Italy
| | - Cristina Cereda
- Center of Functional Genomics and Rare Diseases, Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
| | - Valeria Calcaterra
- Department of Pediatrics, Buzzi Children’s Hospital, Milan, Italy
- Department of Internal Medicine, University of Pavia, Pavia, Italy
| | - Gloria Pelizzo
- Pediatric Surgery Unit, Buzzi Children’s Hospital, Milan, Italy
- Department of Biomedical and Clinical Science, University of Milan, Milan, Italy
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Evaluation of the relationship between mesenchymal stem cells and immune system in vitro conditions. Mol Biol Rep 2023; 50:4347-4356. [PMID: 36935445 DOI: 10.1007/s11033-023-08374-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/03/2023] [Indexed: 03/21/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs), are a novel therapeutic option as the most common cell source, play an important role in the immunomodulation. In this study, it was aimed to determine the effect of MSCs on cytokines secreted by the immune system cells. METHODS Intracellular cytokine levels (Interleukin-4 (IL-4), Interferon-γ (IFN-γ), and Interleukin-17 (IL-17)) detected by flow cytometry before and after co-culture between peripheral blood mononuclear cells (PBMCs) and MCSs. At the same time, supernatant cytokine levels were measured using the ELISA. RESULTS In our study, MSCs were isolated from cord blood (CB) and Wharton's Jelly (WJ), and their surface markers (CD44 (100%), CD73 (99.6%), CD90 (100%), CD105 (88%)) shown by flow cytometry method. Both CB-MSCs and WJ-MSCs were used in co-culture MSC/PBMC ratios of 1/5 and 1/10, incubation times of 24 h and 72 h. In the present study, when we compared co-cultures of CB-MSC or WJ-MSC with PBMCs, intracellular levels of cytokines IFN-γ, IL-17 (pro-inflamatory) and IL-4 (anti-inflamatory) were increased, and supernatant levels were decreased significantly (p < 0.05). The level of transforming growth factor beta (TGF-β) (anti-inflamatory) was significantly decreased for both CB-MSC and WJ-MSC in supernatant (p < 0.05). CONCLUSIONS It was investigated pro-inflammatory and anti-inflammatory effects of CB-MSCs and WJ-MSCs on PBMCs with the obtained results. According to the results, MSCs demonstrated different immunologic effects after the incubation time and ratios. For further studies, it should be known between interaction of MSCs and immune system.
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Hoseinzadeh A, Rezaieyazdi Z, Afshari JT, Mahmoudi A, Heydari S, Moradi R, Esmaeili SA, Mahmoudi M. Modulation of Mesenchymal Stem Cells-Mediated Adaptive Immune Effectors' Repertoire in the Recovery of Systemic Lupus Erythematosus. Stem Cell Rev Rep 2023; 19:322-344. [PMID: 36272020 DOI: 10.1007/s12015-022-10452-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/10/2022] [Indexed: 02/07/2023]
Abstract
The breakdown of self-tolerance of the immune response can lead to autoimmune conditions in which chronic inflammation induces tissue damage. Systemic lupus erythematosus (SLE) is a debilitating multisystemic autoimmune disorder with a high prevalence in women of childbearing age; however, SLE incidence, prevalence, and severity are strongly influenced by ethnicity. Although the mystery of autoimmune diseases remains unsolved, disturbance in the proportion and function of B cell subsets has a major role in SLE's pathogenesis. Additionally, colocalizing hyperactive T helper cell subgroups within inflammatory niches are indispensable. Despite significant advances in standard treatments, nonspecific immunosuppression, the risk of serious infections, and resistance to conventional therapies in some cases have raised the urgent need for new treatment strategies. Without the need to suppress the immune system, mesenchymal stem cells (MSCs), as ''smart" immune modulators, are able to control cellular and humoral auto-aggression responses by participating in precursor cell development. In lupus, due to autologous MSCs disorder, the ability of allogenic engrafted MSCs in tissue regeneration and resetting immune homeostasis with the provision of a new immunocyte repertoire has been considered simultaneously. In Brief The bone marrow mesenchymal stem cells (BM-MSCs) lineage plays a critical role in maintaining the hematopoietic stem-cell microstructure and modulating immunocytes. The impairment of BM-MSCs and their niche partially contribute to the pathogenesis of SLE-like diseases. Allogenic MSC transplantation can reconstruct BM microstructure, possibly contributing to the recovery of immunocyte phenotype restoration of immune homeostasis. In terms of future prospects of MSCs, artificially gained by ex vivo isolation and culture adaptation, the wide variety of potential mediators and mechanisms might be linked to the promotion of the immunomodulatory function of MSCs.
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Affiliation(s)
- Akram Hoseinzadeh
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Zahra Rezaieyazdi
- Department of Rheumatology, Ghaem Hospital, Mashhad University of Medical Science, Mashhad, Iran.,Rheumatic Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jalil Tavakol Afshari
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Mahmoudi
- Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sahar Heydari
- Department of Physiology and Pharmacology, Faculty of Medicine, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | - Reza Moradi
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. .,Department of Immunology, Mashhad University of Medical Sciences, Azadi Square, Kalantari Blvd, Pardi's campusMashhad, Iran.
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10
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Liu G, Li X, Yang F, Qi J, Shang L, Zhang H, Li S, Xu F, Li L, Yu H, Li Y, Dong X, Song Q, Zhu F, Chen G, Cao C, Jiang L, Su J, Yang L, Xu X, Zhang Z, Zhao RC, Li B. C-Phycocyanin Ameliorates the Senescence of Mesenchymal Stem Cells through ZDHHC5-Mediated Autophagy via PI3K/AKT/mTOR Pathway. Aging Dis 2023:AD.2023.0121. [PMID: 37163424 PMCID: PMC10389819 DOI: 10.14336/ad.2023.0121] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 01/15/2023] [Indexed: 05/12/2023] Open
Abstract
The senescence of mesenchymal stem cells (MSCs) impairs their regenerative capacity to maintain tissue homeostasis. Numerous studies are focusing on the interventions and mechanisms to attenuate the senescence of MSCs. C-phycocyanin (C-PC) is reported to have multiple functions such as antitumor, antioxidation, anti-inflammation and anti-aging roles, but there is little research about the effects of C-PC on the senescence of MSCs. Here we investigated the roles and mechanism of C-PC on MSCs senescence. In vitro results showed that C-PC could reduce senescence, enhance proliferation, promote the adipogenic and osteogenic differentiation in senescent MSCs induced by oxidative stress. In vivo D-Galactose (D-Gal) induced rats aging models showed C-PC also increased the viability and differentiation of intrinsic senescent bone marrow derived MSCs (BMSCs). Furthermore, C-PC also decreased the levels of oxidative stress markers ROS or MDA, elevated the SOD activity, and increased the anti-inflammatory factors. Proteomic chip analysis showed that C-PC interacted with ZDHHC5, and their interaction was verified by pull down assay. Overexpression of ZDHHC5 aggravated the senescence of MSCs and greatly lessened the beneficial effects of C-PC on senescence. In addition, we found ZDHHC5 regulated autophagy by altering LC3, Beclin1 and PI3K/AKT/mTOR pathway. In summary, our data indicated that C-PC ameliorates the senescence of MSCs through zinc finger Asp-His-His-Cys (DHHC) domain-containing protein 5 (ZDHHC5) mediated autophagy via PI3K/AKT/mTOR pathway. The present study uncovered the key role of autophagy in MSCs senescence and PI3K/AKT/mTOR pathway may be a potential target for anti-senescence studies of MSCs.
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Affiliation(s)
- Guoxiang Liu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaoxia Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Fanghao Yang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Jingyu Qi
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lipeng Shang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Huhu Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Shuang Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Fenghua Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lingne Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Huaxin Yu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Yang Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaolei Dong
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Qinghang Song
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Feng Zhu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Guang Chen
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Can Cao
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Liangqian Jiang
- Department of Medical Genetics, Linyi People's Hospital, Linyi, China
| | - Junzhe Su
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Lina Yang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Xiaohui Xu
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Zhe Zhang
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
| | - Robert Chunhua Zhao
- College of Basic Medicine, Institute of Stem Cell and Regenerative Medicine, Qingdao University, Qingdao, China
- Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
- School of Life Sciences, Shanghai University, Shanghai, China
| | - Bing Li
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, China
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, China
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11
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Tang F, Zhou Z, Huang K, Deng W, Lin J, Chen R, Li M, Xu F. MicroRNAs in the regulation of Th17/Treg homeostasis and their potential role in uveitis. Front Genet 2022; 13:848985. [PMID: 36186459 PMCID: PMC9515448 DOI: 10.3389/fgene.2022.848985] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
Th17 and regulatory T cells (Tregs) play crucial roles in the pathogenesis of autoimmune diseases. Th17/Treg homeostasis is critically involved in maintaining the immune balance. Disturbed Th17/Treg homeostasis contributes to the progression of autoimmune diseases. MicroRNAs (miRNAs) have emerged as a new vital factor in the regulation of disturbed Th17/Treg homeostasis. To better understand the epigenetic mechanisms of miRNAs in regulating Treg/Th17 homeostasis, we included and evaluated 97 articles about autoimmune diseases and found that miRNAs were involved in the regulation of Treg/Th17 homeostasis from several aspects positively or negatively, including Treg differentiation and development, Treg induction, Treg stability, Th17 differentiation, and Treg function. Uveitis is one of the ocular autoimmune diseases, which is also characterized with Th17/Treg imbalance. However, our understanding of the miRNAs in the pathogenesis of uveitis is elusive and not well-studied. In this review, we further summarized miRNAs found to be involved in autoimmune uveitis and their potential role in the regulation of Th17/Treg homeostasis.
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Affiliation(s)
| | | | | | | | | | | | - Min Li
- *Correspondence: Fan Xu, ; Min Li,
| | - Fan Xu
- *Correspondence: Fan Xu, ; Min Li,
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12
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Naqvi RA, Datta M, Khan SH, Naqvi AR. Regulatory roles of MicroRNA in shaping T cell function, differentiation and polarization. Semin Cell Dev Biol 2022; 124:34-47. [PMID: 34446356 PMCID: PMC11661912 DOI: 10.1016/j.semcdb.2021.08.003] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 07/09/2021] [Accepted: 08/07/2021] [Indexed: 12/12/2022]
Abstract
T lymphocytes are an integral component of adaptive immunity with pleotropic effector functions. Impairment of T cell activity is implicated in various immune pathologies including autoimmune diseases, AIDS, carcinogenesis, and periodontitis. Evidently, T cell differentiation and function are under robust regulation by various endogenous factors that orchestrate underlying molecular pathways. MicroRNAs (miRNA) are a class of noncoding, regulatory RNAs that post-transcriptionally control multiple mRNA targets by sequence-specific interaction. In this article, we will review the recent progress in our understanding of miRNA-gene networks that are uniquely required by specific T cell effector functions and provide miRNA-mediated mechanisms that govern the fate of T cells. A subset of miRNAs may act in a synergistic or antagonistic manner to exert functional suppression of genes and regulate pathways that control T cell activation and differentiation. Significance of T cell-specific miRNAs and their dysregulation in immune-mediated diseases is discussed. Exosome-mediated horizontal transfer of miRNAs from antigen presenting cells (APCs) to T cells and from one T cell to another T cell subset and their impact on recipient cell functions is summarized.
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Affiliation(s)
- Raza Ali Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago 60612, IL, USA.
| | - Manali Datta
- Amity Institute of Biotechnology, Amity University Rajasthan, Jaipur, Rajasthan, India
| | - Samia Haseeb Khan
- Graduate School of Medicine, Science and Technology, Shinshu University, 8304 Minami-Minowa, Kami-Ina, Nagano 399-4598, Japan
| | - Afsar R Naqvi
- Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago 60612, IL, USA.
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13
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Chen T, Jiang Y, Xu S, Cheuk YC, Wang J, Yang C, Rong R. Poly(I:C)-Induced Mesenchymal Stem Cells Protect the Kidney Against Ischemia/Reperfusion Injury via the TLR3/PI3K Pathway. Front Med (Lausanne) 2021; 8:755849. [PMID: 34901066 PMCID: PMC8655722 DOI: 10.3389/fmed.2021.755849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/04/2021] [Indexed: 11/24/2022] Open
Abstract
Objective: To investigate the effect and protective mechanism of mesenchymal stem cell subpopulations on acute kidney injury by establishing a mouse model of renal ischemia-reperfusion injury. Methods: Male C57BL/6 mice were randomly divided into five groups, namely, sham-operation group and those treated with normal saline, untreated mesenchymal stem cells, mesenchymal stem cells treated with lipopolysaccharide (LPS, pro-inflammatory phenotype) and mesenchymal stem cells treated with polyinosinic-polycytidylic acid (poly[I:C], anti-inflammatory phenotype) respectively. The renal function, histopathological damage, circulating inflammation levels and antioxidant capacity of mice were evaluated. The PI3 kinase p85 (PI3K) inhibitor was added into the conventional mesenchymal stem cell cultures in vitro to observe its effects on the secretion of anti-inflammatory cytokines. Results: Mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) could effectively reduce serum creatinine and blood urea nitrogen, attenuate histopathological damage and apoptosis level, decrease the level of circulating pro-inflammatory cytokines and increase the level of circulating anti-inflammatory cytokines, enhance peroxidase activity and reduce malondialdehyde content at each time point. After the addition of the PI3K inhibitor, the mRNA expression and protein secretion of indoleamine 2,3-dioxygenase 1 and heme oxygenase 1 of various mesenchymal stem cells were significantly reduced, and that of mesenchymal stem cells treated with poly(I:C) (anti-inflammatory phenotype) was more obvious. Conclusions: Polyriboinosinic-polyribocytidylic acid (poly[I:C]), a synthetic double-stranded RNA, whose pretreatment induces mesenchymal stem cells to differentiate into the anti-inflammatory phenotype. Anti-inflammatory mesenchymal stem cells induced by poly(I:C) can better protect renal function, alleviate tissue damage, reduce circulating inflammation levels and enhance antioxidant capacity, and achieve stronger anti-inflammatory effects through the TLR3/PI3K pathway.
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Affiliation(s)
- Tian Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yamei Jiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Shihao Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiyan Wang
- Department of Urology, Shanghai Public Health Clinical Center, Shanghai, China
| | - Cheng Yang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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14
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Li R, Wang R, Zhong S, Asghar F, Li T, Zhu L, Zhu H. TGF-β1-overexpressing mesenchymal stem cells reciprocally regulate Th17/Treg cells by regulating the expression of IFN-γ. Open Life Sci 2021; 16:1193-1202. [PMID: 34761110 PMCID: PMC8565592 DOI: 10.1515/biol-2021-0118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/22/2021] [Accepted: 09/27/2021] [Indexed: 12/23/2022] Open
Abstract
Transforming growth factor (TGF)-β1 and mesenchymal stromal cells (MSCs) are two effective immunosuppressive agents for organ transplantation technology. This study aims to explore the molecular mechanism of TGF-β1-overexpressed MSCs on T cell immunosuppression. To achieve that, BM-MSCs were isolated from canine bone marrow, and their osteogenic differentiation and surface markers were detected. The TGF-β1 gene was transferred into lentivirus and modified MSCs (TGF-β1/MSCs) by lentivirus transfection. Furthermore, TGF-β1/MSCs were co-cultured with T cells to investigate their effect on differentiation and immune regulation. Results showed that TGF-β1/MSCs significantly downregulated the proportion of CD4+ CD8+ T cells in lymphocytes and significantly upregulated the proportion of CD4+ CD25+ T cells. Moreover, TGF-β1/MSCs significantly upregulated the expression of IL-10 in CD4+ T cells and downregulated the expression of IL-17A, IL-21, and IL-22. Meanwhile, interferon-γ (IFN-γ) neutralizing antibody blocked the effects of TGF-β1/MSCs on the differentiation inhibition of Th17. Overall, our results confirm the strong immunosuppressive effect of TGF-β1/MSCs in vitro and demonstrate that IFN-γ mediates the immunosuppressive effect of TGF-β1/MSC.
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Affiliation(s)
- Ruixue Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Renyong Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Shijie Zhong
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Farhan Asghar
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Tiehan Li
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Lei Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
| | - Hong Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650101, China
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15
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Mrahleh MA, Matar S, Jafar H, Wehaibi S, Aslam N, Awidi A. Human Wharton's Jelly-Derived Mesenchymal Stromal Cells Primed by Tumor Necrosis Factor-α and Interferon-γ Modulate the Innate and Adaptive Immune Cells of Type 1 Diabetic Patients. Front Immunol 2021; 12:732549. [PMID: 34650558 PMCID: PMC8506215 DOI: 10.3389/fimmu.2021.732549] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
The unique immunomodulation and immunosuppressive potential of Wharton’s jelly-derived mesenchymal stromal cells (WJ-MSCs) make them a promising therapeutic approach for autoimmune diseases including type 1 diabetes (T1D). The immunomodulatory effect of MSCs is exerted either by cell-cell contact or by secretome secretion. Cell-cell contact is a critical mechanism by which MSCs regulate immune-responses and generate immune regulatory cells such as tolerogenic dendritic cells (tolDCs) and regulatory T cell (Tregs). In this study, we primed WJ-MSCs with TNF-α and IFN-γ and investigated the immunomodulatory properties of primed WJ-MSCs on mature dendritic cells (mDCs) and activated T cells differentiated from mononuclear cells (MNCs) of T1D patient’s. Our findings revealed that primed WJ-MSCs impaired the antigen-mediated immunity, upregulated immune-tolerance genes and downregulated immune-response genes. We also found an increase in the production of anti-inflammatory cytokines and suppression of the production of pro-inflammatory cytokines. Significant upregulation of FOXP3, IL10 and TGFB1 augmented an immunosuppressive effect on adaptive T cell immunity which represented a strong evidence in support of the formation of Tregs. Furthermore, upregulation of many critical genes involved in the immune-tolerance mechanism (IDO1 and PTGES2/PTGS) was detected. Interestingly, upregulation of ENTPD1/NT5E genes express a strong evidence to switch immunostimulatory response toward immunoregulatory response. We conclude that WJ-MSCs primed by TNF-α and IFN-γ may represent a promising tool to treat the autoimmune disorders and can provide a new evidence to consider MSCs- based therapeutic approach for the treatment of TID.
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Affiliation(s)
| | - Suzan Matar
- Department of Clinical Laboratory Science, The University of Jordan, School of Science, Amman, Jordan
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Anatomy & Histology, The University of Jordan, School of Medicine, Amman, Jordan
| | - Suha Wehaibi
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman, Jordan
| | - Abdalla Awidi
- Cell Therapy Center, The University of Jordan, Amman, Jordan.,Department of Hematology & Oncology, The University of Jordan, School of Medicine, Amman, Jordan
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16
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Sobah ML, Liongue C, Ward AC. SOCS Proteins in Immunity, Inflammatory Diseases, and Immune-Related Cancer. Front Med (Lausanne) 2021; 8:727987. [PMID: 34604264 PMCID: PMC8481645 DOI: 10.3389/fmed.2021.727987] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 08/16/2021] [Indexed: 01/10/2023] Open
Abstract
Cytokine signaling represents one of the cornerstones of the immune system, mediating the complex responses required to facilitate appropriate immune cell development and function that supports robust immunity. It is crucial that these signals be tightly regulated, with dysregulation underpinning immune defects, including excessive inflammation, as well as contributing to various immune-related malignancies. A specialized family of proteins called suppressors of cytokine signaling (SOCS) participate in negative feedback regulation of cytokine signaling, ensuring it is appropriately restrained. The eight SOCS proteins identified regulate cytokine and other signaling pathways in unique ways. SOCS1–3 and CISH are most closely involved in the regulation of immune-related signaling, influencing processes such polarization of lymphocytes and the activation of myeloid cells by controlling signaling downstream of essential cytokines such as IL-4, IL-6, and IFN-γ. SOCS protein perturbation disrupts these processes resulting in the development of inflammatory and autoimmune conditions as well as malignancies. As a consequence, SOCS proteins are garnering increased interest as a unique avenue to treat these disorders.
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Affiliation(s)
| | - Clifford Liongue
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
| | - Alister C Ward
- School of Medicine, Deakin University, Geelong, VIC, Australia.,Institue of Mental and Physical Health and Clinical Translation, Deakin University, Geelong, VIC, Australia
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17
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ArefNezhad R, Motedayyen H, Mohammadi A. Therapeutic Aspects of Mesenchymal Stem Cell-Based Cell Therapy with a Focus on Human Amniotic Epithelial Cells in Multiple Sclerosis: A Mechanistic Review. Int J Stem Cells 2021; 14:241-251. [PMID: 34158417 PMCID: PMC8429946 DOI: 10.15283/ijsc21032] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/04/2021] [Accepted: 04/13/2021] [Indexed: 12/14/2022] Open
Abstract
Multiple sclerosis (MS) is an inflammatory disease of central nervous system (CNS). The mmune system plays an important role in its pathogenesis. Current treatments are unable to cure patients and prevent the progression of MS lesions. Stem cell-based cell therapy has opened a new window for MS treatment. Stem cells regulate immune responses and improve axonal remyelination. Stem cells can be obtained from different origins such as embryonic, neural, bone marrow, and adipose tissues. But yet there is a challenge for the selection of the best cell source for stem cell therapy. Mesenchymal stem cells (MSCs) are a type of stem cell obtained from different origins and have significant immunomodulatory effects on the immune system. The increasing evidence have suggested that umbilical cord and adipose tissue can be a suitable source for isolation of MSCs. Moreover, human amniotic epithelial cells (hAECs) as novel stem cell origins by having immunoregulatory effects, regenerative effects, and less capacity of antigenicity can be a candidate for MS treatment. This review discussed the mechanistic effects of MSCs with a focus on human amniotic epithelial cells, which can be used to treatment and improvement of outcome in MS disease.
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Affiliation(s)
- Reza ArefNezhad
- Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hossein Motedayyen
- Autoimmune Diseases Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | - Ali Mohammadi
- Cell Biology and Molecular-Genetics Department, Marand Azad University, Marand, Iran
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18
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Sun H, Wang Y, Wang Y, Ji F, Wang A, Yang M, He X, Li L. Bivalent Regulation and Related Mechanisms of H3K4/27/9me3 in Stem Cells. Stem Cell Rev Rep 2021; 18:165-178. [PMID: 34417934 DOI: 10.1007/s12015-021-10234-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/31/2021] [Indexed: 12/24/2022]
Abstract
The "bivalent domain" is a unique histone modification region consisting of two histone tri-methylation modifications. Over the years, it has been revealed that the maintenance and dynamic changes of the bivalent domains play a vital regulatory role in the differentiation of various stem cell systems, as well as in other cells, such as immunomodulation. Tri-methylation modifications involved in the formation of the bivalent domains are interrelated and mutually regulated, thus regulating many life processes of cells. Tri-methylation of histone H3 at lysine 4 (H3K4me3), tri-methylation of histone H3 at lysine 9 (H3K9me3) and tri-methylation of histone H3 at lysine 27 (H3K27me3) are the main tri-methylation modifications involved in the formation of bivalent domains. The three form different bivalent domains in pairs. Furthermore, it is equally clear that H3K4me3 is a positive regulator of transcription and that H3K9me3/H3K27me3 are negative regulators. Enzymes related to the regulation of histone methylation play a significant role in the "homeostasis" and "breaking homeostasis" of the bivalent domains. Bivalent domains regulate target genes, upstream transcription, downstream targeting regulation and related cytokines during the establishment and breakdown of homeostasis, and exert the specific regulation of stem cells. Indeed, a unified mechanism to explain the bivalent modification in all stem cells has been difficult to define, and whether the bivalent modification is antagonistic in inducing the differentiation of homologous stem cells is controversial. In this review, we focus on the different bivalent modifications in several key stem cells and explore the main mechanisms and effects of these modifications involved. Finally, we discussed the close relationship between bivalent domains and immune cells, and put forward the prospect of the application of bivalent domains in the field of stem cells.
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Affiliation(s)
- Han Sun
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Yin Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Ying Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Feng Ji
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - An Wang
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China
| | - Ming Yang
- Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
| | - Xu He
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
| | - Lisha Li
- The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China.
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19
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Luo Y, Guo J, Zhang P, Cheuk YC, Jiang Y, Wang J, Xu S, Rong R. Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis. Front Immunol 2021; 12:684197. [PMID: 34122446 PMCID: PMC8194268 DOI: 10.3389/fimmu.2021.684197] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 05/10/2021] [Indexed: 12/20/2022] Open
Abstract
The increase in T helper 17 cell (Th17)-mediated pro-inflammatory response and decrease in regulatory T cell (Treg)-mediated anti-inflammatory effect aggravate renal tubular epithelial cell (RTEC) injury. However, increasing evidence indicated that mesenchymal stem cell (MSC) possessed the ability to control the imbalance between Th17 and Treg. Given that Th17 and Treg are derived from a common CD4+ T cell precursor, we summarize the current knowledge of MSC-mediated inhibition of the mammalian target of rapamycin (mTOR), which is a master regulator of CD4+ T cell polarization. During CD4+ T cell differentiation, mTOR signaling mediates Th17 and Treg differentiation via hypoxia-inducible factor-1α (HIF-1α)-dependent metabolic regulation and signaling pathway, as well as mTOR-mediated phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5. Through interfering with mTOR signaling, MSC restrains CD4+ T cell differentiation into Th17, but in turn promotes Treg generation. Thus, this review indicates that MSC-mediated Th17-to-Treg polarization is expected to act as new immunotherapy for kidney injury.
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Affiliation(s)
- Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jingjing Guo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Pingbao Zhang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yamei Jiang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiyan Wang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Shihao Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
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20
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Guo K, Zhang X. Cytokines that Modulate the Differentiation of Th17 Cells in Autoimmune Uveitis. J Immunol Res 2021; 2021:6693542. [PMID: 33816637 PMCID: PMC7990547 DOI: 10.1155/2021/6693542] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 02/01/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence has suggested that T helper 17 (Th17) cells play a central role in the pathogenesis of ocular immune disease. The association between pathogenic Th17 cells and the development of uveitis has been confirmed in experimental and clinical studies. Several cytokines affect the initiation and stabilization of the differentiation of Th17 cells. Therefore, understanding the mechanism of related cytokines in the differentiation of Th17 cells is important for exploring the pathogenesis and the potential therapeutic targets of uveitis. This article briefly describes the structures, mechanisms, and targeted drugs of cytokines-including interleukin (IL)-6, transforming growth factor-β1 (TGF-β1), IL-1β, IL-23, IL-27, IL-35, IL-2, IL-4, IL-21, and interferon (IFN)-γ-which have an important influence on the differentiation of Th17 cells and discusses their potential as therapeutic targets for treating autoimmune uveitis.
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Affiliation(s)
- Kailei Guo
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
| | - Xiaomin Zhang
- Tianjin Key Laboratory of Retinal Functions and Diseases, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin 300384, China
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21
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22
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Sergeant E, Buysse M, Devos T, Sprangers B. Multipotent mesenchymal stromal cells in kidney transplant recipients: The next big thing? Blood Rev 2020; 45:100718. [PMID: 32507576 DOI: 10.1016/j.blre.2020.100718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 04/13/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
Abstract
Bone marrow-derived multipotent mesenchymal stromal cells (BM-MSCs) are non-haematopoietic cells present in the bone marrow stroma. They have the potential to modulate immune responses and exhibit a capacity to promote immune tolerance. Although the efficacy of immunosuppressive drugs has improved significantly, thereby ameliorating renal graft outcome, the use of these drugs still carries an increased risk of malignancies and opportunistic infections, and sometimes fail to prevent chronic allograft rejection or recurrence of the original kidney disease. As such, there is strong interest in ways to induce immune tolerance and thereby tempering or avoiding conventional immunosuppressive drugs. Cellular immunomodulation by MSCs can create a new way to induce transplant tolerance. This review will give a critical overview of the use of BM-MSCs as a cell-based immunosuppressive therapy in kidney transplant recipients. In vitro studies revealed several mechanisms that can clarify the immunomodulatory potential of BM-MSCs. Several clinical studies showed that BM-MSCs can modulate T-cell proliferation and can alter the ratio of T-cell subsets, favoring immune tolerance. However, this immunomodulation was often not associated with better clinical outcome during follow-up when compared to control groups. Some clinical studies found that BM-MSCs allow a reduction in dose of conventional immunosuppressive drugs and prevent acute graft dysfunction. Most clinical studies emphasized that BM-MSC infusion was safe. This review suggests that the use of BM-MSCs as cell-based immunosuppression therapy in kidney transplant recipients has potential, however some caution regarding their clinical use is appropriate. Mechanisms by which BM-MSCs induce transplant tolerance and factors that can alter their functionality need to be analyzed in more detail before clinical use.
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Affiliation(s)
- Elien Sergeant
- Division of Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
| | - Malicorne Buysse
- Division of Hematology, University Hospitals Ghent, Ghent, Belgium.
| | - Timothy Devos
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Hematology, University Hospitals Leuven, Leuven, Belgium.
| | - Ben Sprangers
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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23
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Cui SJ, Zhang T, Fu Y, Liu Y, Gan YH, Zhou YH, Yang RL, Wang XD. DPSCs Attenuate Experimental Progressive TMJ Arthritis by Inhibiting the STAT1 Pathway. J Dent Res 2020; 99:446-455. [PMID: 31977264 DOI: 10.1177/0022034520901710] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Severe inflammation, progressive cartilage, and bone destruction are typical pathologic changes in temporomandibular joint (TMJ) arthritis and lead to great difficulty for treatment. However, current therapy is inefficient to improve degenerative changes in progressive TMJ arthritis. This study investigated the therapeutic effects of human dental pulp stem cells (DPSCs) on severe inflammatory TMJ diseases. Progressive TMJ arthritis in rats was induced by intra-articular injection of complete Freund's adjuvant and monosodium iodoacetate. DPSCs were injected into the articular cavity to treat rat TMJ arthritis, with normal saline injection as control. Measurement of head withdrawal threshold, micro-computed tomography scanning, and histologic staining were applied to evaluate the severity of TMJ arthritis. Results showed that local injection of DPSCs in rats with TMJ arthritis relieved hyperalgesia and synovial inflammation, attenuated cartilage matrix degradation, and induced bone regeneration. Inflammatory factors TNF-α and IFN-γ were elevated in progressive TMJ arthritis and partially decreased by local injection of DPSCs. MMP3 and MMP13 were elevated in the arthritis + normal saline group and decreased in the arthritis + DPSCs group, which indicated amelioration of matrix degradation. The isolated primary synoviocytes were cocultured with DPSCs after inflammatory factors stimulated to explore the possible biological mechanisms. The expression of MMP3 and MMP13 in synoviocytes was elevated after TNF-α and IFN-γ stimulation and partially reversed by DPSC treatment in the in vitro study. The signal transducer and activator of transcription 1 (STAT1) was activated by inflammatory stimulation and suppressed by DPSC coculture. The upregulation of MMP3 and MMP13 triggered by inflammation was blocked by STAT1-specific inhibitor, suggesting that STAT1 regulated the expression of MMP3 and MMP13. In conclusion, this study demonstrated the possible therapeutic effects of local injection of DPSCs on progressive TMJ arthritis by inhibiting the expression of MMP3 and MMP13 through the STAT1 pathway.
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Affiliation(s)
- S J Cui
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - T Zhang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Y Fu
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
- Fourth Clinical Division, Peking University School and Hospital of Stomatology, Beijing, China
| | - Y Liu
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - Y H Gan
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
- Center for Temporomandibular Disorders and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
| | - Y H Zhou
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - R L Yang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
| | - X D Wang
- Department of Orthodontics, Peking University School and Hospital of Stomatology, Beijing, China
- National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing, China
- Beijing Key Laboratory of Digital Stomatology, Beijing, China
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24
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Wang K, Shi YJ, Song ZL, Wu B, Zhou CL, Liu W, Gao W. Regulatory effect of rat bone marrow mesenchymal stem cells on Treg/Th17 immune balance in vitro. Mol Med Rep 2020; 21:2123-2130. [PMID: 32186771 PMCID: PMC7115201 DOI: 10.3892/mmr.2020.11019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 02/20/2020] [Indexed: 12/29/2022] Open
Abstract
Bone marrow mesenchymal stem cells (BM-MSCs) regulate the balance between regulatory T cells (Tregs) and T helper 17 (Th17) cells. However, the role of different factors on BM-MSCs-mediated regulation of the Treg/Th17 balance is unknown. BM-MSCs and CD4+ T lymphocytes were co-cultured with various treatments. The ratio of Treg/Th17 cells was calculated and the expression of different cytokines was measured. BM-MSCs were found to have a proliferative effect on Th17 cells at a basal concentration and at a 2-fold increase in the number of BM-MSCs. However, when the number of BM-MSCs used was increased 4-fold, they had an inhibitory effect on the Th17 cells. The effect of BM-MSCs on Tregs was inhibited by the addition of tacrolimus but not rapamycin. The effect of BM-MSCs on Th17 cells was inhibited by rapamycin. Additionally, the effect of BM-MSCs on Tregs were inhibited by the addition of a transforming growth factor-β (TGF-β) blocker, whereas these TGF-β-blockers had no effect on Th17 cells. Addition of an interleukin (IL)-2 blocker reduced the proportion of Th17 cells when co-cultured with a high number of MSCs compared with the low concentration group and the proportion of Treg cells was significantly decreased when cells were treated with an IL-2 blocker compared with the control group. Together, these results showed the varying effects of MSCs on the ratio of Treg/Th17, its dependence on the number of MSCs and the effects of cytokines in inducing these changes in the balance.
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Affiliation(s)
- Kai Wang
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Yan-Jun Shi
- Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA 15224, USA
| | - Zhuo-Lun Song
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Bin Wu
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Chun-Lei Zhou
- Clinical Laboratory, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Liu
- Blood Transfusion Department, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Wei Gao
- Department of Transplant Surgery, Tianjin First Central Hospital, Tianjin 300192, P.R. China
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25
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Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif 2020; 53:e12712. [PMID: 31730279 PMCID: PMC6985662 DOI: 10.1111/cpr.12712] [Citation(s) in RCA: 382] [Impact Index Per Article: 76.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/11/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can be derived from various adult tissues with multipotent and self-renewal abilities. The characteristics of presenting no major ethical concerns, having low immunogenicity and possessing immune modulation functions make MSCs promising candidates for stem cell therapies. MSCs could promote inflammation when the immune system is underactivated and restrain inflammation when the immune system is overactivated to avoid self-overattack. These cells express many immune suppressors to switch them from a pro-inflammatory phenotype to an anti-inflammatory phenotype, resulting in immune effector cell suppression and immune suppressor cell activation. We would discuss the mechanisms governing the immune modulation function of these cells in this review, especially the immune-suppressive effects of MSCs.
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Affiliation(s)
- Wei Jiang
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
| | - Jianyong Xu
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
- Department of ImmunologyHealth Science CenterShenzhen UniversityShenzhenChina
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26
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de Castro LL, Lopes-Pacheco M, Weiss DJ, Cruz FF, Rocco PRM. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med (Berl) 2019; 97:605-618. [PMID: 30903229 DOI: 10.1007/s00109-019-01776-y] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 02/17/2019] [Accepted: 03/11/2019] [Indexed: 12/14/2022]
Abstract
Several studies have demonstrated the anti-inflammatory potential of mesenchymal stromal cells (MSCs) isolated from bone marrow, adipose tissue, placenta, and other sources. Nevertheless, MSCs may also induce immunosuppression when administered systemically or directly to injured environments, as shown in different preclinical disease models. MSCs express certain receptors, including toll-like receptors and the aryl-hydrocarbon receptor, that are activated by the surrounding environment, thus leading to modulation of their immunosuppressive activity. Once MSCs are activated, they can affect a wide range of immune cells (e.g., neutrophils, monocytes/macrophages, dendritic cells, natural killer cells, T and B lymphocytes), a phenomenon that has been correlated to secretion of several mediators (e.g., indolamine 2,3-dioxygenase, galectins, prostaglandin E2, nitric oxide, and damage- and pathogen-associated molecular patterns) and stimulation of certain signaling pathways (e.g., protein kinase R, signal transducer and activator of transcription-1, nuclear factor-κB). Additionally, MSC manipulation and culture conditions, as well as the number of passages, duration of cryopreservation, and O2 content available, can significantly affect the immunosuppressive properties of MSCs. This review sheds light on current knowledge regarding the mechanisms by which MSCs exert immunosuppressive effects both in vitro and in vivo, focusing on the receptors expressed by MSCs, the correlation between soluble factors secreted by MSCs and their immunosuppressive effects, and interactions between MSCs and immune cells.
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Affiliation(s)
- Ligia Lins de Castro
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Miquéias Lopes-Pacheco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Daniel Jay Weiss
- Department of Medicine, College of Medicine, University of Vermont, Burlington, VT, USA
| | - Fernanda Ferreira Cruz
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil
| | - Patricia Rieken Macêdo Rocco
- Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. .,National Institute of Science and Technology for Regenerative Medicine, Rio de Janeiro, Brazil.
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27
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Shi B, Qi J, Yao G, Feng R, Zhang Z, Wang D, Chen C, Tang X, Lu L, Chen W, Sun L. Mesenchymal stem cell transplantation ameliorates Sjögren's syndrome via suppressing IL-12 production by dendritic cells. Stem Cell Res Ther 2018; 9:308. [PMID: 30409219 PMCID: PMC6225717 DOI: 10.1186/s13287-018-1023-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 09/01/2018] [Accepted: 09/30/2018] [Indexed: 12/29/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have been demonstrated to be effective in treating autoimmune diseases including Sjögren’s syndrome (SS). We aim to compare the effects of MSC transplantation (MSCT) and the role of serum interleukin-12 (IL-12) in SS. Methods IL-12 levels were measured by ELISA. IL-12 mRNA transcripts in dendritic cells (DCs) were determined by RT-PCR. After co-culturing with MSCs, IL-12 mRNA transcripts in mouse and human DCs were detected. Non-obese diabetic (NOD) mice received MSCT, recombinant IL-12, or anti-IL-12 mAb treatment, respectively. Then, salivary flow rates, histopathology of salivary glands, and splenic lymphocyte subsets were examined in these mice. Results IL-12 levels in the serum were significantly increased in SS patients and positively correlated with the EULAR 2010 Sjögren’s syndrome disease activity index. DCs from SS patients produced more IL-12 than those from the control. Likewise, IL-12 treatment in NOD mice significantly decreased salivary flow rates and promoted lymphocyte infiltration in salivary glands. IL-12 antibodies downregulated Th1, Th17, and Tfh cell. MSCT enhanced salivary flow rates and decreased lymphocyte infiltrations in salivary glands of NOD mice. MSCT downregulated Th17 and Tfh cells but upregulated regulatory T cells. MSCT reduced IL-12 productions in both SS patients and mice. Conclusion Our results indicate that MSCs ameliorate SS possibly via suppressing IL-12 production in DCs and that IL-12 could be a potential therapeutic target of SS. Trial registration NTC00953485. Registered June 2009. Electronic supplementary material The online version of this article (10.1186/s13287-018-1023-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Bingyu Shi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Jingjing Qi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
| | - Ruihai Feng
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhuoya Zhang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Dandan Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Chen Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Liwei Lu
- Department of Pathology and Center of Infection and Immunology, University of Hong Kong, Hong Kong, China
| | - Wanjun Chen
- National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
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28
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Ding FM, Zhang XY, Chen YQ, Liao RM, Xie GG, Zhang PY, Shao P, Zhang M. Lentivirus-mediated overexpression of suppressor of cytokine signaling-3 reduces neutrophilic airway inflammation by suppressing T-helper 17 responses in mice with chronic Pseudomonas aeruginosa lung infections. Int J Mol Med 2018; 41:2193-2200. [PMID: 29393363 DOI: 10.3892/ijmm.2018.3417] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 01/08/2018] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to explore the effect of overexpressed suppressor of cytokine signaling‑3 (SOCS3) on T-helper (Th)17 cell responses and neutrophilic airway inflammation in mice with chronic Pseudomonas aeruginosa (PA) infections. SOCS3 expression was enhanced via the administration of tail vein injections of therapeutic lentivirus in mice with chronic PA lung infections. SOCS3 expression in the blood and lung tissue was assessed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. Total and differential cell numbers and myeloperoxidase levels in the bronchoalveolar lavage (BAL) fluid were assessed, as well as the number of bacterial colonies in the lungs. Histological analysis of lung tissue was performed using hematoxylin and eosin staining and phosphorylated‑signal transducer and activator of transcription‑3 (p‑STAT3) expression was measured by western blot analysis and immunohistochemistry. The expression of STAT3 mRNA and retinoid‑related orphan receptor (ROR)γt were measured by RT‑qPCR. The percentage of interleukin (IL)‑17+ cells among cluster of differentiation (CD)4+ cells was calculated using flow cytometry and levels of IL‑17A and IL‑6 were assessed by ELISA. The expression of SOCS3 was significantly increased in CD4+ T cells following lentivirus injection and the inflammation of neutrophilic airways was notably ameliorated. Enhanced SOCS3 expression was associated with a significant decrease in the expression of p‑STAT3 and RORγt in CD4+ T cells. Additionally, the percentage of IL‑17+ cells among CD4+ T cells and the IL‑17 contents in the BAL fluid were significantly decreased. Lentivirus‑mediated overexpression of SOCS3 was revealed to ameliorate neutrophilic airway inflammation by inhibiting pulmonary Th17 responses in mice with chronic PA lung infections.
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Affiliation(s)
- Feng-Ming Ding
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Xing-Yi Zhang
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Yu-Qing Chen
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Ruo-Min Liao
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Guo-Gang Xie
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Peng-Yu Zhang
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Ping Shao
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Min Zhang
- Department of Respiratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
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29
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Krajewska-Włodarczyk M, Owczarczyk-Saczonek A, Placek W, Osowski A, Engelgardt P, Wojtkiewicz J. Role of Stem Cells in Pathophysiology and Therapy of Spondyloarthropathies-New Therapeutic Possibilities? Int J Mol Sci 2017; 19:ijms19010080. [PMID: 29283375 PMCID: PMC5796030 DOI: 10.3390/ijms19010080] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 12/14/2022] Open
Abstract
Considerable progress has been made recently in understanding the complex pathogenesis and treatment of spondyloarthropathies (SpA). Currently, along with traditional disease modifying anti-rheumatic drugs (DMARDs), TNF-α, IL-12/23 and IL-17 are available for treatment of such diseases as ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Although they adequately control inflammatory symptoms, they do not affect the abnormal bone formation processes associated with SpA. However, the traditional therapeutic approach does not cover the regenerative treatment of damaged tissues. In this regards, stem cells may offer a promising, safe and effective therapeutic option. The aim of this paper is to present the role of mesenchymal stromal cells (MSC) in pathogenesis of SpA and to highlight the opportunities for using stem cells in regenerative processes and in the treatment of inflammatory changes in articular structures.
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Affiliation(s)
- Magdalena Krajewska-Włodarczyk
- Department of Rheumatology, Municipal Hospital in Olsztyn, 10-900 Olsztyn, Poland.
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Agnieszka Owczarczyk-Saczonek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Waldemar Placek
- Department of Dermatology, Sexually Transmitted Diseases and Clinical Immunology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Adam Osowski
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Piotr Engelgardt
- Department of Forensic Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
| | - Joanna Wojtkiewicz
- Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Laboratory for Regenerative Medicine, Faculty of Medicine, University of Warmia and Mazury, 10-900 Olsztyn, Poland.
- Foundation for Nerve Cell Regeneration, University of Warmia and Mazury in Olsztyn, 10-900 Olsztyn, Poland.
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30
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Wang M, Chen B, Sun XX, Zhao XD, Zhao YY, Sun L, Xu CG, Shen B, Su ZL, Xu WR, Zhu W. Gastric cancer tissue-derived mesenchymal stem cells impact peripheral blood mononuclear cells via disruption of Treg/Th17 balance to promote gastric cancer progression. Exp Cell Res 2017; 361:19-29. [PMID: 28964780 DOI: 10.1016/j.yexcr.2017.09.036] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 09/08/2017] [Accepted: 09/26/2017] [Indexed: 12/20/2022]
Abstract
Gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) are important resident stromal cells in the tumor microenvironment (TME) and have been shown to play a key role in gastric cancer progression. Whether GC-MSCs exert a tumor-promoting function by affecting anti-tumor immunity is still unclear. In this study, we used GC-MSC conditioned medium (GC-MSC-CM) to pretreat peripheral blood mononuclear cells (PBMCs) from healthy donors. We found that GC-MSC-CM pretreatment markedly reversed the inhibitory effect of PBMCs on gastric cancer growth in vivo, but did not affect functions of PBMCs on gastric cancer cell proliferation, cell cycle and apoptosis in vitro. PBMCs pretreated with GC-MSC-CM significantly promoted gastric cancer migration and epithelial-mesenchymal transition in vitro and liver metastases in vivo. Flow cytometry analysis showed that GC-MSC-CM pretreatment increased the proportion of Treg cells and reduced that of Th17 cells in PBMCs. CFSE labeling and naïve CD4+ T cells differentiation analysis revealed that GC-MSC-CM disrupted the Treg/Th17 balance in PBMCs by suppressing Th17 cell proliferation and inducing differentiation of Treg cells. Overall, our collective results indicate that GC-MSCs impair the anti-tumor immune response of PBMCs through disruption of Treg/Th17 balance, thus providing new evidence that gastric cancer tissue-derived MSCs contribute to the immunosuppressive TME.
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Affiliation(s)
- Mei Wang
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Bin Chen
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiao-Xian Sun
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xiang-Dong Zhao
- Zhenjiang Provincial Blood Center, Zhenjiang, Jiangsu, China
| | - Yuan-Yuan Zhao
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Li Sun
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Chang-Gen Xu
- Zhenjiang Provincial Blood Center, Zhenjiang, Jiangsu, China
| | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhao-Liang Su
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wen-Rong Xu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Wei Zhu
- School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China.
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31
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Contreras-Kallens P, Terraza C, Oyarce K, Gajardo T, Campos-Mora M, Barroilhet MT, Álvarez C, Fuentes R, Figueroa F, Khoury M, Pino-Lagos K. Mesenchymal stem cells and their immunosuppressive role in transplantation tolerance. Ann N Y Acad Sci 2017; 1417:35-56. [PMID: 28700815 DOI: 10.1111/nyas.13364] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/13/2017] [Accepted: 03/29/2017] [Indexed: 12/23/2022]
Abstract
Since they were first described, mesenchymal stem cells (MSCs) have been shown to have important effector mechanisms and the potential for use in cell therapy. A great deal of research has been focused on unveiling how MSCs contribute to anti-inflammatory responses, including describing several cell populations involved and identifying soluble and other effector molecules. In this review, we discuss some of the contemporary evidence for use of MSCs in the field of immune tolerance, with a special emphasis on transplantation. Although considerable effort has been devoted to understanding the biological function of MSCs, additional resources are required to clarify the mechanisms of their induction of immune tolerance, which will undoubtedly lead to improved clinical outcomes for MSC-based therapies.
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Affiliation(s)
- Pamina Contreras-Kallens
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Claudia Terraza
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Karina Oyarce
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Tania Gajardo
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Mauricio Campos-Mora
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - María Teresa Barroilhet
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Carla Álvarez
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Ricardo Fuentes
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Fernando Figueroa
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Maroun Khoury
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Cells for Cells, Santiago, Chile.,Consorcio Regenero, Chilean Consortium for Regenerative Medicine, Santiago, Chile
| | - Karina Pino-Lagos
- Centro de Investigación Biomédica, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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32
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Kitada S, Kayama H, Okuzaki D, Koga R, Kobayashi M, Arima Y, Kumanogoh A, Murakami M, Ikawa M, Takeda K. BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection. J Exp Med 2017; 214:1313-1331. [PMID: 28356392 PMCID: PMC5413328 DOI: 10.1084/jem.20161076] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 12/08/2016] [Accepted: 02/07/2017] [Indexed: 12/22/2022] Open
Abstract
Inappropriate IL-17 responses are implicated in chronic tissue inflammation. IL-23 contributes to Trypanosoma cruzi-specific IL-17 production, but the molecular mechanisms underlying regulation of the IL-23-IL-17 axis during T. cruzi infection are poorly understood. Here, we demonstrate a novel function of BATF2 as a negative regulator of Il23a in innate immune cells. IL-17, but not IFN-γ, was more highly produced by CD4+ T cells from spleens and livers of T. cruzi-infected Batf2-/- mice than by those of wild-type mice. In this context, Batf2-/- mice showed severe multiorgan pathology despite reduced parasite burden. T. cruzi-induced IL-23 production was increased in Batf2-/- innate immune cells. The T. cruzi-induced enhanced Th17 response was abrogated in Batf2-/-Il23a-/- mice. The interaction of BATF2 with c-JUN prevented c-JUN-ATF-2 complex formation, inhibiting Il23a expression. These results demonstrate that IFN-γ-inducible BATF2 in innate immune cells controls Th17-mediated immunopathology by suppressing IL-23 production during T. cruzi infection.
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Affiliation(s)
- Shoko Kitada
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.,Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Hisako Kayama
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.,Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
| | - Daisuke Okuzaki
- DNA-Chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ritsuko Koga
- Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Masao Kobayashi
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yasunobu Arima
- Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaaki Murakami
- Division of Molecular Neuroimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masahito Ikawa
- Department of Experimental Genome Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan
| | - Kiyoshi Takeda
- Department of Microbiology and Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan .,WPI Immunology Frontier Research Center, Osaka University, Suita, Osaka 565-0871, Japan.,Core Research for Evolutional Science and Technology, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
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33
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Qu X, Han J, Zhang Y, Wang Y, Zhou J, Fan H, Yao R. MiR-384 Regulates the Th17/Treg Ratio during Experimental Autoimmune Encephalomyelitis Pathogenesis. Front Cell Neurosci 2017; 11:88. [PMID: 28400721 PMCID: PMC5368215 DOI: 10.3389/fncel.2017.00088] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Accepted: 03/14/2017] [Indexed: 12/29/2022] Open
Abstract
Specific miRNAs are involved in the pathogenesis of multiple sclerosis (MS), during which IL-17-producing CD4+ T helper (Th17) cells accumulate in the central nervous system (CNS). In this study, we identified levels of miR-384 as significantly increased in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Over-expression of miR-384 in vivo led to severe EAE, characterized by exacerbated demyelination, and increased inflammatory cell infiltration of the spinal cord; inhibition of miR-384 reversed these changes. Both the percentage of Th17, and ratio of Th17/regulatory T (Treg), cells were elevated in miR-384-transfected EAE mice, which was consistent with the observed upregulation of expression of IL-17 and the Th17 lineage-specific transcription factor, RORγt. Importantly, transfer of miR-384 overexpressing naïve T cells from wild-type (WT) to Rag1-/- mice, which are deficient in functional autologous T and B cells, led to aggravated EAE pathogenesis, while an miR-384 inhibited group was protected from EAE. Moreover, miR-384 promoted differentiation of naïve T cells into Th17 cells in vitro. Furthermore, target prediction and dual luciferase reporter assays demonstrated that suppressor of cytokine signaling 3 (SOCS3), a gene encoding protein with an established role in Th17 differentiation, was a direct target of miR-384. Our results demonstrate an important role for miR-384 in regulation of the Th17/Treg ratio during the pathogenesis of EAE, indicating that this molecule may have potential as a biomarker and/or therapeutic target in MS.
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Affiliation(s)
- Xuebin Qu
- Department of Neurobiology, Xuzhou Medical University Xuzhou, China
| | - Jingjing Han
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University Xuzhou, China
| | - Ying Zhang
- Department of Neurobiology, Xuzhou Medical University Xuzhou, China
| | - Yuanyuan Wang
- Department of Neurobiology, Xuzhou Medical University Xuzhou, China
| | - Jun Zhou
- Department of Neurobiology, Xuzhou Medical University Xuzhou, China
| | - Hongbin Fan
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University Xuzhou, China
| | - Ruiqin Yao
- Department of Neurobiology, Xuzhou Medical University Xuzhou, China
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34
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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35
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Ji J, Wu Y, Meng Y, Zhang L, Feng G, Xia Y, Xue W, Zhao S, Gu Z, Shao X. JAK-STAT signaling mediates the senescence of bone marrow-mesenchymal stem cells from systemic lupus erythematosus patients. Acta Biochim Biophys Sin (Shanghai) 2017; 49:208-215. [PMID: 28177455 DOI: 10.1093/abbs/gmw134] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Indexed: 01/22/2023] Open
Abstract
Previous studies have revealed that bone marrow-mesenchymal stem cells (BM-MSCs) from systemic lupus erythematosus (SLE) patients exhibited early signs of senescence, which may participate in the development of SLE. However, the molecular mechanisms about this phenomenon have not been fully elucidated. In the current study, we aimed to investigate whether Janus kinase (JAK)-signaling transducers and activators of transcription (STAT) signaling mediated the senescence of BM-MSCs from SLE patients. Twelve female SLE patients and healthy subjects were enrolled in the study. All BM-MSCs were isolated by density gradient centrifugation. Western blot analysis was used to test the expression of JAK-STAT signaling molecules. We observed the activity of β-gal of cells, the changes of cytoskeletal structure by F-actin staining, and the distribution of cell cycle by flow cytometry. BM-MSCs from SLE patients showed prominent features of senescence, and abnormal activation of JAK-STAT signaling transduction, high level of phosphorylated JAK2, and STAT3. After stimulation of IFN-γ in normal MSCs, JAK-STAT signaling was activated. The cell volume and the number of senescence-associated β-galactosidase (SA-β-gal) positive in SLE BM-MSCs were increased. The organization of cytoskeleton was nearly disordered. The rate of cell proliferation was decreased. AG490, the inhibitor of JAK2, and knockdown of STAT3 in BM-MSCs, could significantly reverse the senescence. In summary, our study indicated that JAK-STAT signaling pathway may play a critical role in the senescence of SLE BM-MSCs.
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Affiliation(s)
- Juan Ji
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yeqing Wu
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200000, China
| | - Lijuan Zhang
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Guijuan Feng
- Department of Stomatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yunfei Xia
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Wenrong Xue
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Shuyang Zhao
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Zhifeng Gu
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Xiaoyi Shao
- Department of Immunology, Medical College, Nantong University, Nantong 226001, China
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36
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Sharma J, Bhar S, Devi CS. A review on interleukins: The key manipulators in rheumatoid arthritis. Mod Rheumatol 2017; 27:723-746. [DOI: 10.1080/14397595.2016.1266071] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jatin Sharma
- School of Biosciences and Technology, VIT University, Vellore, India
| | - Sutonuka Bhar
- School of Biosciences and Technology, VIT University, Vellore, India
| | - C. Subathra Devi
- School of Biosciences and Technology, VIT University, Vellore, India
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37
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Yang C, Zheng C, Lin H, Li J, Zhao K. Role of Suppressor of Cytokine Signaling 3 in the Immune Modulation of Mesenchymal Stromal Cells. Inflammation 2016; 39:257-268. [PMID: 26318865 DOI: 10.1007/s10753-015-0246-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The underlying mechanisms of mesenchymal stromal cells (MSCs) on immune modulation to treat allergic diseases remain unclear. Here, we showed that the suppressor of cytokine signaling 3 (SOCS3) is an important immune modulator expressed by MSCs, which is significantly increased by interferon-γ (IFN-γ). In addition, we observed that SOCS3 is a crucial mediator of the anti-proliferative and functional effects of MSCs on T cells and B cells. The immune modulation of MSCs through SOCS3 is mediated by cell-cell contacts. Moreover, SOCS3 could serve as an indicator to predict the potential immune modulatory of MSCs derived from different donors. Furthermore, treatment with anti-SOCS3 Ab significantly decreased ovalbumin-specific antibodies and neutrophil infiltration in ovalbumin-induced allergic rhinitis (AR) mice. Our results suggest that SOCS3 serves as an immune modulator interfering with T cells and B cells, and SOCS3 may act as a predictive marker for immune modulatory of MSCs.
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Affiliation(s)
- Chen Yang
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China.,Department of Otolaryngology, Ruijin Hospital, School of medicine, Shanghai Jiao Tong University, 197 Ruijiner Road, Huangpu District, Shanghai, 200025, China
| | - Chunquan Zheng
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China.
| | - Hai Lin
- Department of Otolaryngology, The Sixth People's Hospital, School of medicine, Shanghai Jiao tong University, 600 Yishan Road, Xuhui District, Shanghai, 200233, China
| | - Jing Li
- Department of Otolaryngology, First People's Hospital of Hangzhou City, Hangzhou, Zhejiang Province, 310006, China
| | - Keqing Zhao
- Department of Otolaryngology-Head and Neck Surgery, Eye Ear Nose and Throat Hospital, Fudan University, 83 Fenyang Road, Xuhui District, Shanghai, 200031, China
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38
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Bi L, Wu J, Ye A, Wu J, Yu K, Zhang S, Han Y. Increased Th17 cells and IL-17A exist in patients with B cell acute lymphoblastic leukemia and promote proliferation and resistance to daunorubicin through activation of Akt signaling. J Transl Med 2016; 14:132. [PMID: 27176825 PMCID: PMC4866013 DOI: 10.1186/s12967-016-0894-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune regulation is crucial for the pathogenesis of B-cell acute lymphoblastic leukemia (B-ALL). It has been reported that Th17 cells as a newly identified subset of CD4(+) T cells are involved in the pathogenesis of several hematological disorders. However, the role of Th17 cells in the pathophysiology of B-ALL is still unclear. METHODS The frequencies of T cells were determined by flow cytometry in the peripheral blood and bone marrow of 44 newly diagnosed B-ALL patients and 25 age-matched healthy donors. The cell viability and apoptosis were determined by CCK-8 assay and Annexin V staining, respectively. Western blot was applied to identify the level of Akt and Stat3 phosphorylation. RESULTS We assessed and observed a significantly increased frequency of Th17 cells and a drastically decreased frequency of Th1 cells in peripheral blood mononuclear cells and bone marrow mononuclear cells from newly diagnosed B-ALL patients compared with healthy donors. Furthermore, increased levels of Th17-related cytokines including IL-17, IL-21, IL-23, IL-1β, and IL-6 were presented in between blood and marrow in B-ALL patients. Both IL-17A and IL-21, two Th17-secreted cytokines, induced the proliferation of B-ALL cell line Nalm-6 and patient B-ALL cells isolated from B-ALL patients, herein either cytokine led to the phosphorylation of Akt and Stat3. Additionally, IL-17A promoted resistance to daunorubicin via activation of Akt signaling and the PI3K/Akt inhibitor LY294002 or perifosine almost completely rescued daunorubicin-induced cell death in B-ALL cells. CONCLUSIONS Our findings suggest that elevated Th17 cells secrete IL-17A by which promotes the proliferation and resistance to daunorubicin in B-ALL cells through activation of Akt signaling. Th17 cells may represent a novel target to improve B-ALL immunotherapy.
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Affiliation(s)
- Laixi Bi
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Junqing Wu
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Aifang Ye
- Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Jianbo Wu
- Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Kang Yu
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China
| | - Shenghui Zhang
- Department of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
| | - Yixiang Han
- Laboratory of Internal Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015, China.
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Mishra KK, Gupta S, Banerjee K. SOCS3 induces neurite differentiation and promotes neuronal cell survival. IUBMB Life 2016; 68:468-76. [PMID: 27118613 DOI: 10.1002/iub.1505] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 04/05/2016] [Indexed: 12/29/2022]
Abstract
Cytokines and growth factors play an important role in neuronal survival as well as cell death. The family of suppressors of cytokine signalling (SOCS) proteins, which includes SOCS1-7 and cytokine-induced suppressor (CIS), has been shown to act as negative regulators of cytokine-induced signalling. In this report, we highlight the role of SOCS3 in regulating neuronal differentiation and survival. We observed increased SOCS3 expression upon differentiation of PC12 cells as well as neural stem cells. SOCS3 overexpression upregulated differentiation of both neural stem cells and PC12 cells even in the absence of NGF, as evidenced by enhanced neurite outgrowth and upregulation of GAP43, marker associated with neurite outgrowth. siRNA-mediated silencing of SOCS3 confirmed the potential role of SOCS3 in neuritogenesis. We observed that, SOCS3-induced neurite differentiation was mediated via the PI3 kinase pathway. Another interesting observation was that SOCS3 overexpression promoted neuronal cell survival under H2 O2 -mediated stress indicating its fundamental role in cell survival. In conclusion, our results indicate that SOCS3 promotes differentiation and survival of neural cells and could be potentially useful in future therapy for treatment of neurodegenerative disorders. © 2016 IUBMB Life, 68(6):468-476, 2016.
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Affiliation(s)
- Kanchan Kumar Mishra
- Eukaryotic Gene Expression Lab National Institute of Immunology, New Delhi, India
| | - Sakshi Gupta
- Eukaryotic Gene Expression Lab National Institute of Immunology, New Delhi, India
| | - Kakoli Banerjee
- Eukaryotic Gene Expression Lab National Institute of Immunology, New Delhi, India
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40
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Rokunohe A, Matsuzaki Y, Rokunohe D, Sakuraba Y, Fukui T, Nakano H, Sawamura D. Immunosuppressive effect of adipose-derived stromal cells on imiquimod-induced psoriasis in mice. J Dermatol Sci 2016; 82:50-3. [DOI: 10.1016/j.jdermsci.2015.12.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 12/08/2015] [Accepted: 12/16/2015] [Indexed: 01/26/2023]
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Acerbi E, Viganò E, Poidinger M, Mortellaro A, Zelante T, Stella F. Continuous time Bayesian networks identify Prdm1 as a negative regulator of TH17 cell differentiation in humans. Sci Rep 2016; 6:23128. [PMID: 26976045 PMCID: PMC4791550 DOI: 10.1038/srep23128] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/29/2016] [Indexed: 02/05/2023] Open
Abstract
T helper 17 (TH17) cells represent a pivotal adaptive cell subset involved in multiple immune disorders in mammalian species. Deciphering the molecular interactions regulating TH17 cell differentiation is particularly critical for novel drug target discovery designed to control maladaptive inflammatory conditions. Using continuous time Bayesian networks over a time-course gene expression dataset, we inferred the global regulatory network controlling TH17 differentiation. From the network, we identified the Prdm1 gene encoding the B lymphocyte-induced maturation protein 1 as a crucial negative regulator of human TH17 cell differentiation. The results have been validated by perturbing Prdm1 expression on freshly isolated CD4(+) naïve T cells: reduction of Prdm1 expression leads to augmentation of IL-17 release. These data unravel a possible novel target to control TH17 polarization in inflammatory disorders. Furthermore, this study represents the first in vitro validation of continuous time Bayesian networks as gene network reconstruction method and as hypothesis generation tool for wet-lab biological experiments.
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Affiliation(s)
- Enzo Acerbi
- Singapore Centre on Environmental Life Sciences Engineering (Nanyang Technological University), Singapore 637551
- Singapore Immunology Network (SIgN), ASTAR, 8A Biomedical Grove, Immunos #04-06, Singapore 138648
| | - Elena Viganò
- Singapore Immunology Network (SIgN), ASTAR, 8A Biomedical Grove, Immunos #04-06, Singapore 138648
| | - Michael Poidinger
- Singapore Immunology Network (SIgN), ASTAR, 8A Biomedical Grove, Immunos #04-06, Singapore 138648
| | - Alessandra Mortellaro
- Singapore Immunology Network (SIgN), ASTAR, 8A Biomedical Grove, Immunos #04-06, Singapore 138648
| | - Teresa Zelante
- Singapore Immunology Network (SIgN), ASTAR, 8A Biomedical Grove, Immunos #04-06, Singapore 138648
- Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy
| | - Fabio Stella
- Department of Informatics, Systems and Communication, University of Milano-Bicocca, Viale Sarca 336, Building U14, 20126 Milan, Italy
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Kol A, Walker NJ, Nordstrom M, Borjesson DL. Th17 Pathway As a Target for Multipotent Stromal Cell Therapy in Dogs: Implications for Translational Research. PLoS One 2016; 11:e0148568. [PMID: 26872054 PMCID: PMC4752288 DOI: 10.1371/journal.pone.0148568] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 11/11/2015] [Indexed: 01/13/2023] Open
Abstract
Detrimental Th17 driven inflammatory and autoimmune disease such as Crohn's disease, graft versus host disease and multiple sclerosis remain a significant cause of morbidity and mortality worldwide. Multipotent stromal/stem cell (MSC) inhibit Th17 polarization and activation in vitro and in rodent models. As such, MSC based therapeutic approaches are being investigated as novel therapeutic approaches to treat Th17 driven diseases in humans. The significance of naturally occurring diseases in dogs is increasingly recognized as a realistic platform to conduct pre-clinical testing of novel therapeutics. Full characterization of Th17 cells in dogs has not been completed. We have developed and validated a flow-cytometric method to detect Th17 cells in canine blood. We further demonstrate that Th17 and other IL17 producing cells are present in tissues of dogs with naturally occurring chronic inflammatory diseases. Finally, we have determined the kinetics of a canine specific Th17 polarization in vitro and demonstrate that canine MSC inhibit Th17 polarization in vitro, in a PGE2 independent mechanism. Our findings provide fundamental research tools and suggest that naturally occurring diseases in dogs, such as inflammatory bowel disease, may be harnessed to translate novel MSC based therapeutic strategies that target the Th17 pathway.
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MESH Headings
- Animals
- Cell Differentiation/immunology
- Cell- and Tissue-Based Therapy/methods
- Dermatitis/immunology
- Dermatitis/pathology
- Dermatitis/therapy
- Dermatitis/veterinary
- Dog Diseases/immunology
- Dog Diseases/metabolism
- Dog Diseases/pathology
- Dog Diseases/therapy
- Dogs
- Gene Expression Regulation
- Gingivitis/immunology
- Gingivitis/pathology
- Gingivitis/therapy
- Gingivitis/veterinary
- Humans
- Immunophenotyping
- Inflammation
- Inflammatory Bowel Diseases/immunology
- Inflammatory Bowel Diseases/pathology
- Inflammatory Bowel Diseases/therapy
- Inflammatory Bowel Diseases/veterinary
- Interleukin-17/genetics
- Interleukin-17/immunology
- Meningoencephalitis/immunology
- Meningoencephalitis/pathology
- Meningoencephalitis/therapy
- Meningoencephalitis/veterinary
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/immunology
- Nuclear Receptor Subfamily 1, Group F, Member 1/genetics
- Nuclear Receptor Subfamily 1, Group F, Member 1/immunology
- Primary Cell Culture
- Receptors, CCR6/genetics
- Receptors, CCR6/immunology
- Receptors, Interleukin/genetics
- Receptors, Interleukin/immunology
- T-Lymphocytes, Regulatory/cytology
- T-Lymphocytes, Regulatory/immunology
- Th17 Cells/cytology
- Th17 Cells/immunology
- Translational Research, Biomedical/methods
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Affiliation(s)
- A. Kol
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, 95616, United States of America
| | - N. J. Walker
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, 95616, United States of America
| | - M. Nordstrom
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, 95616, United States of America
| | - D. L. Borjesson
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, California, 95616, United States of America
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43
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Ren S, Hu J, Chen Y, Yuan T, Hu H, Li S. Human umbilical cord derived mesenchymal stem cells promote interleukin-17 production from human peripheral blood mononuclear cells of healthy donors and systemic lupus erythematosus patients. Clin Exp Immunol 2015; 183:389-96. [PMID: 26507122 DOI: 10.1111/cei.12737] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2015] [Indexed: 01/14/2023] Open
Abstract
Inflammation instigated by interleukin (IL)-17-producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL-17-producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL-17 were produced when CD4(+) T cells from healthy donors were co-cultured with hUC-MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2 ) and IL-1β, without IL-23 involvement. We then co-cultured hUC-MSCs with human CD4(+) T cells from systemic lupus erythematosus patients. Ex-vivo inductions of IL-17 by hUC-MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL-23. Taken together, our results represent that hUC-MSCs can promote the IL-17 production from CD4(+) T cells in both healthy donor and SLE patients. PGE2 and IL-1β might also be partially involved in the promotive effect of hUC-MSCs.
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Affiliation(s)
- S Ren
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - J Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - Y Chen
- Department of Hepatobiliary Surgery, General Hospital of Beijing Military Area Command, Beijing, China
| | - T Yuan
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - H Hu
- Department of Hematology, National Center for Clinical Laboratories and Beijing Hospital, Beijing, China
| | - S Li
- Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, Beijing, China
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44
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Mesenchymal stem cells and induced pluripotent stem cells as therapies for multiple sclerosis. Int J Mol Sci 2015; 16:9283-302. [PMID: 25918935 PMCID: PMC4463588 DOI: 10.3390/ijms16059283] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 04/20/2015] [Accepted: 04/20/2015] [Indexed: 02/07/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic, autoimmune, inflammatory demyelinating disorder of the central nervous system that leads to permanent neurological deficits. Current MS treatment regimens are insufficient to treat the irreversible neurological disabilities. Tremendous progress in the experimental and clinical applications of cell-based therapies has recognized stem cells as potential candidates for regenerative therapy for many neurodegenerative disorders including MS. Mesenchymal stem cells (MSC) and induced pluripotent stem cell (iPSCs) derived precursor cells can modulate the autoimmune response in the central nervous system (CNS) and promote endogenous remyelination and repair process in animal models. This review highlights studies involving the immunomodulatory and regenerative effects of mesenchymal stem cells and iPSCs derived cells in animal models, and their translation into immunomodulatory and neuroregenerative treatment strategies for MS.
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