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Li L, He Y, Zhao J, Yin H, Feng X, Fan X, Wu W, Lu Q. Mesenchymal Stromal Cell-Based Therapy: A Promising Approach for Autoimmune Diseases. Clin Rev Allergy Immunol 2025; 68:21. [PMID: 39982546 DOI: 10.1007/s12016-025-09030-9] [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] [Accepted: 02/04/2025] [Indexed: 02/22/2025]
Abstract
Autoimmune diseases are characterized by immune dysregulation, resulting in aberrant reactivity of T cells and antibodies to self-antigens, leading to various patterns of inflammation and organ dysfunction. However, current therapeutic agents exhibit broad-spectrum activity and lack disease-specific selectivity, leading to enduring adverse effects, notably severe infections, and malignancies, and patients often fail to achieve the intended clinical goals. Mesenchymal stromal cells (MSCs) are multipotent stromal cells that can be easily derived from various tissues, such as adipose tissue, umbilical cords, Wharton's jelly, placenta, and dental tissues. MSCs offer advantages due to their immunomodulatory and anti-inflammatory abilities, low immunogenicity, and a high capacity for proliferation and multipotent differentiation, making them excellent candidates for cell-based treatment in autoimmune disorders. This review will cover preclinical studies and clinical trials involving MSCs in autoimmune diseases, as well as the primary challenges associated with the clinical application of MSC therapies and strategies for maximizing their therapeutic potential.
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Affiliation(s)
- Liming Li
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Yong He
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Junpeng Zhao
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
- Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, China
| | - Huiqi Yin
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xiwei Feng
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Xinyu Fan
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Wei Wu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China
| | - Qianjin Lu
- Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
- Key Laboratory of Basic and Translational Research On Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
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武 志, 胡 明, 赵 巧, 吕 凤, 张 晶, 张 伟, 王 永, 孙 晓, 王 慧. [Immunomodulatory mechanism of umbilical cord mesenchymal stem cells modified by miR-125b-5p in systemic lupus erythematosus]. BEIJING DA XUE XUE BAO. YI XUE BAN = JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2024; 56:860-867. [PMID: 39397466 PMCID: PMC11480562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Indexed: 10/15/2024]
Abstract
OBJECTIVE To investigate the mechanism of immunomodulatory effects of umbilical cord mesenchymal stem cells (UC-MSCs) modified by miR-125b-5p on systemic lupus erythematosus (SLE). METHODS The expression level of miR-125b-5p was detected by real-time fluorescence quantitative PCR in UC-MSCs and peripheral blood mononuclear cells (PBMCs) from SLE patients and health checkers. Annexin V-FITC/PI apoptosis detection kit was used to detect the effect of miR-125b-5p on apoptosis of UC-MSCs. MRL/lpr mice in each group were injected with UC-MSCs via tail vein, and T-lymphocyte subsets in the spleen of the MRL/lpr mice were detected by flow cytometry after 5 weeks. The expression levels of interleukin (IL)-4 and IL-17A in serum of MRL/lpr mice were detected by ELISA. Hematoxylin-eosin staining was used to observe the pathological manifestations of the lungs and kidneys of the MRL/lpr mice. RESULTS miR-125b-5p was significantly down-regulated in PBMCs of SLE patients compared with healthy controls (P < 0.01). Compared with the UC-MSCs group, the expression of miR- 125b-5p in UC-MSCs modified by miR-125b-5p group was increased (P < 0.01). The survival rate of UC-MSCs was significantly increased by miR-125b-5p (P < 0.01). Compared with the untreated group of MRL/lpr mice, the expression level of IL-4 in serum was increased (P < 0.05); the expression level of IL-17A was decreased (P < 0.05); the proportion of Th17 cells in the spleen of MRL/lpr mice was decreased (P < 0.05); the inflammatory cells infiltration and micro-thrombosis of lungs and kidneys of MRL/lpr mice were significantly reduced in the UC-MSCs modified by miR-125b-5p treatment group. CONCLUSION UC-MSCs modified by miR-125b-5p have immunomodulatory effects on systemic lupus erythematosus.
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Affiliation(s)
- 志慧 武
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 明智 胡
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 巧英 赵
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 凤凤 吕
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 晶莹 张
- 包头医学院第一附属医院风湿免疫科，内蒙古自治区包头 014010Department of Rheumatism and Immunology, First Affiliated Hospital of Baotou Medical College, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 伟 张
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 永福 王
- 包头医学院第一附属医院风湿免疫科，内蒙古自治区包头 014010Department of Rheumatism and Immunology, First Affiliated Hospital of Baotou Medical College, Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 晓林 孙
- 包头医学院第一附属医院中心实验室(内蒙古自治区自体免疫学重点实验室)，内蒙古自治区包头 014010Central Laboratory, First Affiliated Hospital of Baotou Medical College (Inner Mongolia Key Laboratory of Autoimmunology), Baotou 014010, Inner Mongolia Autonomous Region, China
| | - 慧 王
- 包头医学院第一附属医院风湿免疫科，内蒙古自治区包头 014010Department of Rheumatism and Immunology, First Affiliated Hospital of Baotou Medical College, Baotou 014010, Inner Mongolia Autonomous Region, China
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Poblano-Pérez LI, Monroy-García A, Fragoso-González G, Mora-García MDL, Castell-Rodríguez A, Mayani H, Álvarez-Pérez MA, Pérez-Tapia SM, Macías-Palacios Z, Vallejo-Castillo L, Montesinos JJ. Mesenchymal Stem/Stromal Cells Derived from Dental Tissues Mediate the Immunoregulation of T Cells through the Purinergic Pathway. Int J Mol Sci 2024; 25:9578. [PMID: 39273524 PMCID: PMC11395442 DOI: 10.3390/ijms25179578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Revised: 08/26/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Human dental tissue mesenchymal stem cells (DT-MSCs) constitute an attractive alternative to bone marrow-derived mesenchymal stem cells (BM-MSCs) for potential clinical applications because of their accessibility and anti-inflammatory capacity. We previously demonstrated that DT-MSCs from dental pulp (DP-MSCs), periodontal ligaments (PDL-MSCs), and gingival tissue (G-MSCs) show immunosuppressive effects similar to those of BM, but to date, the DT-MSC-mediated immunoregulation of T lymphocytes through the purinergic pathway remains unknown. In the present study, we compared DP-MSCs, PDL-MSCs, and G-MSCs in terms of CD26, CD39, and CD73 expression; their ability to generate adenosine (ADO) from ATP and AMP; and whether the concentrations of ADO that they generate induce an immunomodulatory effect on T lymphocytes. BM-MSCs were included as the gold standard. Our results show that DT-MSCs present similar characteristics among the different sources analyzed in terms of the properties evaluated; however, interestingly, they express more CD39 than BM-MSCs; therefore, they generate more ADO from ATP. In contrast to those produced by BM-MSCs, the concentrations of ADO produced by DT-MSCs from ATP inhibited the proliferation of CD3+ T cells and promoted the generation of CD4+CD25+FoxP3+CD39+CD73+ Tregs and Th17+CD39+ lymphocytes. Our data suggest that DT-MSCs utilize the adenosinergic pathway as an immunomodulatory mechanism and that this mechanism is more efficient than that of BM-MSCs.
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Affiliation(s)
- Luis Ignacio Poblano-Pérez
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
- Programa de Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Alberto Monroy-García
- Immunology and Cancer Laboratory, Oncology Research Unit, Oncology Hospital, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Gladis Fragoso-González
- Institute of Biomedical Research, Department of Immunology, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - María de Lourdes Mora-García
- Immunobiology Laboratory, Cell Differentiation and Cancer Unit, Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México, Mexico City 09230, Mexico
| | - Andrés Castell-Rodríguez
- Department of Cellular and Tissue Biology, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Héctor Mayani
- Hematopoietic Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Marco Antonio Álvarez-Pérez
- Tissue Bioengineering Laboratory, Postgraduate Studies, Research Division, Faculty of Dentistry, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Sonia Mayra Pérez-Tapia
- Research and Development in Biotherapeutic Unit (UDIBI), National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City 11340, Mexico
- National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products (LANSEIDI-FarBiotec-CONACyT), Instituto Politécnico Nacional, Mexico City 11340, Mexico
- Department of Immunology, National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Zaira Macías-Palacios
- Research and Development in Biotherapeutic Unit (UDIBI), National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City 11340, Mexico
- National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products (LANSEIDI-FarBiotec-CONACyT), Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Luis Vallejo-Castillo
- Research and Development in Biotherapeutic Unit (UDIBI), National School of Biological Sciences, Instituto Politécnico Nacional, Mexico City 11340, Mexico
- National Laboratory for Specialized Services of Investigation, Development and Innovation (I+D+i) for Pharma Chemicals and Biotechnological Products (LANSEIDI-FarBiotec-CONACyT), Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Juan José Montesinos
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, Centro Médico Nacional SXXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
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García-Arévalo F, Leija-Montoya AG, González-Ramírez J, Isiordia-Espinoza M, Serafín-Higuera I, Fuchen-Ramos DM, Vazquez-Jimenez JG, Serafín-Higuera N. Modulation of myeloid-derived suppressor cell functions by oral inflammatory diseases and important oral pathogens. Front Immunol 2024; 15:1349067. [PMID: 38495880 PMCID: PMC10940359 DOI: 10.3389/fimmu.2024.1349067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/21/2024] [Indexed: 03/19/2024] Open
Abstract
The oral cavity presents a diverse microbiota in a dynamic balance with the host. Disruption of the microbial community can promote dysregulation of local immune response which could generate oral diseases. Additionally, alterations in host immune system can result in inflammatory disorders. Different microorganisms have been associated with establishment and progression of the oral diseases. Oral cavity pathogens/diseases can modulate components of the inflammatory response. Myeloid-derived suppressor cells (MDSCs) own immunoregulatory functions and have been involved in different inflammatory conditions such as infectious processes, autoimmune diseases, and cancer. The aim of this review is to provide a comprehensive overview of generation, phenotypes, and biological functions of the MDSCs in oral inflammatory diseases. Also, it is addressed the biological aspects of MDSCs in presence of major oral pathogens. MDSCs have been mainly analyzed in periodontal disease and Sjögren's syndrome and could be involved in the outcome of these diseases. Studies including the participation of MDSCs in other important oral diseases are very scarce. Major oral bacterial and fungal pathogens can modulate expansion, subpopulations, recruitment, metabolism, immunosuppressive activity and osteoclastogenic potential of MDSCs. Moreover, MDSC plasticity is exhibited in presence of oral inflammatory diseases/oral pathogens and appears to be relevant in the disease progression and potentially useful in the searching of possible treatments. Further analyses of MDSCs in oral cavity context could allow to understand the contribution of these cells in the fine-tuned balance between host immune system and microorganism of the oral biofilm, as well as their involvement in the development of oral diseases when this balance is altered.
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Affiliation(s)
- Fernando García-Arévalo
- Laboratorio de Biología Celular, Centro de Ciencias de la Salud Mexicali, Facultad de Odontología Mexicali, Universidad Autónoma de Baja California, Mexicali, BC, Mexico
| | | | - Javier González-Ramírez
- Laboratorio de Biología Molecular, Centro de Ciencias de la Salud Mexicali, Facultad de Enfermería Mexicali, Universidad Autónoma de Baja California, Mexicali, BC, Mexico
| | - Mario Isiordia-Espinoza
- Instituto de Investigación en Ciencias Médicas, Departamento de Clínicas, División de Ciencias Biomédicas, Centro Universitario de los Altos, Universidad de Guadalajara, Tepatitlán de Morelos, Jal, Mexico
| | - Idanya Serafín-Higuera
- Laboratorio de Microbiología, Facultad de Medicina, Universidad Autónoma de Baja California, Tijuana, BC, Mexico
| | - Dulce Martha Fuchen-Ramos
- Laboratorio de Biología Celular, Centro de Ciencias de la Salud Mexicali, Facultad de Odontología Mexicali, Universidad Autónoma de Baja California, Mexicali, BC, Mexico
| | | | - Nicolas Serafín-Higuera
- Laboratorio de Biología Celular, Centro de Ciencias de la Salud Mexicali, Facultad de Odontología Mexicali, Universidad Autónoma de Baja California, Mexicali, BC, Mexico
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Lv J, Ma S, Wang X, Dang J, Ma F. PSMD12 promotes non-small cell lung cancer progression through activating the Nrf2/TrxR1 pathway. Genes Genomics 2024; 46:263-277. [PMID: 38243044 DOI: 10.1007/s13258-023-01484-5] [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: 08/31/2023] [Accepted: 12/19/2023] [Indexed: 01/21/2024]
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) contributes to the vast majority of cancer-related deaths. Proteasome 26S subunit, non-ATPase 12 (PSMD12), a subunit of 26S proteasome complex, is known to play the tumor-promoting role in several types of cancer but its function in NSCLC remains elusive. OBJECTIVE To explore the role and underlying mechanisms of PSMD12 in NSCLC. METHODS The PSMD12 expression in human normal lung epithelial cell line (BEAS-2B) and four NSCLC cell lines (A549, NCI-H1299, NCI-H1975, Calu-1) were determined by qRT-PCR and western blot. Malignant phenotypes of NSCLC cells were detected by CCK-8, EdU staining, immunofluorescence staining for E-cadherin, flow cytometry, and Transwell assays to assess cell viability, proliferation, epithelial-mesenchymal transition (EMT), apoptosis, migration and invasion. Dual luciferase assay was used to verify the regulatory role of transcription factor on the promoter. RESULTS We identified the upregulation of PSMD12 in NSCLC tissues based on the GEO datasets, which further verified in NSCLC and BEAS-2B cell lines. PSMD12 knockdown significantly suppressed malignant behaviors of NSCLC cells, including cell growth, invasion, and migration, while PSMD12 overexpression presented the opposite effects. Interestingly, we found that PSMD12 upregulated the tumor-promoting factor TrxR1 mRNA expression. For its potential mechanisms, we demonstrated that PSMD12 elevated transcription factor Nrf2 protein level and promoted Nrf2 nuclear translocation. And Nrf2 further increased TrxR1 promoter activity and enhanced TrxR1 transcription. Meanwhile, we proved that TrxR1 overexpression erased the inhibitory effect of PSMD12 knockdown. CONCLUSION PSMD12 promotes NSCLC progression by activating the Nrf2/TrxR1 pathway, providing a novel prognostic and therapeutic target for NSCLC treatment.
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Affiliation(s)
- Junqi Lv
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301, Zhengyuan North Street, Yinchuan, Ningxia, People's Republic of China.
| | - Shengmao Ma
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301, Zhengyuan North Street, Yinchuan, Ningxia, People's Republic of China
| | - Xiaowen Wang
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301, Zhengyuan North Street, Yinchuan, Ningxia, People's Republic of China
| | - Jifang Dang
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301, Zhengyuan North Street, Yinchuan, Ningxia, People's Republic of China
| | - Fuchun Ma
- Department of Thoracic Surgery, People's Hospital of Ningxia Hui Autonomous Region, No. 301, Zhengyuan North Street, Yinchuan, Ningxia, People's Republic of China
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Poblano-Pérez LI, Castro-Manrreza ME, González-Alva P, Fajardo-Orduña GR, Montesinos JJ. Mesenchymal Stromal Cells Derived from Dental Tissues: Immunomodulatory Properties and Clinical Potential. Int J Mol Sci 2024; 25:1986. [PMID: 38396665 PMCID: PMC10888494 DOI: 10.3390/ijms25041986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 01/30/2024] [Accepted: 02/05/2024] [Indexed: 02/25/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells located in different areas of the human body. The oral cavity is considered a potential source of MSCs because they have been identified in several dental tissues (D-MSCs). Clinical trials in which cells from these sources were used have shown that they are effective and safe as treatments for tissue regeneration. Importantly, immunoregulatory capacity has been observed in all of these populations; however, this function may vary among the different types of MSCs. Since this property is of clinical interest for cell therapy protocols, it is relevant to analyze the differences in immunoregulatory capacity, as well as the mechanisms used by each type of MSC. Interestingly, D-MSCs are the most suitable source for regenerating mineralized tissues in the oral region. Furthermore, the clinical potential of D-MSCs is supported due to their adequate capacity for proliferation, migration, and differentiation. There is also evidence for their potential application in protocols against autoimmune diseases and other inflammatory conditions due to their immunosuppressive capacity. Therefore, in this review, the immunoregulatory mechanisms identified at the preclinical level in combination with the different types of MSCs found in dental tissues are described, in addition to a description of the clinical trials in which MSCs from these sources have been applied.
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Affiliation(s)
- Luis Ignacio Poblano-Pérez
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Marta Elena Castro-Manrreza
- Immunology and Stem Cells Laboratory, FES Zaragoza, National Autonomous University of Mexico (UNAM), Mexico City 09230, Mexico;
| | - Patricia González-Alva
- Tissue Bioengineering Laboratory, Postgraduate Studies, Research Division, Faculty of Dentistry, National Autonomous University of Mexico (UNAM), Mexico City 04510, Mexico;
| | - Guadalupe R. Fajardo-Orduña
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
| | - Juan José Montesinos
- Mesenchymal Stem Cell Laboratory, Oncology Research Unit, Oncology Hospital, National Medical Center (IMSS), Mexico City 06720, Mexico; (L.I.P.-P.); (G.R.F.-O.)
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Jia D, Han J, Cai J, Huan Z, Wang Y, Ge X. Mesenchymal stem cells overexpressing PBX1 alleviates haemorrhagic shock-induced kidney damage by inhibiting NF-κB activation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119571. [PMID: 37673222 DOI: 10.1016/j.bbamcr.2023.119571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/21/2023] [Accepted: 08/26/2023] [Indexed: 09/08/2023]
Abstract
Mesenchymal stem cells (MSCs) have favourable outcomes in the treatment of kidney diseases. Pre-B-cell leukaemia transcription factor 1 (PBX1) has been reported to be a regulator of self-renewal of stem cells. Whether PBX1 is beneficial to MSCs in the treatment of haemorrhagic shock (HS)-induced kidney damage is unknown. We overexpressed PBX1 in rat bone marrow-derived mesenchymal stem cells (rBMSCs) and human bone marrow-derived mesenchymal stem cells (hBMSCs) to treat rats with HS and hypoxia-treated human proximal tubule epithelial cells (HK-2), respectively. The results indicated that PBX1 enhanced the homing capacity of rBMSCs to kidney tissues and that treatment with rBMSCs overexpressing PBX1 improved the indicators of kidney function, alleviated structural damage to kidney tissues. Furthermore, administration with rBMSCs overexpressing PBX1 inhibited HS-induced NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation and the release of proinflammatory cytokines, and further attenuated apoptosis. We then determined whether NF-κB, an important factor in NLRP3 activation and the regulation of inflammation, participates in HS-induced kidney damage, and we found that rBMSCs overexpressing PBX1 inhibited NF-κB activation by decreasing the p-IκBα/IκBα and p-p65/p65 ratios and inhibiting the nuclear translocation and decreasing the DNA-binding capacity of NF-κB. hBMSCs overexpressing PBX1 also exhibited protective effects on HK-2 cells exposed to hypoxia, as shown by the increase in cell viability, the mitigation of apoptosis, the decrease in inflammation, and the inhibition of NF-κB and NLRP3 inflammasome activation. Our study demonstrates that MSCs overexpressing PBX1 ameliorates HS-induced kidney damage by inhibiting NF-κB pathway-mediated NLRP3 inflammasome activation and the inflammatory response.
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Affiliation(s)
- Di Jia
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China
| | - Jiahui Han
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China
| | - Jimin Cai
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China
| | - Zhirong Huan
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China
| | - Yan Wang
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China
| | - Xin Ge
- Department of Critical Care Medicine, Wuxi 9th People's Hospital Affiliated to Soochow University, Wuxi, Jiangsu 214000, People's Republic of China; Orthopedic Institution of Wuxi City, Wuxi, Jiangsu 214000, People's Republic of China.
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Walewska A, Janucik A, Tynecka M, Moniuszko M, Eljaszewicz A. Mesenchymal stem cells under epigenetic control - the role of epigenetic machinery in fate decision and functional properties. Cell Death Dis 2023; 14:720. [PMID: 37932257 PMCID: PMC10628230 DOI: 10.1038/s41419-023-06239-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/12/2023] [Accepted: 10/20/2023] [Indexed: 11/08/2023]
Abstract
Mesenchymal stem cells (mesenchymal stromal cells, MSC) are multipotent stem cells that can differentiate into cells of at least three mesodermal lineages, namely adipocytes, osteoblasts, and chondrocytes, and have potent immunomodulatory properties. Epigenetic modifications are critical regulators of gene expression and cellular differentiation of mesenchymal stem cells (MSCs). Epigenetic machinery controls MSC differentiation through direct modifications to DNA and histones. Understanding the role of epigenetic machinery in MSC is crucial for the development of effective cell-based therapies for degenerative and inflammatory diseases. In this review, we summarize the current understanding of the role of epigenetic control of MSC differentiation and immunomodulatory properties.
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Affiliation(s)
- Alicja Walewska
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Adrian Janucik
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marlena Tynecka
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
| | - Marcin Moniuszko
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland
- Department of Regenerative Medicine and Immune Regulation, Medical University of Bialystok, ul. Waszyngtona 13, 15-269, Bialystok, Poland
- Department of Allergology and Internal Medicine, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24A, 15-276, Bialystok, Poland
| | - Andrzej Eljaszewicz
- Centre of Regenerative Medicine, Medical University of Bialystok, ul. Waszyngtona 15B, 15-269, Bialystok, Poland.
- Tissue and Cell Bank, Medical University of Bialystok Clinical Hospital, ul. Waszyngtona 13, 15-069, Bialystok, Poland.
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9
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Li L, Li J, Guan H, Oishi H, Takahashi S, Zhang C. Human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications: applications and research advances. Int J Med Sci 2023; 20:1492-1507. [PMID: 37790847 PMCID: PMC10542192 DOI: 10.7150/ijms.87472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/22/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetes mellitus and its complications pose a major threat to global health and affect the quality of life and life expectancy of patients. Currently, the application of traditional therapeutic drugs for diabetes mellitus has great limitations and can only temporarily control blood glucose but not fundamentally cure it. Mesenchymal stem cells, as pluripotent stromal cells, have multidirectional differentiation potential, high self-renewal, immune regulation, and low immunogenicity, which provide a new idea and possible development direction for diabetes mellitus treatment. Regenerative medicine with mesenchymal stem cells treatment as the core treatment will become another treatment option for diabetes mellitus after traditional treatment. Recently, human umbilical cord mesenchymal stem cells have been widely used in basic and clinical research on diabetes mellitus and its complications because of their abundance, low ethical controversy, low risk of infection, and high proliferation and differentiation ability. This paper reviews the therapeutic role and mechanism of human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications and highlights the challenges faced by the clinical application of human umbilical cord mesenchymal stem cells to provide a more theoretical basis for the application of human umbilical cord mesenchymal stem cells in diabetes mellitus patients.
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Affiliation(s)
- Luyao Li
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Jicui Li
- Department of Nephrology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Haifei Guan
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate 24 School of Medical Sciences, Aichi 467-8601, Nagoya, Japan
| | - Satoru Takahashi
- Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Tsukuba, Japan
| | - Chuan Zhang
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
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10
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Abo-Aziza FAM, Wasfy BM, Wahba SMR, Abd-Elhalem SS. Mesenchymal Stem Cells and Myeloid-Derived Suppressor Cells Interplay in Adjuvant-Induced Arthritis Rat Model. Int Immunopharmacol 2023; 120:110300. [PMID: 37192553 DOI: 10.1016/j.intimp.2023.110300] [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: 04/07/2023] [Revised: 04/27/2023] [Accepted: 05/05/2023] [Indexed: 05/18/2023]
Abstract
There has not been much researchs on the biological relationship between myeloid-derived suppressor cells (MDSCs) and mesenchymal stem cells (MSCs). The goal of the current work is to examine how these cells cooperate with one another in a rat model of adjuvant-induced arthritis (AIA). Three groups of equal numbers of rats were created; the first group served as the control. Complete Freund's adjuvant (CFA) was injected into the second group to induce AIA. The third group underwent MSCstreatment. Three weeks later, ANA, IL-1β, IL-4, IL-6, IL-10, TNF-α, IFN-γ, M-CSF, iNOS and Arg-1 were determined using ELISA. Flowcytometric studies for MDSCs using CD11bc + and His48 + antibodies were performed. Current results showed significantly higher levels of WBCs, ANA, IL-1, IL-4, IL-6, IL-10, TNF-α, M-CSF, iNOS and Arg-1 along with a significant rise in MDSCs % in the AIA group compared to the control group. As opposed to AIA animals, MSCs administration resulted in a considerable improvement in cytokine levels, supporting the immunomodulation function of MSCs. Histological examination of the joints in the AIA group revealed articular cartilage degradation as well as infiltration of inflammatory cells and fibroplasia. These several evidences suggested that MDSCs may perform various roles in autoimmunity. Understanding how MDSCs and MSCs contribute to arthritis may help their prospective application in immunotherapy. Therefore, the reciprocal collaboration of MSCs and MDSCs must therefore be the subject of new investigations, which can offer new platforms for the development of more effective and individualized therapies for the treatment of immunological illnesses.
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Affiliation(s)
- Faten A M Abo-Aziza
- Department of Parasitology and Animal Diseases, Veterinary Research Institute, National Research Centre, 12622 Cairo, Egypt.
| | - Basma M Wasfy
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
| | - Sanaa M R Wahba
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
| | - Sahar S Abd-Elhalem
- Department of Zoology, Faculty of Women for Arts, Science and Education, Ain Shams University, 11757 Cairo, Egypt
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11
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Qi J, Zhou X, Bai Z, Lu Z, Zhu X, Liu J, Wang J, Jin M, Liu C, Li X. FcγRIIIA activation-mediated up-regulation of glycolysis alters MDSCs modulation in CD4 + T cell subsets of Sjögren syndrome. Cell Death Dis 2023; 14:86. [PMID: 36746935 PMCID: PMC9902521 DOI: 10.1038/s41419-023-05631-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/07/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023]
Abstract
Our and other researchers' previous studies found that myeloid-derived suppressor cells (MDSCs) were increased, and these MDSCs, supposed to play immunosuppressive roles, showed significant pro-inflammatory effects in Sjögren's syndrome (SS). However, the key factors and potential mechanisms leading MDSCs to be inflammatory remain unclear. In this study, we found that MDSCs from SS patients were positively correlated with the percentages of Th17 cells, disease activity and serum autoantibodies, and showed higher levels of Fc gamma receptor (FcγR) IIIA and glycolysis. Most importantly, SS MDSCs or heat-aggregated IgG (HAIG)-treated MDSCs down-regulated Th1/Th2 ratio and up-regulated Th17/Treg ratio, which could be obviously rescued by IgG monomer or glycolysis inhibitor 2-DG. As well, the levels of FcγRIV and glycolysis in MDSCs and the ratio of Th17/Treg were increased, and the ratio of Th1/Th2 was decreased in SS-like NOD mice. Our study indicated that MDSCs showed pro-inflammatory phenotypes by disturbing CD4+ T-cell balances in SS. The pro-inflammatory effects of MDSCs might be directly linked to the enhanced glycolysis mediated by FcγRIIIA activation.
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Affiliation(s)
- Jingjing Qi
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Xinyang Zhou
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Ziran Bai
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Zhimin Lu
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
- Department of Rheumatology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, 226006, People's Republic of China
| | - Xiaolu Zhu
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Jiaqing Liu
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Junli Wang
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Minli Jin
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China
| | - Chang Liu
- Department of Rheumatology and Immunology, Dalian Municipal Central Hospital, Dalian, Liaoning, 116083, People's Republic of China.
| | - Xia Li
- Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, Liaoning, 116044, People's Republic of China.
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12
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The role of PGE2 and EP receptors on lung's immune and structural cells; possibilities for future asthma therapy. Pharmacol Ther 2023; 241:108313. [PMID: 36427569 DOI: 10.1016/j.pharmthera.2022.108313] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 10/06/2022] [Accepted: 11/17/2022] [Indexed: 11/27/2022]
Abstract
Asthma is the most common airway chronic disease with treatments aimed mainly to control the symptoms. Adrenergic receptor agonists, corticosteroids and anti-leukotrienes have been used for decades, and the development of more targeted asthma treatments, known as biological therapies, were only recently established. However, due to the complexity of asthma and the limited efficacy as well as the side effects of available treatments, there is an urgent need for a new generation of asthma therapies. The anti-inflammatory and bronchodilatory effects of prostaglandin E2 in asthma are promising, yet complicated by undesirable side effects, such as cough and airway irritation. In this review, we summarize the most important literature on the role of all four E prostanoid (EP) receptors on the lung's immune and structural cells to further dissect the relevance of EP2/EP4 receptors as potential targets for future asthma therapy.
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13
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Hu Y, Huang J, Chen C, Wang Y, Hao Z, Chen T, Wang J, Li J. Strategies of Macrophages to Maintain Bone Homeostasis and Promote Bone Repair: A Narrative Review. J Funct Biomater 2022; 14:18. [PMID: 36662065 PMCID: PMC9864083 DOI: 10.3390/jfb14010018] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/17/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Bone homeostasis (a healthy bone mass) is regulated by maintaining a delicate balance between bone resorption and bone formation. The regulation of physiological bone remodeling by a complex system that involves multiple cells in the skeleton is closely related to bone homeostasis. Loss of bone mass or repair of bone is always accompanied by changes in bone homeostasis. However, due to the complexity of bone homeostasis, we are currently unable to identify all the mechanisms that affect bone homeostasis. To date, bone macrophages have been considered a third cellular component in addition to osteogenic spectrum cells and osteoclasts. As confirmed by co-culture models or in vivo experiments, polarized or unpolarized macrophages interact with multiple components within the bone to ensure bone homeostasis. Different macrophage phenotypes are prone to resorption and formation of bone differently. This review comprehensively summarizes the mechanisms by which macrophages regulate bone homeostasis and concludes that macrophages can control bone homeostasis from osteoclasts, mesenchymal cells, osteoblasts, osteocytes, and the blood/vasculature system. The elaboration of these mechanisms in this narrative review facilitates the development of macrophage-based strategies for the treatment of bone metabolic diseases and bone defects.
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Affiliation(s)
- Yingkun Hu
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Jinghuan Huang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200000, China
| | - Chunying Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Yi Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Zhuowen Hao
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Tianhong Chen
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Junwu Wang
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
| | - Jingfeng Li
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan 430000, China
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14
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Sun T, Liu S, Yang G, Zhu R, Li Z, Yao G, Chen H, Sun L. Mesenchymal stem cell transplantation alleviates Sjögren's syndrome symptoms by modulating Tim-3 expression. Int Immunopharmacol 2022; 111:109152. [PMID: 36007392 DOI: 10.1016/j.intimp.2022.109152] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 07/17/2022] [Accepted: 07/18/2022] [Indexed: 11/29/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation has been proven to be an effective treatment for Sjögren's syndrome (SS) to improve salivary gland pathology and exocrine function, but the mechanism remains unclear. A recently reported inhibitory receptor, Tim-3, also appears to be closely related to autoimmune diseases. Here, we aimed to explore the roles of Tim-3 in the pathogenesis of SS and MSC treatment. The results showed that Tim-3 was downregulated in T cells of SS patients and nonobese diabetic (NOD) mice, which is correlated with SS pathogenesis. MSC transplantation ameliorated SS-like symptoms and pathological changes in the submandibular glands with modulated Tim-3 expression, resulting in attenuation of localized inflammation, fibrosis, and epithelial-mesenchymal transition. Furthermore, Tim-3 is crucial for the inhibitory effect of MSCs on PBMC proliferation in vitro. Therefore, our work has demonstrated that MSC transplantation effectively mitigates the pathological changes of SS by regulating Tim-3 expression, which provides a novel mechanism of MSC treatment and indicates a brand-new perspective of the combination of inhibitory-receptor-targeted treatment and MSC therapy in SS.
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Affiliation(s)
- Tian Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China
| | - Shanshan Liu
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China
| | - Guangxia Yang
- Nanjing Drum Tower Hospital, Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, China
| | - Rujie Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, China
| | - Zutong Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China
| | - Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China
| | - Hongwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, Jiangsu, China.
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15
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Yao G, Qi J, Li X, Tang X, Li W, Chen W, Xia N, Wang S, Sun L. Mesenchymal stem cell transplantation alleviated atherosclerosis in systemic lupus erythematosus through reducing MDSCs. Stem Cell Res Ther 2022; 13:328. [PMID: 35850768 PMCID: PMC9290280 DOI: 10.1186/s13287-022-03002-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 05/19/2022] [Indexed: 12/02/2022] Open
Abstract
Objective The mechanism by which mesenchymal stem cell (MSC) transplantation alleviates atherosclerosis in systemic lupus erythematosus (SLE) remains elusive. In this study, we aim to explore the efficacy and mechanism of MSC in ameliorating atherosclerosis in SLE. Methods ApoE−/− and Fas−/− mice on the B6 background were cross-bred to generate SLE mice with atherosclerosis. Myeloid-derived suppressor cells (MDSCs) were sorted and quantified. The apoE−/−Fas−/− mice were either treated with anti-Gr antibody or injected with MDSCs. The lupus-like autoimmunity and atherosclerotic lesions were evaluated. Furthermore, the apoE−/−Fas−/− mice were transplanted with MSCs and lupus-like autoimmunity and atherosclerotic lesions were assessed. Results MDSCs in peripheral blood, spleen, draining lymph nodes increased in apoE−/−Fas−/− mice compared with B6 mice. Moreover, the adoptive transfer of MDSCs aggravated both atherosclerosis and SLE pathologies, whereas depleting MDSCs ameliorated those pathologies in apoE−/−Fas−/− mice. MSC transplantation in apoE−/−Fas−/− mice decreased the percentage of MDSCs, alleviated the typical atherosclerotic lesions, including atherosclerotic lesions in aortae and liver, and reduced serum cholesterol, triglyceride and low-density lipoprotein levels. MSC transplantation also reduced SLE pathologies, including splenomegaly, glomerular lesions, anti-dsDNA antibody in serum, urine protein and serum creatinine. Moreover, MSC transplantation regulated the generation and function of MDSCs through secreting prostaglandin E 2 (PGE2). Conclusion Taken together, these results indicated that the increased MDSCs contributed to atherosclerosis in SLE. MSC transplantation ameliorated the atherosclerosis and SLE through reducing MDSCs by secreting PGE2. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-03002-y.
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Affiliation(s)
- Genhong Yao
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Jingjing Qi
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.,Department of Immunology, College of Basic Medical Science, Dalian Medical University, Dalian, China
| | - Xiaojing Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Xiaojun Tang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Wenchao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Weiwei Chen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Nan Xia
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China
| | - Shiying Wang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, China.
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16
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Huldani H, Abdalkareem Jasim S, Olegovich Bokov D, Abdelbasset WK, Nader Shalaby M, Thangavelu L, Margiana R, Qasim MT. Application of extracellular vesicles derived from mesenchymal stem cells as potential therapeutic tools in autoimmune and rheumatic diseases. Int Immunopharmacol 2022; 106:108634. [PMID: 35193053 DOI: 10.1016/j.intimp.2022.108634] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 02/02/2022] [Accepted: 02/14/2022] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cells (MSCs) have been proven to have superior potential to be used astherapeutic candidates in various disorders. Nevertheless, the clinical application of these cells have been restricted because of their tumorigenic properties. Increasing evidence has established that the valuable impacts of MSCs are mainly attributable to the paracrine factors including extracellular vesicles (EVs). EVs are nanosized double-layer phospholipid membrane vesicles contain various proteins, lipids and miRNAs which mediate cell-to-cell communications. Due to their inferior immunogenicity and tumorigenicity, as well as easier management, EVs have drawn attention as potential cell-free replacement therapy to MSCs. For that reason, herein, we reviewed the recent findings of researches on different MSC-EVs and their effectiveness in the treatment of several autoimmune and rheumatic diseases including multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, osteoporosis, and systemic lupus erythematosus as well as Sjogren's syndrome, systemic sclerosis and other autoimmune diseases.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Lambung Mangkurat University, Banjarmasin, South Borneo, Indonesia.
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-maarif University College, Al-anbar-Ramadi, Iraq
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow 119991, Russian Federation; Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow 109240, Russian Federation
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Egypt
| | - Lakshmi Thangavelu
- Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Science, Saveetha University, Chennai, India
| | - Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Andrology Program, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia; Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Maytham T Qasim
- Department of Anesthesia, College of Health and Medical Technology, Al-Ayen University, Thi-Qar, Iraq
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Cheuk YC, Xu S, Zhu D, Luo Y, Chen T, Chen J, Li J, Shi Y, Zhang Y, Rong R. Monocytic Myeloid-Derived Suppressor Cells Inhibit Myofibroblastic Differentiation in Mesenchymal Stem Cells Through IL-15 Secretion. Front Cell Dev Biol 2022; 10:817402. [PMID: 35252184 PMCID: PMC8891503 DOI: 10.3389/fcell.2022.817402] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 01/04/2022] [Indexed: 01/02/2025] Open
Abstract
Background: Accumulating evidence indicates that mesenchymal stem cells (MSCs) are precursors of myofibroblasts, which play a vital role in renal fibrosis. The close interaction between MSCs and other immune cells regulates the development of multiple fibrosis-related diseases. However, the effect of myeloid-derived suppressor cells (MDSCs) on MSCs remains unexplored. Here, we investigated the effect of MDSCs on the myofibroblastic differentiation of MSCs. Methods: MSCs were induced to undergo myofibroblastic differentiation with transforming growth factor beta 1 (TGF-β1). M-MDSCs and G-MDSCs were sorted by flow cytometry. Supernatants derived from MDSCs were administered to cultured bone marrow MSCs (BM-MSCs) undergoing TGF-β1-induced myofibroblastic differentiation. Myofibroblastic differentiation was evaluated by immunostaining. The expression of fibrosis-related genes was determined by quantitative PCR and western blot analysis. In vitro, M-MDSC supernatant or M-MDSC supernatant with interleukin (IL)-15 mAbs was administered following unilateral renal ischemia-reperfusion injury (IRI) to observe the myofibroblast differentiation of renal resident MSCs (RRMSCs) in a murine model. Results: Myofibroblastic differentiation of MSCs was hindered when the cells were treated with MDSC-derived supernatants, especially that from M-MDSCs. The inhibitory effect of M-MDSC supernatant on the myofibroblastic differentiation of MSCs was partially mediated by IL-15-Ras-Erk1/2-Smad2/3 signaling. Treatment with M-MDSC supernatant ameliorated renal fibrosis and myofibroblastic differentiation in RRMSCs through IL-15. Additionally, M-MDSC supernatant increased M-MDSC infiltration in the kidney in a mouse IRI model. M-MDSC supernatant downregulated the adhesion and migration marker CD44 on the cell membrane of MSCs via IL-15. Conclusion: M-MDSC-derived supernatant inhibited the TGF-β1-induced myofibroblastic differentiation of MSCs through IL-15. Our findings shed new light on the effect of MDSCs on myofibroblastic differentiation and adhesion of MSCs, which might provide a new perspective in the development of treatment strategies for renal fibrosis.
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Affiliation(s)
- Yin Celeste Cheuk
- 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
| | - Dong Zhu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yongsheng Luo
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Tian Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Juntao Chen
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiawei Li
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yi Shi
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
- Institute of Clinical Science, Zhongshan Hospital, Fudan University, 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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18
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Bizymi N, Georgopoulou A, Mastrogamvraki N, Matheakakis A, Gontika I, Fragiadaki I, Mavroudi I, Papadaki HA. Myeloid-Derived Suppressor Cells (MDSC) in the Umbilical Cord Blood: Biological Significance and Possible Therapeutic Applications. J Clin Med 2022; 11:jcm11030727. [PMID: 35160177 PMCID: PMC8836851 DOI: 10.3390/jcm11030727] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/20/2022] [Accepted: 01/25/2022] [Indexed: 02/04/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous population of myeloid cells that suppress immune responses in cancer, infection, and trauma. They mainly act by inhibiting T-cells, natural-killer cells, and dendritic cells, and also by inducing T-regulatory cells, and modulating macrophages. Although they are mostly associated with adverse prognosis of the underlying disease entity, they may display positive effects in specific situations, such as in allogeneic hematopoietic stem cell transplantation (HSCT), where they suppress graft-versus-host disease (GVHD). They also contribute to the feto-maternal tolerance, and in the fetus growth process, whereas several pregnancy complications have been associated with their defects. Human umbilical cord blood (UCB) is a source rich in MDSCs and their myeloid progenitor cells. Recently, a number of studies have investigated the generation, isolation, and expansion of UCB-MDSCs for potential clinical application associated with their immunosuppressive properties, such as GVHD, and autoimmune and inflammatory diseases. Given that a significant proportion of UCB units in cord blood banks are not suitable for clinical use in HSCT, they might be used as a significant source of MDSCs for research and clinical purposes. The current review summarizes the roles of MDSCs in the UCB, as well as their promising applications.
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Affiliation(s)
- Nikoleta Bizymi
- Department of Haematology, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (N.B.); (A.M.); (I.M.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece
| | - Anthie Georgopoulou
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
| | - Natalia Mastrogamvraki
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
| | - Angelos Matheakakis
- Department of Haematology, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (N.B.); (A.M.); (I.M.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece
| | - Ioanna Gontika
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
| | - Irene Fragiadaki
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
| | - Irene Mavroudi
- Department of Haematology, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (N.B.); (A.M.); (I.M.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
| | - Helen A. Papadaki
- Department of Haematology, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (N.B.); (A.M.); (I.M.)
- Haemopoiesis Research Laboratory, School of Medicine, University of Crete, 71003 Heraklion, Crete, Greece
- Public Cord Blood Bank of Crete, University Hospital of Heraklion, 71500 Heraklion, Crete, Greece; (A.G.); (N.M.); (I.G.); (I.F.)
- Correspondence: ; Tel.: +30-2810394637
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Wang S, Tan Q, Hou Y, Dou H. Emerging Roles of Myeloid-Derived Suppressor Cells in Diabetes. Front Pharmacol 2021; 12:798320. [PMID: 34975496 PMCID: PMC8716856 DOI: 10.3389/fphar.2021.798320] [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: 10/20/2021] [Accepted: 12/01/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes is a syndrome characterized by hyperglycemia with or without insulin resistance. Its etiology is attributed to the combined action of genes, environment and immune cells. Myeloid-derived suppressor cell (MDSC) is a heterogeneous population of immature cells with immunosuppressive ability. In recent years, different studies have debated the quantity, activity changes and roles of MDSC in the diabetic microenvironment. However, the emerging roles of MDSC have not been fully documented with regard to their interactions with diabetes. Here, the manifestations of MDSC and their subsets are reviewed with regard to the incidence of diabetes and diabetic complications. The possible drugs targeting MDSC are discussed with regard to their potential of treating diabetes. We believe that understanding MDSC will offer opportunities to explain pathological characteristics of different diabetes. MDSC also will be used for personalized immunotherapy of diabetes.
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Affiliation(s)
- Shiqi Wang
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Qian Tan
- Department of Burns and Plastic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China
| | - Huan Dou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China
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20
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Li A, Guo F, Pan Q, Chen S, Chen J, Liu HF, Pan Q. Mesenchymal Stem Cell Therapy: Hope for Patients With Systemic Lupus Erythematosus. Front Immunol 2021; 12:728190. [PMID: 34659214 PMCID: PMC8516390 DOI: 10.3389/fimmu.2021.728190] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 09/14/2021] [Indexed: 12/26/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease. Although previous studies have demonstrated that SLE is related to the imbalance of cells in the immune system, including B cells, T cells, and dendritic cells, etc., the mechanisms underlying SLE pathogenesis remain unclear. Therefore, effective and low side-effect therapies for SLE are lacking. Recently, mesenchymal stem cell (MSC) therapy for autoimmune diseases, particularly SLE, has gained increasing attention. This therapy can improve the signs and symptoms of refractory SLE by promoting the proliferation of Th2 and Treg cells and inhibiting the activity of Th1, Th17, and B cells, etc. However, MSC therapy is also reported ineffective in some patients with SLE, which may be related to MSC- or patient-derived factors. Therefore, the therapeutic effects of MSCs should be further confirmed. This review summarizes the status of MSC therapy in refractory SLE treatment and potential reasons for the ineffectiveness of MSC therapy from three perspectives. We propose various MSC modification methods that may be beneficial in enhancing the immunosuppression of MSCs in SLE. However, their safety and protective effects in patients with SLE still need to be confirmed by further experimental and clinical evidence.
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Affiliation(s)
- Aifen Li
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Fengbiao Guo
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Quanren Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shuxian Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jiaxuan Chen
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Hua-Feng Liu
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Qingjun Pan
- Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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21
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Zhao Y, Yang X, Li S, Zhang B, Li S, Wang X, Wang Y, Jia C, Chang Y, Wei W. sTNFRII-Fc modification protects human UC-MSCs against apoptosis/autophagy induced by TNF-α and enhances their efficacy in alleviating inflammatory arthritis. Stem Cell Res Ther 2021; 12:535. [PMID: 34627365 PMCID: PMC8502322 DOI: 10.1186/s13287-021-02602-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 09/07/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Tumor necrosis factor (TNF)-α inhibitors represented by Etanercept (a fusion protein containing soluble TNF receptor II (sTNFRII) and the Fc segment of human IgG1) play a pivotal role in Rheumatoid arthritis (RA) treatment. However, long-term use increases the risk of infection and tumors for their systemic inhibition of TNF-α, which disrupts the regular physiological function of this molecular. Mesenchymal stem cells (MSCs)-based delivery system provides new options for RA treatment with their "homing" and immune-regulation capacities, whereas inflammatory environment (especially TNF-α) is not conducive to MSCs' therapeutic effects by inducing apoptosis/autophagy. Here, we constructed a strain of sTNFRII-Fc-expressing MSCs (sTNFRII-MSC), aiming to offset the deficiency of those two interventions. METHODS Constructed sTNFRII-Fc lentiviral vector was used to infect human umbilical cord-derived MSCs, and sTNFRII-MSC stable cell line was generated by monoclonal cultivation. In vitro and vivo characteristics of sTNFRII-MSC were assessed by coculture assay and an acute inflammatory model in NOD/SCID mice. The sTNFRII-MSC were transplanted into CIA model, pathological and immunological indicators were detected to evaluate the therapeutic effects of sTNFRII-MSC. The distribution of sTNFRII-MSC was determined by immunofluorescence assay. Apoptosis and autophagy were analyzed by flow cytometry, western blot and immunofluorescence. RESULTS sTNFRII-Fc secreted by sTNFRII-MSC present biological activity both in vitro and vivo. sTNFRII-MSC transplantation effectively alleviates mice collagen-induced arthritis (CIA) via migrating to affected area, protecting articular cartilage destruction, modulating immune balance and sTNFRII-MSC showed prolonged internal retention via resisting apoptosis/autophagy induced by TNF-α. CONCLUSION sTNFRII-Fc modification protects MSCs against apoptosis/autophagy induced by TNF-α, in addition to releasing sTNFRII-Fc neutralizing TNF-α to block relevant immune-inflammation cascade, and thus exert better therapeutic effects in alleviating inflammatory arthritis.
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Affiliation(s)
- Yingjie Zhao
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China.,Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China
| | - Xuezhi Yang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Siyu Li
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Bingjie Zhang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Susu Li
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Xinwei Wang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Yueye Wang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Chengyan Jia
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China
| | - Yan Chang
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
| | - Wei Wei
- Key Laboratory of Anti-Inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-Inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Medical University, Ministry of Education, Hefei, 230032, China.
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Chihaby N, Orliaguet M, Le Pottier L, Pers JO, Boisramé S. Treatment of Sjögren's Syndrome with Mesenchymal Stem Cells: A Systematic Review. Int J Mol Sci 2021; 22:10474. [PMID: 34638813 PMCID: PMC8508641 DOI: 10.3390/ijms221910474] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 01/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are ubiquitous in the human body. Mesenchymal stem cells were initially isolated from bone marrow and later from other organs such as fatty tissues, umbilical cords, and gingiva. Their secretory capacities give them interesting immunomodulatory properties in cell therapy. Some studies have explored the use of MSCs to treat Sjögren's syndrome (SS), a chronic inflammatory autoimmune disease that mainly affects exocrine glands, including salivary and lacrimal glands, although current treatments are only palliative. This systematic review summarizes the current data about the application of MSCs in SS. Reports show improvements in salivary secretions and a decrease in lymphocytic infiltration in salivary glands in patients and mice with SS after intravenous or infra-peritoneal injections of MSCs. MSC injections led to a decrease in inflammatory cytokines and an increase in anti-inflammatory cytokines. However, the intrinsic mechanism of action of these MSCs currently remains unknown.
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Affiliation(s)
- Najwa Chihaby
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
| | - Marie Orliaguet
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
| | - Laëtitia Le Pottier
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- Inserm, LBAI, University of Western Brittany, UMR1227, 29609 Brest, France
| | - Jacques-Olivier Pers
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
- Inserm, LBAI, University of Western Brittany, UMR1227, 29609 Brest, France
| | - Sylvie Boisramé
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
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Razazian M, Khosravi M, Bahiraii S, Uzan G, Shamdani S, Naserian S. Differences and similarities between mesenchymal stem cell and endothelial progenitor cell immunoregulatory properties against T cells. World J Stem Cells 2021; 13:971-984. [PMID: 34567420 PMCID: PMC8422932 DOI: 10.4252/wjsc.v13.i8.971] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/28/2021] [Accepted: 07/16/2021] [Indexed: 02/06/2023] Open
Abstract
Bone-marrow-derived mesenchymal stem cells and endothelial progenitor cells have some interesting biological properties that make them unique for cell therapy of degenerative and cardiovascular disorders. Although both cell populations have been already studied and used for their regenerative potentials, recently their special immunoregulatory features have brought much more attention. Mesenchymal stem cells and endothelial progenitor cells have both proangiogenic functions and have been shown to suppress the immune response, particularly T cell proliferation, activation, and cytokine production. This makes them suitable choices for allogeneic stem cell transplantation. Nevertheless, these two cells do not have equal immunoregulatory activities. Many elements including their extraction sources, age/passage, expression of different markers, secretion of bioactive mediators, and some others could change the efficiency of their immunosuppressive function. However, to our knowledge, no publication has yet compared mesenchymal stem cells and endothelial progenitor cells for their immunological interaction with T cells. This review aims to specifically compare the immunoregulatory effect of these two populations including their T cell suppression, deactivation, cytokine production, and regulatory T cells induction capacities. Moreover, it evaluates the implications of the tumor necrosis factor alpha-tumor necrosis factor receptor 2 axis as an emerging immune checkpoint signaling pathway controlling most of their immunological properties.
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Affiliation(s)
- Mehdi Razazian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
| | - Maryam Khosravi
- Microenvironment & Immunity Unit, Institut Pasteur, Paris 75724, France
- Institut national de la santé et de la recherche médicale (Inserm) Unit 1224, Paris 75724, France
| | - Sheyda Bahiraii
- Department of Pharmacognosy, University of Vienna, Vienna 1090, Austria
| | - Georges Uzan
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
| | - Sara Shamdani
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France
| | - Sina Naserian
- Institut national de la santé et de la recherche médicale (Inserm) Unité Mixte de Recherche-Inserm-Ministère de la Défense 1197, Hôpital Paul Brousse, Villejuif 94800, France
- Paris-Saclay University, Villejuif 94800, France
- CellMedEx; Saint Maur Des Fossés 94100, France.
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Role of Myeloid-derived suppressor cell (MDSC) in autoimmunity and its potential as a therapeutic target. Inflammopharmacology 2021; 29:1307-1315. [PMID: 34283371 DOI: 10.1007/s10787-021-00846-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 07/04/2021] [Indexed: 02/07/2023]
Abstract
Myeloid suppressor cells (MDSCs) are an important class of immune-regulating cells that can suppress T cell function. Most of our knowledge about the function of MDSC comes from studies of cancer models. Recent studies, however, have greatly contributed to the description of MDSC involvement in autoimmune diseases. They are known as a cell population that may negatively affect immune responses by regulating the function of CD4+ and CD8+ cells, which makes them an attractive target for autoimmune diseases therapy. However, many questions about MDSC activation, differentiation, and inhibitory functions remain unanswered. In this study, we have summarized the role of MDSCs in various autoimmune diseases, and the potential of targeting them for therapeutic benefits has been discussed.
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van Geffen C, Deißler A, Beer-Hammer S, Nürnberg B, Handgretinger R, Renz H, Hartl D, Kolahian S. Myeloid-Derived Suppressor Cells Dampen Airway Inflammation Through Prostaglandin E2 Receptor 4. Front Immunol 2021; 12:695933. [PMID: 34322123 PMCID: PMC8311661 DOI: 10.3389/fimmu.2021.695933] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/24/2021] [Indexed: 01/22/2023] Open
Abstract
Emerging evidence suggests a mechanistic role for myeloid-derived suppressor cells (MDSCs) in lung diseases like asthma. Previously, we showed that adoptive transfer of MDSCs dampens lung inflammation in murine models of asthma through cyclooxygenase-2 and arginase-1 pathways. Here, we further dissected this mechanism by studying the role and therapeutic relevance of the downstream mediator prostaglandin E2 receptor 4 (EP4) in a murine model of asthma. We adoptively transferred MDSCs generated using an EP4 agonist in a murine model of asthma and studied the consequences on airway inflammation. Furthermore, pegylated human arginase-1 was used to model MDSC effector activities. We demonstrate that the selective EP4 agonist L-902,688 increased the number and suppressive activity of MDSCs through arginase-1 and nitric oxide synthase-2. These results showed that adoptive transfer of EP4-primed MDSCs, EP4 agonism alone or arginase-1 administration ameliorated lung inflammatory responses and histopathological changes in asthmatic mice. Collectively, our results provide evidence that MDSCs dampen airway inflammation in murine asthma through a mechanism involving EP4.
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MESH Headings
- Adoptive Transfer
- Animals
- Antigens, Dermatophagoides/immunology
- Arginase/metabolism
- Arginase/pharmacology
- Arthropod Proteins/immunology
- Asthma/immunology
- Asthma/metabolism
- Asthma/therapy
- Cells, Cultured
- Cytokines/metabolism
- Dinoprostone/pharmacology
- Disease Models, Animal
- Female
- Lung/drug effects
- Lung/immunology
- Lung/metabolism
- Mice, Inbred BALB C
- Myeloid-Derived Suppressor Cells/drug effects
- Myeloid-Derived Suppressor Cells/immunology
- Myeloid-Derived Suppressor Cells/metabolism
- Myeloid-Derived Suppressor Cells/transplantation
- Nitric Oxide Synthase Type II/metabolism
- Pneumonia/immunology
- Pneumonia/metabolism
- Pneumonia/therapy
- Pyroglyphidae/immunology
- Pyrrolidinones/pharmacology
- Receptors, Prostaglandin E, EP2 Subtype/agonists
- Receptors, Prostaglandin E, EP2 Subtype/metabolism
- Receptors, Prostaglandin E, EP4 Subtype/agonists
- Receptors, Prostaglandin E, EP4 Subtype/metabolism
- Signal Transduction
- Tetrazoles/pharmacology
- Mice
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Affiliation(s)
- Chiel van Geffen
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Astrid Deißler
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
| | - Sandra Beer-Hammer
- Department of Pharmacology, Experimental Therapy & Toxicology and Interfaculty Center of Pharmacogenomics & Drug Research (IZePhA), University Hospitals and Clinics, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Bernd Nürnberg
- Department of Pharmacology, Experimental Therapy & Toxicology and Interfaculty Center of Pharmacogenomics & Drug Research (IZePhA), University Hospitals and Clinics, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Rupert Handgretinger
- Children’s University Hospital, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Harald Renz
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
| | - Dominik Hartl
- Department of Pediatrics I, Eberhard Karls University of Tübingen, Tübingen, Germany
- Translational Medicine, Novartis Institutes for BioMedical Research, Basel, Switzerland
| | - Saeed Kolahian
- Department of Experimental and Clinical Pharmacology and Pharmacogenomics, University Hospital Tübingen, Tübingen, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany
- Universities of Giessen and Marburg Lung Center, German Center for Lung Research (DZL), Marburg, Germany
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26
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Long X, Li X, Li T, Yan Q, Wen L, Yang X, Li H, Sun L. Umbilical cord mesenchymal stem cells enhance the therapeutic effect of imipenem by regulating myeloid-derived suppressor cells in septic mice. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:404. [PMID: 33842625 PMCID: PMC8033360 DOI: 10.21037/atm-20-6371] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background Umbilical cord mesenchymal stem cells (UC-MSCs), which possess potent immunomodulatory effects and low immunogenicity, are considered to be a promising stem cell-based therapy for sepsis. In the current study, we aimed to investigate whether the combined use of UC-MSCs and imipenem has a better effect than imipenem alone in treating Escherichia coli (E. coli)-induced sepsis and to explore the mechanism by which UC-MSCs exert their therapeutic effect in septic mice. Methods We randomly divided mice into five groups with 10 mice in each group: the normal control group (control group), the sepsis group (vehicle group), the MSCs treatment group (MSCs group), the imipenem treatment group (imipenem group), and the imipenem plus MSCs treatment group (imipenem + MSCs group). We monitored the survival rate in each group every 12 h for 3 days. After observing the survival rate, another 50 mice were also randomly divided into five groups, and the mice were sacrificed after 24 h. Bacterial colonies from the blood and peritoneal lavage fluid were counted in a blinded manner. Organ injury was analyzed by hematoxylin and eosin (HE) staining. Frequencies of myeloid-derived suppressor cells (MDSCs) in the blood, spleen, and bone marrow (BM) were determined by flow cytometry. Plasma levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-1β, and IL-10 were detected by enzyme-linked immunosorbent assay (ELISA). Results Compared with imipenem treatment, the co-administration of UC-MSCs and imipenem dramatically improved the survival rate, decreased the bacterial load, and ameliorated organ injury. Furthermore, UC-MSCs treatment, either alone or in combination with imipenem, significantly increased plasma levels of IL-10 and the percentage of MDSCs by inducing arginase-1 in septic mice. Conclusions Our results indicated that UC-MSCs protect mice against sepsis by acting on MDSCs. Combination therapy of UC-MSCs and imipenem may be a new approach for the future clinical treatment of sepsis.
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Affiliation(s)
- Xianming Long
- School of Medicine, Southeast University, Nanjing, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.,Department of Rheumatology and Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaojing Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Tao Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Qing Yan
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Lihui Wen
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Xixi Yang
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Hui Li
- Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Lingyun Sun
- School of Medicine, Southeast University, Nanjing, China.,Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
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