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Feng Z, Yang Y, Liu XZ, Sun HJ, Wen BY, Chen Z, Wei B. Application of cell therapy in rheumatoid Arthritis: Focusing on the immunomodulatory strategies of Mesenchymal stem cells. Int Immunopharmacol 2025; 147:114017. [PMID: 39778278 DOI: 10.1016/j.intimp.2025.114017] [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: 11/16/2024] [Revised: 12/24/2024] [Accepted: 01/02/2025] [Indexed: 01/11/2025]
Abstract
Rheumatoid arthritis (RA) is a common chronic autoimmune disease that primarily affects the joints, leading to synovial inflammation and hyperplasia, which subsequently causes joint pain, swelling, and damage. The microenvironment of RA is characterized by hypoxia, high reactive oxygen species (ROS), low pH, and levels of high inflammatory factors. Traditional treatments only partially alleviate symptoms and often cause various adverse reactions with long-term use. Therefore, there is an urgent need for safer and more effective treatments. In recent years, mesenchymal stem cells (MSCs) have shown significant potential in treating RA due to their diverse immunomodulatory mechanisms. MSCs paracrine a variety of soluble factors to improve the inflammatory microenvironment in RA patients by inhibiting T cell proliferation or inducing T cell differentiation to regulatory T cells (Tregs), inhibiting B cell proliferation and differentiation and immunoglobulin production, prompting macrophage polarization toward an anti-inflammatory phenotype, and inhibiting neutrophil recruitment and preventing the maturation of dendritic cells (DCs). This review summarizes the immunomodulatory effects of MSCs in RA and their application in animal models and clinical trials. Although the immunomodulatory mechanisms of MSCs are not yet fully elucidated, their significant potential in RA treatment has been widely recognized. Future research should further explore the immunomodulatory mechanisms of MSCs and optimize their functions in different pathological microenvironments to develop more effective and safer therapeutic strategies.
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Affiliation(s)
- Zhi Feng
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Ying Yang
- Department of Specialty Medicine, School of Public Health, Hengyang Medical College, University of South China, Hengyang, Hunan 421001, China
| | - Xiang-Zhuo Liu
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Hui-Jiao Sun
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Bo-Ya Wen
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Zhi Chen
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China
| | - Bo Wei
- Institute of Translational Medicine, School of Basic Medical, Hengyang Medical College, University of South China, Hengyang, Hunan 42100l, China.
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Duan R, Wang T, Li Z, Jiang L, Yu X, He D, Tao T, Liu X, Huang Z, Feng L, Su W. Ketogenic diet modulates immune cell transcriptional landscape and ameliorates experimental autoimmune uveitis in mice. J Neuroinflammation 2024; 21:319. [PMID: 39627787 PMCID: PMC11613848 DOI: 10.1186/s12974-024-03308-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 11/20/2024] [Indexed: 12/08/2024] Open
Abstract
BACKGROUND Uveitis manifests as immune-mediated inflammatory disorders within the eye, posing a serious threat to vision. The ketogenic diet (KD) has emerged as a promising dietary intervention, yet its impact on the immune microenvironments and role in uveitis remains unclear. METHODS Utilizing single-cell RNA sequencing (scRNA-seq) data from lymph node and retina of mice, we conduct a comprehensive investigation into the effects of KD on immune microenvironments. Flow cytometry is conducted to verify the potential mechanisms. RESULTS This study demonstrates that KD alters the composition and function of immune profiles. Specifically, KD promotes the differentiation of Treg cells and elevates its proportion in heathy mice. In response to experimental autoimmune uveitis challenges, KD alleviates the inflammatory symptoms, lowers CD4+ T cell pathogenicity, and corrects the Th17/Treg imbalance. Additionally, KD decreases the proportion of Th17 cell and increases Treg cells in the retina. Analysis of combined retinal and CDLN immune cells reveals that retinal immune cells, particularly CD4+ T cells, exhibit heightened inflammatory responses, which KD partially reverses. CONCLUSIONS The KD induces inhibitory structural and functional alterations in immune cells from lymph nodes to retina, suggesting its potential as a therapy for uveitis.
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Affiliation(s)
- Runping Duan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Tianfu Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Zhaohuai Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Loujing Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Xiaoyang Yu
- Guangzhou University of Chinese Medicine, Guangzhou, 510060, China
| | - Daquan He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Tianyu Tao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Xiuxing Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Zhaohao Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China
| | - Lei Feng
- Eye Center, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangdong Provincial Clinical Research Center for Ocular Diseases, Guangzhou, 510060, China.
- Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 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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Vadhan A, Gupta T, Hsu WL. Mesenchymal Stem Cell-Derived Exosomes as a Treatment Option for Osteoarthritis. Int J Mol Sci 2024; 25:9149. [PMID: 39273098 PMCID: PMC11395657 DOI: 10.3390/ijms25179149] [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: 07/30/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/15/2024] Open
Abstract
Osteoarthritis (OA) is a leading cause of pain and disability worldwide in elderly people. There is a critical need to develop novel therapeutic strategies that can effectively manage pain and disability to improve the quality of life for older people. Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for age-related disorders due to their multilineage differentiation and strong paracrine effects. Notably, MSC-derived exosomes (MSC-Exos) have gained significant attention because they can recapitulate MSCs into therapeutic benefits without causing any associated risks compared with direct cell transplantation. These exosomes help in the transport of bioactive molecules such as proteins, lipids, and nucleic acids, which can influence various cellular processes related to tissue repair, regeneration, and immune regulation. In this review, we have provided an overview of MSC-Exos as a considerable treatment option for osteoarthritis. This review will go over the underlying mechanisms by which MSC-Exos may alleviate the pathological hallmarks of OA, such as cartilage degradation, synovial inflammation, and subchondral bone changes. Furthermore, we have summarized the current preclinical evidence and highlighted promising results from in vitro and in vivo studies, as well as progress in clinical trials using MSC-Exos to treat OA.
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Affiliation(s)
- Anupama Vadhan
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan
| | - Tanvi Gupta
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 701401, Taiwan
| | - Wen-Li Hsu
- National Center for Geriatrics and Welfare Research, National Health Research Institutes, Yunlin 632007, Taiwan
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 807378, Taiwan
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Liu T, Chen Y, Hou L, Yu Y, Ma D, Jiang T, Zhao G. Immune cell-mediated features of atherosclerosis. Front Cardiovasc Med 2024; 11:1450737. [PMID: 39234608 PMCID: PMC11371689 DOI: 10.3389/fcvm.2024.1450737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 08/05/2024] [Indexed: 09/06/2024] Open
Abstract
Atherosclerosis is a chronic inflammatory disease characterized by innate and adaptive immune responses, which seriously threatens human life and health. It is a primary cause of coronary heart disease, myocardial infarction, and peripheral vascular disease. Research has demonstrated that immune cells are fundamental to the development of atherosclerosis and chronic inflammation. Therefore, it is anticipated that immunotherapy targeting immune cells will be a novel technique in the management of atherosclerosis. This article reviews the growth of research on the regulatory role of immune cells in atherosclerosis and targeted therapy approaches. The purpose is to offer new therapeutic approaches for the control and treatment of cardiovascular illnesses caused by atherosclerosis.
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Affiliation(s)
- Tingting Liu
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Yanjun Chen
- Department of Pathology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lianjie Hou
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Yulu Yu
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Dan Ma
- School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China
| | - Ting Jiang
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
| | - Guojun Zhao
- Affiliated Qingyuan Hospital, Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, Guangdong, China
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Fang Q, Wu W, Xiao Z, Zeng D, Liang R, Wang J, Yuan J, Su W, Xu X, Zheng Y, Lai T, Sun J, Fu Q, Zheng SG. Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models. iScience 2024; 27:109818. [PMID: 38766356 PMCID: PMC11099335 DOI: 10.1016/j.isci.2024.109818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 03/25/2024] [Accepted: 04/24/2024] [Indexed: 05/22/2024] Open
Abstract
Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.
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Affiliation(s)
- Qiannan Fang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Medical Research Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Wenbin Wu
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zexiu Xiao
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Donglan Zeng
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Rongzhen Liang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
| | - Julie Wang
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
- Division of Rheumatology and Immunology, Department of Internal Medicine, The Ohio State University School of Medicine, Columbus, OH, USA
| | - Jia Yuan
- Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, Guangdong, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, Daping Hospital, Army Medical University, Chongqing, China
| | - Yue Zheng
- Department of Dermatology Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Tianwen Lai
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Qingling Fu
- Otorhinolaryngology Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Jiaotong University School of Medicine Affiliated Songjiang Hospital, Shanghai, China
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Wang SY, Zhang SJ, Meng HF, Xu HQ, Guo ZX, Yan JF, Gao JL, Niu LN, Wang SL, Jiao K. DPSCs regulate epithelial-T cell interactions in oral submucous fibrosis. Stem Cell Res Ther 2024; 15:113. [PMID: 38650025 PMCID: PMC11036714 DOI: 10.1186/s13287-024-03720-5] [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: 10/21/2023] [Accepted: 04/07/2024] [Indexed: 04/25/2024] Open
Abstract
BACKGROUND Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options. METHODS A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy. RESULTS A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19 + MIF + epithelial cells and via epithelial-stromal crosstalk. CONCLUSIONS Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.
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Affiliation(s)
- S Y Wang
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
| | - S J Zhang
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
| | - H F Meng
- Beijing SH Bio-tech Co., 100071, Beijing, P.R. China
| | - H Q Xu
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
- The College of Life Science, Northwest University, 710032, Xi'an, Shaanxi, P.R. China
| | - Z X Guo
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
| | - J F Yan
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
| | - J L Gao
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China
| | - L N Niu
- State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China.
| | - S L Wang
- Beijing Laboratory of Oral Health, Capital Medical University, 10 Xitoutiao, Fengtai District, 100069, Beijing, P.R. China.
- Laboratory of Homeostatic Medicine, School of Medicine, Southern University of Science and Technology, No. 1088 Xueyuan Avenue, Nanshan District, 518055, Shenzhen, P.R. China.
| | - K Jiao
- Department of Stomatology, Tangdu Hospital & State Key Laboratory of Oral and Maxillofacial Reconstruction and Regeneration & School of Stomatology, The Fourth Military Medical University, 169 West Changle Road, Xincheng District, 710032, Xi'an, Shaanxi, P. R. China.
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Chen J, Shi X, Deng Y, Dang J, Liu Y, Zhao J, Liang R, Zeng D, Wu W, Xiong Y, Yuan J, Chen Y, Wang J, Lin W, Chen X, Huang W, Olsen N, Pan Y, Fu Q, Zheng SG. miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model. JCI Insight 2024; 9:e177841. [PMID: 38652539 PMCID: PMC11141912 DOI: 10.1172/jci.insight.177841] [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: 11/22/2023] [Accepted: 04/10/2024] [Indexed: 04/25/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.
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Affiliation(s)
- Jingrong Chen
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiaoyi Shi
- Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Department of Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yanan Deng
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Junlong Dang
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yan Liu
- Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jun Zhao
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rongzhen Liang
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | | | - Yiding Xiong
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jia Yuan
- Department of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ye Chen
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Julie Wang
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weidong Lin
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiangfang Chen
- Department of Endocrinology, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Weishan Huang
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Nancy Olsen
- Division of Rheumatology, Department of Medicine, The Penn State University Hershey Medical Center, Hershey, Pennsylvania, USA
| | - Yunfeng Pan
- Department of Internal Medicine, Division of Rheumatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qingling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Song Guo Zheng
- Department of Immunology, School of Cell and Gene Therapy, Shanghai Songjiang Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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9
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Zhao J, Liu Y, Shi X, Dang J, Liu Y, Li S, Cai W, Hou Y, Zeng D, Chen Y, Yuan J, Xiong Y, Wu W, Cai P, Chen J, Sun J, Shao Y, Brand DD, Zheng SG. Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis. J Adv Res 2024; 58:79-91. [PMID: 37169220 PMCID: PMC10982864 DOI: 10.1016/j.jare.2023.05.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/21/2023] [Accepted: 05/04/2023] [Indexed: 05/13/2023] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. OBJECTIVES To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. METHODS The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. RESULTS We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. CONCLUSION Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.
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Affiliation(s)
- Jun Zhao
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yan Liu
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Xiaoyi Shi
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Junlong Dang
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China
| | - Yu Liu
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin 541000, China
| | - Siwen Li
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China
| | - Wei Cai
- Department of Neurology, Mental and Neurological Disease Research Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuluan Hou
- Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Donglan Zeng
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ye Chen
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jia Yuan
- Division of Stomatology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yiding Xiong
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Wenbin Wu
- Department of Spine Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Peihong Cai
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jingrong Chen
- Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jianbo Sun
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
| | - Yiming Shao
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China
| | - David D Brand
- The Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN 38163, United States
| | - Song Guo Zheng
- Department of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China; The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan 523710, China.
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10
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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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11
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Liu Y, Luo X, Chen Y, Dang J, Zeng D, Guo X, Weng W, Zhao J, Shi X, Chen J, Dong B, Zhong S, Ren J, Li Y, Wang J, Zhang J, Sun J, Xu H, Lu Y, Brand D, Zheng SG, Pan Y. Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis. Redox Biol 2024; 69:103008. [PMID: 38142586 PMCID: PMC10788633 DOI: 10.1016/j.redox.2023.103008] [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: 11/20/2023] [Revised: 12/12/2023] [Accepted: 12/18/2023] [Indexed: 12/26/2023] Open
Abstract
Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.
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Affiliation(s)
- Yan Liu
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiqing Luo
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Ye Chen
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Junlong Dang
- Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China
| | - Donglan Zeng
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xinghua Guo
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Weizhen Weng
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jun Zhao
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaoyi Shi
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jingrong Chen
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China; Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bo Dong
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Shuyuan Zhong
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jianhua Ren
- Department of Joint and Trauma Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yuhang Li
- Department of Joint and Trauma Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Julie Wang
- Division of Rheumatology and Immunology, Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Jingwen Zhang
- Department of Hematology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jianbo Sun
- Department of Clinical Research, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong, China
| | - Hanshi Xu
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yan Lu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - David Brand
- The Lt. Col. Luke Weathers, Jr. VA Medical Center, Memphis, TN, 38163, United States
| | - Song Guo Zheng
- Division of Rheumatology and Immunology, Department of Immunology, School of Cell and Gene Therapy, Songjiang Research Institute, Shanghai Songjiang District Central Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
| | - Yunfeng Pan
- Department of Rheumatology and Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China.
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12
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Tolouei AE, Oruji F, Tehrani S, Rezaei S, Mozaffari A, Jahri M, Nasiri K. Gingival mesenchymal stem cell therapy, immune cells, and immunoinflammatory application. Mol Biol Rep 2023; 50:10461-10469. [PMID: 37904011 DOI: 10.1007/s11033-023-08826-2] [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: 07/06/2023] [Accepted: 09/12/2023] [Indexed: 11/01/2023]
Abstract
MSC-based therapeutic strategies have proven to be incredibly effective. Robust self-renewal, multilineage differentiation, and potential for tissue regeneration and disease treatments are all features of MSCs isolated from oral tissue. Human exfoliated deciduous teeth, dental follicles, dental pulp, apical papilla SCs, and alveolar bone are the primary sources of oral MSC production. The early immunoinflammatory response is the first stage of the healing process. Oral MSCs can interact with various cells, such as immune cells, revealing potential immunomodulatory regulators. They also have strong differentiation and regeneration potential. Therefore, a ground-breaking strategy would be to research novel immunomodulatory approaches for treating disease and tissue regeneration that depend on the immunomodulatory activities of oral MSCs during tissue regeneration.
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Affiliation(s)
| | - Farshid Oruji
- College of Medicine, Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sahar Tehrani
- Department of Pediatric Dentistry, School of Dentistry, Ahvaz Jundishapour University of Medical Sciences Ahvaz, Ahvaz, Iran
| | - Sara Rezaei
- Restorative Dentistry Resident, Faculty of Dentistry, Kerman University of Medical Sciences, Kerman, Iran
| | - Asieh Mozaffari
- Department of Periodontics, Faculty of Dentistry, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Mohammad Jahri
- Dental Research Center, Research Institute of Dental Sciences, School of Dentistry, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Kamyar Nasiri
- Department of Dentistry, Islamic Azad University, Tehran, Iran.
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13
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Galgaro BC, Beckenkamp LR, Naasani LIS, Wink MR. Adenosine metabolism by mesenchymal stromal cells isolated from different human tissues. Hum Cell 2023; 36:2247-2258. [PMID: 37535223 DOI: 10.1007/s13577-023-00957-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/18/2023] [Indexed: 08/04/2023]
Abstract
Mesenchymal stromal cells (MSCs) have unique biological properties and play important functions, which make them attractive tools for cell-based therapies. The basic mechanisms of these cells are not fully understood. However, the adenosinergic pathway contributes to the main effects attributed to MSCs. Adenosine is a highly immunosuppressive molecule and exerts a central role in inflammation by neutralizing the proinflammatory ATP influence. This nucleoside is produced by purinergic signaling, an important physiological pathway for MSCs, which involves proliferation, migration, differentiation, and apoptosis. Therefore, in this study, we analyzed the extracellular AMP hydrolysis and consequent adenosine production, as well as the expression of CD73 and adenosine receptors on the cell surface of MSCs isolated from different human tissues: dermis (D-MSCs), adipose tissue (AD-MSCs), and umbilical cord (UC-MSCs). All cells confirmed their multipotent capacity by adipogenic, osteogenic, and chondrogenic differentiation, as well as the expression of cell surface markers including CD44 + , CD105 + , and CD90 + . All MSCs expressed similar levels of CD73 and CD26 without a statistical difference among the different tissues, whereas ADA expression was lower in AD-MSCs. In addition, A1R and A3R mRNA levels were higher in D-MSCs and AD-MSCs, respectively. Enzymatic assay showed that AD-MSCs have the highest hydrolysis rate of AMP, leading to increased amount of adenosine production. Moreover, despite all MSCs completely hydrolyze extracellular AMP generating adenosine, the pattern of nucleosides metabolism was different. Therefore, although MSCs share certain characteristics as the multilineage potential and immunophenotype, they show different adenosinergic profiles according to tissue origin.
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Affiliation(s)
- Bruna Campos Galgaro
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre, UFCSPA, Rua Sarmento Leite, 245, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Liziane Raquel Beckenkamp
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre, UFCSPA, Rua Sarmento Leite, 245, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Liliana I Sous Naasani
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre, UFCSPA, Rua Sarmento Leite, 245, Porto Alegre, RS, CEP 90050-170, Brazil
| | - Márcia Rosângela Wink
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre, UFCSPA, Rua Sarmento Leite, 245, Porto Alegre, RS, CEP 90050-170, Brazil.
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14
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Camarca A, Rotondi Aufiero V, Mazzarella G. Role of Regulatory T Cells and Their Potential Therapeutic Applications in Celiac Disease. Int J Mol Sci 2023; 24:14434. [PMID: 37833882 PMCID: PMC10572745 DOI: 10.3390/ijms241914434] [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: 08/03/2023] [Revised: 09/12/2023] [Accepted: 09/14/2023] [Indexed: 10/15/2023] Open
Abstract
Celiac disease (CeD) is a T-cell-mediated immune disease, in which gluten-derived peptides activate lamina propria effector CD4+ T cells. While this effector T cell subset produces proinflammatory cytokines, which cause substantial tissue injury in vivo, additional subsets of T cells exist with regulatory functions (Treg). These subsets include CD4+ type 1 regulatory T cells (Tr1) and CD4+ CD25+ T cells expressing the master transcription factor forkhead box P3 (Foxp3) that may have important implications in disease pathogenesis. In this review, we provide an overview of the current knowledge about the effects of immunomodulating cytokines on CeD inflammatory status. Moreover, we outline the main Treg cell populations found in CeD and how their regulatory activity could be influenced by the intestinal microenvironment. Finally, we discuss the Treg therapeutic potential for the development of alternative strategies to the gluten-free diet (GFD).
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Affiliation(s)
- Alessandra Camarca
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
| | - Vera Rotondi Aufiero
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, 80138 Naples, Italy
| | - Giuseppe Mazzarella
- Institute of Food Sciences, National Research Council—CNR, 83100 Avellino, Italy (V.R.A.)
- Department of Medical Translational Sciences and European Laboratory for the Investigation of Food-Induced Diseases, University Federico II, 80138 Naples, Italy
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15
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Fadl A, Leask A. Hiding in Plain Sight: Human Gingival Fibroblasts as an Essential, Yet Overlooked, Tool in Regenerative Medicine. Cells 2023; 12:2021. [PMID: 37626831 PMCID: PMC10453328 DOI: 10.3390/cells12162021] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 08/01/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Adult human gingival fibroblasts (HGFs), the most abundant cells in the oral cavity, are essential for maintaining oral homeostasis. Compared with other tissues, adult oral mucosal wounds heal regeneratively, without scarring. Relative to fibroblasts from other locations, HGFs are relatively refractory to myofibroblast differentiation, immunomodulatory, highly regenerative, readily obtained via minimally invasive procedures, easily and rapidly expanded in vitro, and highly responsive to growth factors and cytokines. Consequently, HGFs might be a superior, yet perhaps underappreciated, source of adult mesenchymal progenitor cells to use in tissue engineering and regeneration applications, including the treatment of fibrotic auto-immune connective tissue diseases such as scleroderma. Herein, we highlight in vitro and translational studies that have investigated the regenerative and differentiation potential of HGFs, with the objective of outlining current limitations and inspiring future research that could facilitate translating the regenerative potential of HGFs into the clinic.
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Affiliation(s)
| | - Andrew Leask
- College of Dentistry, University of Saskatchewan, 105 Wiggins Road, Saskatoon, SK S7N 5A2, Canada;
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16
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Gao Y, Duan R, Li H, Jiang L, Tao T, Liu X, Zhu L, Li Z, Chen B, Zheng S, Lin X, Su W. Single-cell analysis of immune cells on gingiva-derived mesenchymal stem cells in experimental autoimmune uveitis. iScience 2023; 26:106729. [PMID: 37216113 PMCID: PMC10192653 DOI: 10.1016/j.isci.2023.106729] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 03/22/2023] [Accepted: 04/19/2023] [Indexed: 05/24/2023] Open
Abstract
Gingiva-derived mesenchymal stem cells (GMSCs) have shown astonishing efficacy in the treatment of various autoimmune diseases. However, the mechanisms underlying these immunosuppressive properties remain poorly understood. Here, we generated a lymph node single-cell transcriptomic atlas of GMSC-treated experimental autoimmune uveitis mice. GMSC exerted profound rescue effects on T cells, B cells, dendritic cells, and monocytes. GMSCs rescued the proportion of T helper 17 (Th17) cells and increased the proportion of regulatory T cells. In addition to globally altered transcriptional factors (Fosb and Jund), we observed cell type-dependent gene regulation (e.g., Il17a and Rac1 in Th17 cells), highlighting the GMSCs' cell type-dependent immunomodulatory capacity. GMSCs strongly influenced the phenotypes of Th17 cells, suppressing the formation of the highly inflammatory CCR6-CCR2+ phenotype and enhancing the production of interleukin (IL) -10 in the CCR6+CCR2+ phenotype. Integration of the glucocorticoid-treated transcriptome suggests a more specific immunosuppressive effect of GMSCs on lymphocytes.
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Affiliation(s)
- Yuehan Gao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Runping Duan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - He Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Loujing Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Tianyu Tao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Xiuxing Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Lei Zhu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Zhaohuai Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Binyao Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Songguo Zheng
- The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Xianchai Lin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 51000, China
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Sardana Y, Bhatti GK, Singh C, Sharma PK, Reddy PH, Bhatti JS. Progression of pre-rheumatoid arthritis to clinical disease of joints: Potential role of mesenchymal stem cells. Life Sci 2023; 321:121641. [PMID: 36997059 DOI: 10.1016/j.lfs.2023.121641] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/16/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023]
Abstract
Rheumatoid arthritis (RA) related autoimmunity is developed at mucosal sites due to the interplay between genetic risk factors and environmental triggers. The pre-RA phase that leads to anti-citrullinated protein antibodies, rheumatoid factor, and other autoantibodies spread in the systemic circulation may not affect articular tissue for years until a mysterious second hit triggers the localization of RA-related autoimmunity in joints. Several players in the joint microenvironment mediate the synovial innate and adaptive immunological processes, eventually leading to clinical synovitis. There still exists a gap in the early phase of RA pathogenesis, i.e., the progression of diseases from the systemic circulation to joints. The lack of better understanding of these events results in the inability to answer questions about why only after a certain point of time the disease appears in joints and why in some cases, it simply remains latent and doesn't affect joints at all. In the current review, we focused on the immunomodulatory and regenerative role of mesenchymal stem cells and associated exosomes in RA pathology. We also highlighted the age-related dysregulations in activities of mesenchymal stem cells and how that might trigger homing of systemic autoimmunity to joints.
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Affiliation(s)
- Yogesh Sardana
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India
| | - Gurjit Kaur Bhatti
- Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, India
| | - Charan Singh
- Department of Pharmaceutical Sciences, Hemvati Nandan Bahuguna Garhwal University, Uttarakhand, India
| | | | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Garrison Institute on Aging, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Sciences, Texas Tech University, 1301 Akron Ave, Lubbock, TX 79409, USA.
| | - Jasvinder Singh Bhatti
- Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.
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18
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Li W, Liu Q, Shi J, Xu X, Xu J. The role of TNF-α in the fate regulation and functional reprogramming of mesenchymal stem cells in an inflammatory microenvironment. Front Immunol 2023; 14:1074863. [PMID: 36814921 PMCID: PMC9940754 DOI: 10.3389/fimmu.2023.1074863] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/24/2023] [Indexed: 02/09/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are pluripotent stem cells with multidirectional differentiation potential and strong immunomodulatory capacity. MSCs have been widely used in the treatment of injured, inflammatory, and immune-related diseases. Resting MSCs lack differentiation and immunomodulatory ability. Instead, they rely on microenvironmental factors to: 1) stimulate and regulate their expression of specific cell growth factors, chemokines, immunomodulatory factors, or receptors; or 2) direct their differentiation into specific tissue cells, which ultimately perform tissue regeneration and repair and immunomodulatory functions. Tumor necrosis factor (TNF)-α is central to the creation of an inflammatory microenvironment. TNF-α regulates the fate and functional reprogramming of MSCs, either alone or in combination with a variety of other inflammatory factors. TNF-α can exert opposing effects on MSCs, from inducing MSC apoptosis to enhancing their anti-tumor capacity. In addition, the immunomodulation and osteogenic differentiation capacities of MSCs, as well as their exosome or microvesicle components vary significantly with TNF-α stimulating concentration, time of administration, or its use in combination with or without other factors. Therefore, this review discusses the impact of TNF-α on the fate and functional reprogramming of MSCs in the inflammatory microenvironment, to provide new directions for improving the immunomodulatory and tissue repair functions of MSCs and enhance their therapeutic potential.
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Affiliation(s)
- Weiqiang Li
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China.,Department of Research and Development, Ankerui (Shanxi) Biological Cell Co., Ltd., Shanxi, China
| | - Qianqian Liu
- Department of Research and Development, Ankerui (Shanxi) Biological Cell Co., Ltd., Shanxi, China
| | - Jinchao Shi
- Department of Research and Development, Ankerui (Shanxi) Biological Cell Co., Ltd., Shanxi, China
| | - Xiang Xu
- Department of Stem Cell & Regenerative Medicine, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Army Medical University, Chongqing, China.,Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Army Medical University, Chongqing, China
| | - Jinyi Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
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19
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Abstract
Abstract
The pathogenesis of connective tissue diseases (CTDs), represented by systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), primary Sjögren’s syndrome (pSS), and idiopathic inflammatory myopathies (IIM), includes various immune cells involved in both innate and adaptive immunity. The mesenchymal stem cells (MSCs) are unique due to their regulatory effect on immunity. This makes them a promising therapeutic approach for patients with immune-mediated disorders such as CTD. The safety and clinical efficacy of MSC treatment in CTD have been tested in a growing number of preclinical and clinical studies. Administration of MSCs has consistently shown benefits with both symptomatic and histologic improvement in CTD animal models. MSC therapies in severe and drug-resistant CTD patients have shown promise in a number of the pilot studies, cohort studies, and randomized controlled trials in SLE, RA, and SSc, but some problems still need to be resolved in the transition from the bench to the bedside. The relevant studies in pSS and IIM are still in their infancy, but have displayed encouraging outcomes. Considerable efficacy variations have been observed in terms of the route of delivery, time of MSC injection, origin of the MSCs and dosage. Furthermore, the optimization of conventional drugs combined with MSC therapies and the applications of novel cell engineering approaches requires additional research. In this review, we summarize the current evidence about the immunoregulatory mechanism of MSCs, as well as the preclinical and clinical studies of MSC-based therapy for the treatment of CTDs.
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20
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Ahuja A, Tyagi PK, Kumar M, Sharma N, Prakash S, Radha, Chandran D, Dhumal S, Rais N, Singh S, Dey A, Senapathy M, Saleena LAK, Shanavas A, Mohankumar P, Rajalingam S, Murugesan Y, Vishvanathan M, Sathyaseelan SK, Viswanathan S, Kumar KK, Natta S, Mekhemar M. Botanicals and Oral Stem Cell Mediated Regeneration: A Paradigm Shift from Artificial to Biological Replacement. Cells 2022; 11:2792. [PMID: 36139367 PMCID: PMC9496740 DOI: 10.3390/cells11182792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/03/2022] [Accepted: 09/04/2022] [Indexed: 11/23/2022] Open
Abstract
Stem cells are a well-known autologous pluripotent cell source, having excellent potential to develop into specialized cells, such as brain, skin, and bone marrow cells. The oral cavity is reported to be a rich source of multiple types of oral stem cells, including the dental pulp, mucosal soft tissues, periodontal ligament, and apical papilla. Oral stem cells were useful for both the regeneration of soft tissue components in the dental pulp and mineralized structure regeneration, such as bone or dentin, and can be a viable substitute for traditionally used bone marrow stem cells. In recent years, several studies have reported that plant extracts or compounds promoted the proliferation, differentiation, and survival of different oral stem cells. This review is carried out by following the PRISMA guidelines and focusing mainly on the effects of bioactive compounds on oral stem cell-mediated dental, bone, and neural regeneration. It is observed that in recent years studies were mainly focused on the utilization of oral stem cell-mediated regeneration of bone or dental mesenchymal cells, however, the utility of bioactive compounds on oral stem cell-mediated regeneration requires additional assessment beyond in vitro and in vivo studies, and requires more randomized clinical trials and case studies.
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Affiliation(s)
- Anami Ahuja
- Department of Biotechnology, Dr. A.P.J. Abdul Kalam Technical University, Lucknow 226031, India
- Department of Biotechnology, Meerut Institute of Engineering and Technology, Meerut 250005, India
| | - Pankaj Kumar Tyagi
- Department of Biotechnology, Noida Institute of Engineering & Technology, Greater Noida 201306, India
| | - Manoj Kumar
- Chemical and Biochemical Processing Division, ICAR–Central Institute for Research on Cotton Technology, Mumbai 400019, India
| | - Naveen Sharma
- Division of Biomedical Informatics, Indian Council of Medical Research, New Delhi 110029, India
| | - Suraj Prakash
- School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
| | - Radha
- School of Biological and Environmental Sciences, Shoolini University of Biotechnology and Management Sciences, Solan 173229, India
| | - Deepak Chandran
- Department of Veterinary Sciences and Animal Husbandry, Amrita School of Agricultural Sci-ences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Sangram Dhumal
- Division of Horticulture, RCSM College of Agriculture, Kolhapur 416004, India
| | - Nadeem Rais
- Department of Pharmacy, Bhagwant University, Ajmer 305004, India
| | - Surinder Singh
- Dr. S. S. Bhatnagar University Institute of Chemical Engineering and Technology, Panjab University, Chandigarh 160014, India
| | - Abhijit Dey
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, India
| | - Marisennayya Senapathy
- Department of Rural Development and Agricultural Extension, College of Agriculture, Wolaita Sodo University, Wolaita Sodo P.O. Box 138, Ethiopia
| | - Lejaniya Abdul Kalam Saleena
- Department of Food Science and Nutrition, Faculty of Applied Sciences, UCSI University, Kuala Lampur 56000, Malaysia
| | - Arjun Shanavas
- Division of Medicine, Indian Veterinary Research Institute, Bareilly 243122, India
| | - Pran Mohankumar
- School of Agriculture and Biosciences, Karunya Institute of Technology and Sciences, Coimbatore 641114, India
| | - Sureshkumar Rajalingam
- Department of Agronomy, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Yasodha Murugesan
- Department of Agronomy, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Marthandan Vishvanathan
- Department of Seed Science and Technology, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | | | - Sabareeshwari Viswanathan
- Department of Soil Science and Agricultural Chemistry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Keerthana Krishna Kumar
- Department of Soil Science and Agricultural Chemistry, Amrita School of Agricultural Sciences, Amrita Vishwa Vidyapeetham University, Coimbatore 642109, India
| | - Suman Natta
- ICAR—National Research Centre for Orchids, Pakyong 737106, India
| | - Mohamed Mekhemar
- Clinic for Conservative Dentistry and Periodontology, School of Dental Medicine, Chris-tian-Albrecht’s University, 24105 Kiel, Germany
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21
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Yang M, Wang L, Chen Z, Hao W, You Q, Lin J, Tang J, Zhao X, Gao WQ, Xu H. Topical administration of the secretome derived from human amniotic epithelial cells ameliorates psoriasis-like skin lesions in mice. Stem Cell Res Ther 2022; 13:393. [PMID: 35922852 PMCID: PMC9351215 DOI: 10.1186/s13287-022-03091-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 07/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Psoriasis is a chronic inflammatory skin disease. Tissue stem cells have exhibited a therapeutic effect on psoriatic mice. However, the therapeutic effect of topical administration of the secretome derived from tissue stem cells on psoriasis has not been reported. METHODS The secretome from human amniotic epithelial cells (AEC-SC) and human umbilical cord mesenchymal stem cells (UMSC-SC) was topically administrated on the back of imiquimod-induced psoriasis-like mice. Subsequently, we observed the skin lesions and skin inflammation of psoriasis-like mice. Next, we further analyzed the paracrine factors in AEC-SC and UMSC-SC by protein chips. Lastly, the effect of the crucial paracrine factor was investigated by imiquimod-induced psoriasis-like mice. RESULTS We found that AEC-SC had a better therapeutic effect on attenuating psoriasis-like skin lesions including skin scales, skin redness and skin thickness than UMSC-SC, and it had a better regulatory effect on keratinocyte hyperproliferation and altered differentiation. Thus, we focused on AEC-SC. Further study showed that AEC-SC reduced the infiltration of neutrophils and interleukin-17-producing T cells. Next, the analysis of AEC-SC with protein chip revealed that the levels of anti-inflammatory factor interleukin-1 receptor antagonist (IL-1ra) were much higher in AEC-SC compared to that in UMSC-SC. More importantly, the beneficial effect of AEC-SC on psoriasis-like skin lesions and skin inflammation of mice were significantly impaired when neutralizing with IL-1ra antibody, while the recombinant human IL-1ra showed a less protective effect than AEC-SC. CONCLUSIONS The present study demonstrated that AEC-SC could efficiently ameliorate psoriasis-like skin lesions and skin inflammation and IL-1ra plays an essential role. Therefore, topical administration of AEC-SC may provide a novel strategy for treating psoriasis-like inflammatory skin diseases.
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Affiliation(s)
- Mengbo Yang
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Lanqi Wang
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Zhimin Chen
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Weijie Hao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Qian You
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jingzhi Tang
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xin Zhao
- Department of Dermatology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Wei-Qiang Gao
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. .,Med-X Research Institute and School of Biological Medical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-MedX Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
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22
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Genç D, Bulut O, Günaydin B, Göksu M, Düzgün M, Dere Y, Sezgin S, Aladağ A, Bülbül A. Dental follicle mesenchymal stem cells ameliorated glandular dysfunction in Sjögren's syndrome murine model. PLoS One 2022; 17:e0266137. [PMID: 35511824 PMCID: PMC9070867 DOI: 10.1371/journal.pone.0266137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 03/14/2022] [Indexed: 11/18/2022] Open
Abstract
OBJECTIVE Dental mesenchymal stem cells (MSCs) are potential for use in tissue regeneration in inflammatory diseases due to their rapid proliferating, multilineage differentiation, and strong anti-inflammatory features. In the present study, immunoregulatory and glandular tissue regeneration effects of the dental follicle (DF)MSCs in Sjögren's Syndrome (SS) were investigated. METHODS Dental follicle (DF) tissues were obtained from healthy individuals during tooth extraction, tissues were digested enzymatically and DFMSCs were cultured until the third passage. DFMSCs were labeled with Quantum dot 655 for cell tracking analysis. The induction of the SS mouse model was performed by the injection of Ro60-273-289 peptide intraperitoneally. DFMSCs were injected intraperitoneally, or into submandibular, or lacrimal glands. Splenocytes were analyzed for intracellular cytokine (IFN-γ, IL-17, IL-10) secretion in T helper cells, lymphocyte proliferation, and B lymphocyte subsets. Histologic analysis was done for submandibular and lacrimal glands with hematoxylin-eosin staining for morphologic examination. RESULTS The systemic injection of DFMSCs significantly reduced intracellular IFN-γ and IL-17 secreting CD4+ T cells in splenocytes (p<0.05), and decreased inflammatory cell deposits and fibrosis in the glandular tissues. DFMSCs differentiated to glandular epithelial cells in submandibular and lacrimal injections with a significant reduction in lymphocytic foci. The results showed that few amounts of DFMSCs were deposited in glandular tissues when applied intraperitoneally, while high amounts of DFMSCs were located in glandular tissues and differentiated to glandular epithelial cells when applied locally in SS murine model. CONCLUSION DFMSCs have the potential for the regulation of Th1, Th17, and Treg balance in SS, and ameliorate glandular dysfunction. DFMSCs can be a beneficial therapeutic application for SS.
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Affiliation(s)
- Deniz Genç
- Faculty of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
- Research Laboratories Center, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Osman Bulut
- Milas Veterinary Medicine Faculty, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Burcu Günaydin
- Department of Histology and Embryology, Institute of Health Sciences, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Mizgin Göksu
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Mert Düzgün
- Faculty of Science, Department of Molecular Biology and Genetics, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Yelda Dere
- Faculty of Medicine, Department of Pathology, Muğla Sıtkı Koçman University, Muğla, Turkey
| | - Serhat Sezgin
- Faculty of Dentistry, Muğla Sıtkı Koçman Üniversity, Muğla, Turkey
| | - Akın Aladağ
- Faculty of Dentistry, Muğla Sıtkı Koçman Üniversity, Muğla, Turkey
| | - Aziz Bülbül
- Milas Veterinary Medicine Faculty, Muğla Sıtkı Koçman University, Muğla, Turkey
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23
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Yu Z, Wen Y, Jiang N, Li Z, Guan J, Zhang Y, Deng C, Zhao L, Zheng SG, Zhu Y, Su W, Zhuo Y. TNF-α stimulation enhances the neuroprotective effects of gingival MSCs derived exosomes in retinal ischemia-reperfusion injury via the MEG3/miR-21a-5p axis. Biomaterials 2022; 284:121484. [DOI: 10.1016/j.biomaterials.2022.121484] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 12/14/2022]
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Therapeutic Targets in Allergic Conjunctivitis. Pharmaceuticals (Basel) 2022; 15:ph15050547. [PMID: 35631374 PMCID: PMC9147625 DOI: 10.3390/ph15050547] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 02/02/2023] Open
Abstract
Allergic conjunctivitis (AC) is a common condition resulting from exposure to allergens such as pollen, animal dander, or mold. It is typically mediated by allergen-induced crosslinking of immunoglobulin E attached to receptors on primed conjunctival mast cells, which results in mast cell degranulation and histamine release, as well as the release of lipid mediators, cytokines, and chemokines. The clinical result is conjunctival hyperemia, tearing, intense itching, and chemosis. Refractory and chronic cases can result in ocular surface complications that may be vision threatening. Patients who experience even mild forms of this disease report an impact on their quality of life. Current treatment options range from non-pharmacologic therapies to ocular and systemic options. However, to adequately control AC, the use of multiple agents is often required. As such, a precise understanding of the immune mechanisms responsible for this ocular surface inflammation is needed to support ongoing research for potential therapeutic targets such as chemokine receptors, cytokine receptors, non-receptor tyrosine kinases, and integrins. This review utilized several published articles regarding the current therapeutic options to treat AC, as well as the pathological and immune mechanisms relevant to AC. This review will also focus on cellular and molecular targets in AC, with particular emphasis on potential therapeutic agents that can attenuate the pathology and immune mechanisms driven by cells, receptors, and molecules that participate in the immunopathogenesis and immunopathology of AC.
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25
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Taihi I, Pilon C, Cohen J, Berdal A, Gogly B, Nassif A, Fournier BP. Efficient isolation of human gingival stem cells in a new serum-free medium supplemented with platelet lysate and growth hormone for osteogenic differentiation enhancement. Stem Cell Res Ther 2022; 13:125. [PMID: 35337377 PMCID: PMC8951723 DOI: 10.1186/s13287-022-02790-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 02/25/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The use of distant autografts to restore maxillary bone defects is clinically challenging and has unpredictable outcomes. This variation may be explained by the embryonic origin of long bone donor sites, which are derived from mesoderm, whereas maxillary bones derive from neural crest. Gingival stem cells share the same embryonic origin as maxillary bones. Their stemness potential and ease of access have been repeatedly shown. One limitation in human cell therapy is the use of foetal calf serum during cell isolation and culture. To overcome this problem, a new serum-free medium enriched with an alternative to foetal calf serum, i.e., platelet lysate, needs to be adapted to clinical grade protocols. METHODS Different serum-free media enriched with platelet lysate at various concentrations and supplemented with different growth factors were developed and compared to media containing foetal calf serum. Phenotypic markers, spontaneous DNA damage, and stem cell properties of gingival stem cells isolated in platelet lysate or in foetal calf serum were also compared, as were the immunomodulatory properties of the cells by co-culturing them with activated peripheral blood monocellular cells. T-cell proliferation and phenotype were also assessed by flow cytometry using cell proliferation dye and specific surface markers. Data were analysed with t-test for two-group comparisons, one-way ANOVA for multigroup comparisons and two-way ANOVA for repeated measures and multigroup comparisons. RESULTS Serum-free medium enriched with 10% platelet lysate and growth hormone yielded the highest expansion rate. Gingival stem cell isolation and thawing under these conditions were successful, and no significant DNA lesions were detected. Phenotypic markers of mesenchymal stem cells and differentiation capacities were conserved. Gingival stem cells isolated in this new serum-free medium showed higher osteogenic differentiation potential compared to cells isolated in foetal calf serum. The proportion of regulatory T cells obtained by co-culturing gingival stem cells with activated peripheral blood monocellular cells was similar between the two types of media. CONCLUSIONS This new serum-free medium is well suited for gingival stem cell isolation and proliferation, enhances osteogenic capacity and maintains immunomodulatory properties. It may allow the use of gingival stem cells in human cell therapy for bone regeneration in accordance with good manufacturing practice guidelines.
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Affiliation(s)
- Ihsène Taihi
- Laboratory of Molecular Oral Pathophysiologie, Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, 75006, Paris, France. .,AP-HP, site hospitalier Charles Foix-Pitié Salpêtrière, 94200, Ivry, France.
| | - Caroline Pilon
- AP-HP, site hospitalier Henri Mondor, CIC-BT-504, INSERM UMRS 955, Paris-Est University, Créteil, France
| | - José Cohen
- AP-HP, site hospitalier Henri Mondor, CIC-BT-504, INSERM UMRS 955, Paris-Est University, Créteil, France
| | - Ariane Berdal
- Laboratory of Molecular Oral Pathophysiologie, Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, 75006, Paris, France.,AP-HP, sites hospitaliers Pitié Salpêtrière et Rothschild, Département d'Orthopédie Dento-Faciale, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), 75013-75019, Paris, France
| | - Bruno Gogly
- Laboratory of Molecular Oral Pathophysiologie, Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, 75006, Paris, France.,AP-HP, site hospitalier Henri Mondor, CIC-BT-504, INSERM UMRS 955, Paris-Est University, Créteil, France
| | - Ali Nassif
- Laboratory of Molecular Oral Pathophysiologie, Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, 75006, Paris, France.,AP-HP, sites hospitaliers Pitié Salpêtrière et Rothschild, Département d'Orthopédie Dento-Faciale, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), 75013-75019, Paris, France
| | - Benjamin Philippe Fournier
- Laboratory of Molecular Oral Pathophysiologie, Centre de Recherche des Cordeliers, INSERM, Université de Paris, Sorbonne Université, 75006, Paris, France. .,AP-HP, sites hospitaliers Pitié Salpêtrière et Rothschild, Département d'Orthopédie Dento-Faciale, Centre de Référence Maladies Rares Orales et Dentaires (O-Rares), 75013-75019, Paris, France.
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26
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Paganelli A, Trubiani O, Diomede F, Pisciotta A, Paganelli R. Immunomodulating Profile of Dental Mesenchymal Stromal Cells: A Comprehensive Overview. FRONTIERS IN ORAL HEALTH 2022; 2:635055. [PMID: 35047993 PMCID: PMC8757776 DOI: 10.3389/froh.2021.635055] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Dental mesenchymal stromal cells (MSCs) are multipotent cells present in dental tissues, characterized by plastic adherence in culture and specific surface markers (CD105, CD73, CD90, STRO-1, CD106, and CD146), common to all other MSC subtypes. Dental pulp, periodontal ligament, apical papilla, human exfoliated deciduous teeth, alveolar bone, dental follicle, tooth germ, and gingiva are all different sources for isolation and expansion of MSCs. Dental MSCs have regenerative and immunomodulatory properties; they are scarcely immunogenic but actively modulate T cell reactivity. in vitro studies and animal models of autoimmune diseases have provided evidence for the suppressive effects of dental MSCs on peripheral blood mononuclear cell proliferation, clearance of apoptotic cells, and promotion of a shift in the Treg/Th17 cell ratio. Appropriately stimulated MSCs produce anti-inflammatory mediators, such as transforming growth factor-β (TGF-β), prostaglandin E2, and interleukin (IL)-10. A particular mechanism through which MSCs exert their immunomodulatory action is via the production of extracellular vesicles containing such anti-inflammatory mediators. Recent studies demonstrated MSC-mediated inhibitory effects both on monocytes and activated macrophages, promoting their polarization to an anti-inflammatory M2-phenotype. A growing number of trials focusing on MSCs to treat autoimmune and inflammatory conditions are ongoing, but very few use dental tissue as a cellular source. Recent results suggest that dental MSCs are a promising therapeutic tool for immune-mediated disorders. However, the exact mechanisms responsible for dental MSC-mediated immunosuppression remain to be clarified, and impairment of dental MSCs immunosuppressive function in inflammatory conditions and aging must be assessed before considering autologous MSCs or their secreted vesicles for therapeutic purposes.
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Affiliation(s)
- Alessia Paganelli
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy.,Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Oriana Trubiani
- Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy
| | - Francesca Diomede
- Department of Medical, Oral and Biotechnological Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy
| | - Alessandra Pisciotta
- Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto Paganelli
- Department of Medicine and Aging Sciences, University "G. D'Annunzio" Chieti-Pescara, Chieti, Italy.,YDA, Institute of Clinical Immunotherapy and Advanced Biological Treatments, Pescara, Italy
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Mesenchymal Stem Cell-Based Therapy as a New Approach for the Treatment of Systemic Sclerosis. Clin Rev Allergy Immunol 2022; 64:284-320. [PMID: 35031958 DOI: 10.1007/s12016-021-08892-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/24/2021] [Indexed: 12/13/2022]
Abstract
Systemic sclerosis (SSc) is an intractable autoimmune disease with unmet medical needs. Conventional immunosuppressive therapies have modest efficacy and obvious side effects. Targeted therapies with small molecules and antibodies remain under investigation in small pilot studies. The major breakthrough was the development of autologous haematopoietic stem cell transplantation (AHSCT) to treat refractory SSc with rapidly progressive internal organ involvement. However, AHSCT is contraindicated in patients with advanced visceral involvement. Mesenchymal stem cells (MSCs) which are characterized by immunosuppressive, antifibrotic and proangiogenic capabilities may be a promising alternative option for the treatment of SSc. Multiple preclinical and clinical studies on the use of MSCs to treat SSc are underway. However, there are several unresolved limitations and safety concerns of MSC transplantation, such as immune rejections and risks of tumour formation, respectively. Since the major therapeutic potential of MSCs has been ascribed to their paracrine signalling, the use of MSC-derived extracellular vesicles (EVs)/secretomes/exosomes as a "cell-free" therapy might be an alternative option to circumvent the limitations of MSC-based therapies. In the present review, we overview the current knowledge regarding the therapeutic efficacy of MSCs in SSc, focusing on progresses reported in preclinical and clinical studies using MSCs, as well as challenges and future directions of MSC transplantation as a treatment option for patients with SSc.
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28
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Tian X, Wei W, Cao Y, Ao T, Huang F, Javed R, Wang X, Fan J, Zhang Y, Liu Y, Lai L, Ao Q. Gingival mesenchymal stem cell-derived exosomes are immunosuppressive in preventing collagen-induced arthritis. J Cell Mol Med 2021; 26:693-708. [PMID: 34953015 PMCID: PMC8817124 DOI: 10.1111/jcmm.17086] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 10/26/2021] [Accepted: 11/16/2021] [Indexed: 01/08/2023] Open
Abstract
Due to the unsatisfied effects of clinical drugs used in rheumatoid arthritis (RA), investigators shifted their focus on the biotherapy. Although human gingival mesenchymal stem cells (GMSC) have the potential to be used in treating RA, GMSC‐based therapy has some inevitable side effects such as immunogenicity and tumorigenicity. As one of the most important paracrine mediators, GMSC‐derived exosomes (GMSC‐Exo) exhibit therapeutic effects via immunomodulation in a variety of disease models, bypassing potential shortcomings of the direct use of MSCs. Furthermore, exosomes are not sensitive to freezing and thawing, and can be readily available for use. GMSC‐Exo has been reported to promote tissue regeneration and wound healing, but have not been reported to be effective against autoimmune diseases. We herein compare the immunomodulatory functions of GMSC‐Exo and GMSC in collagen‐induced arthritis (CIA) model and in vitro CD4+ T‐cell co‐culture model. The results show that GMSC‐Exo has the same or stronger effects compared with GMSC in inhibiting IL‐17A and promoting IL‐10, reducing incidences and bone erosion of arthritis, via inhibiting IL‐17RA‐Act1‐TRAF6‐NF‐κB signal pathway. Our results suggest that GMSC‐Exo has many advantages in treating CIA, and may offer a promising new cell‐free therapy strategy for RA and other autoimmune diseases.
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Affiliation(s)
- Xiaohong Tian
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Wumei Wei
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Yue Cao
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Tianrang Ao
- Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Feng Huang
- Department of Clinical Immunology, Sun Yat-sen University, Third Affiliated Hospital, Guangzhou, PR China
| | - Rabia Javed
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Xiaohong Wang
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Jun Fan
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Yanhui Zhang
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China
| | - Yanying Liu
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Laijun Lai
- Department of Allied Health Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Qiang Ao
- Department of Tissue Engineering, School of Intelligent Medicine, China Medical University, Shenyang, China.,National Engineering Research Center for Biomaterials, Institute of Regulatory Science for Medical Device, Sichuan University, Chengdu, China
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29
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Wu B, Gao F, Lin J, Lu L, Xu H, Xu GT. Conditioned Medium of Human Amniotic Epithelial Cells Alleviates Experimental Allergic Conjunctivitis Mainly by IL-1ra and IL-10. Front Immunol 2021; 12:774601. [PMID: 34880869 PMCID: PMC8645696 DOI: 10.3389/fimmu.2021.774601] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2021] [Accepted: 10/25/2021] [Indexed: 01/04/2023] Open
Abstract
Allergic conjunctivitis (AC) is the most prevalent form of mucosal allergy, and the conditioned medium (CM) from mesenchymal stem cells has been reported to attenuate some allergic diseases. However, the therapeutic effects of CM from different tissue stem cells (TSC-CM) on allergic diseases have not been tested. Here, we studied the effects of topical administration of different human TSC-CM on experimental AC (EAC) mice. Only human amniotic epithelial cell-CM (AECM) significantly attenuated allergic eye symptoms and reduced the infiltration of immune cells and the levels of local inflammatory factors in the conjunctiva compared to EAC mice. In addition, AECM treatment decreased immunoglobulin E (IgE) release, histamine production, and the hyperpermeability of conjunctival vessels. Protein chip assays revealed that the levels of anti-inflammatory factors, interleukin-1 receptor antagonist (IL-1ra) and IL-10, were higher in AECM compared to other TSC-CM. Furthermore, the anti-allergic effects of AECM on EAC mice were abrogated when neutralized with IL-1ra or IL-10 antibody, and the similar phenomenon was for the activation and function of B cells and mast cells. Together, the present study demonstrated that AECM alleviates EAC symptoms by multiple anti-allergic mechanisms mainly via IL-1ra and IL-10. Such topical AECM therapy may represent a novel and feasible strategy for treating AC.
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Affiliation(s)
- Binxin Wu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Furong Gao
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Jianhua Lin
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lixia Lu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China
| | - Huiming Xu
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Guo-Tong Xu
- Department of Ophthalmology of Shanghai Tenth People's Hospital, Laboratory of Clinical Visual Science of Tongji Eye Institute, Tongji University School of Medicine, Shanghai, China.,Department of Pharmacology, Tongji University School of Medicine, Shanghai, China
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30
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Zhou Y, Dang J, Chen Y, Zheng SG, Du J. Microstructure and mechanical behaviors of tibia for collagen-induced arthritic mice treated with gingiva-derived mesenchymal stem cells. J Mech Behav Biomed Mater 2021; 124:104719. [PMID: 34481308 DOI: 10.1016/j.jmbbm.2021.104719] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/09/2021] [Accepted: 07/14/2021] [Indexed: 10/20/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic polyarticular arthritis that primarily affects the small joints but also causes bone erosion in large joints. None of the currently existing treatment approaches is curable. In this study, the effects of human gingiva-derived mesenchymal stem cells (GMSCs) on collagen-induced arthritis (CIA) mice are examined by experimentally assessing the microstructure and mechanical behaviors of tibia. Bone morphology and mineral density of mouse tibiae were assessed using micro-X-ray computed tomography (micro-CT). Compression testing was performed on mouse tibia to access its stiffness. The deformation and strain localized inside proximal tibia were mapped using mechanical testing coupled with micro-CT and digital volume correlation of micro-CT images. The results show that CIA disease caused bone erosion in epiphyseal cortical bone, which manifested into the adjacent epiphyseal trabecular bone, and also affected the metaphyseal cortical bone. CIA disease also weakened the load-bearing function of proximal tibia. GMSC treatment interfered with the progress of CIA, attenuated the bone erosion in epiphyseal and metaphyseal trabecular bone and resulted in improved load-bearing function of proximal tibia. GMSCs provide a promising potential treatment of autoimmune arthritis.
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Affiliation(s)
- Yuxiao Zhou
- Department of Mechanical Engineering, Pennsylvania State University, University Park, PA, USA.
| | - Junlong Dang
- Department of Clinical Immunology, Third Affiliated Hospital at the Sun Yat-sen University, Guangzhou, China.
| | - Ye Chen
- Division of Rheumatology and Immunology, Department of Internal Medicine at Ohio State University of Medicine and Wexner Medical Center, Columbus, OH, USA.
| | - Song Guo Zheng
- Division of Rheumatology and Immunology, Department of Internal Medicine at Ohio State University of Medicine and Wexner Medical Center, Columbus, OH, USA.
| | - Jing Du
- Department of Mechanical Engineering, Pennsylvania State University, University Park, PA, USA.
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31
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Shang L, Shao J, Ge S. Immunomodulatory functions of oral mesenchymal stem cells: Novel force for tissue regeneration and disease therapy. J Leukoc Biol 2021; 110:539-552. [PMID: 34184321 DOI: 10.1002/jlb.3mr0321-766r] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs)-based therapeutic strategies have achieved remarkable efficacies. Oral tissue-derived MSCs, with powerful self-renewal and multilineage differentiation abilities, possess the features of abundant sources and easy accessibility and hold great potential in tissue regeneration and disease therapies. Oral MSCs mainly consist of periodontal ligament stem cells, gingival mesenchymal stem cells, dental pulp stem cells, stem cells from human exfoliated deciduous teeth, stem cells from the apical papilla, dental follicle stem cells, and alveolar bone-derived mesenchymal stem. Early immunoinflammatory response stage is the prerequisite phase of healing process. Besides the potent capacities of differentiation and regeneration, oral MSCs are capable of interacting with various immune cells and function as immunomodulatory regulators. Consequently, the immunomodulatory effects of oral MSCs during damage repair seem to be crucial for exploring novel immunomodulatory strategies to achieve disease recovery and tissue regeneration. Herein, we reviewed various oral MSCs with their immunomodulatory properties and the potential mechanism, as well as their effects on immunomodulation-mediated disease therapies and tissue regeneration.
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Affiliation(s)
- Lingling Shang
- Department of Periodontology, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, China
| | - Jinlong Shao
- Department of Periodontology, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, China
| | - Shaohua Ge
- Department of Periodontology, School and Hospital of Stomatology, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Laboratory for Dental Materials and Oral Tissue Regeneration, Jinan, Shandong, China
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32
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Wu J, Chen Z, Zhong F, Yang W, Ouyang X, Ma X, Zheng S, Wei H. Transplantation of Human Gingiva-Derived Mesenchymal Stem Cells Ameliorates Neurotic Erectile Dysfunction in a Rat Model. Front Bioeng Biotechnol 2021; 9:630076. [PMID: 34235136 PMCID: PMC8255925 DOI: 10.3389/fbioe.2021.630076] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 04/22/2021] [Indexed: 12/23/2022] Open
Abstract
Cavernous nerve injury (CNI) is the main cause of erectile dysfunction (ED) following pelvic surgery. Our previous studies have demonstrated that transplantation of different sources of mesenchymal stem cells (MSCs) was able to alleviate ED induced by CNI in rat models. However, little is known about the therapeutic effects of human gingiva-derived MSCs (hGMSCs) in CNI ED rats. Herein, we injected the hGMSCs around the bilateral major pelvic ganglia (MPG) in a rat model of CNI and evaluated their efficacy. The results showed that treatment of hGMSCs could significantly promote the recovery of erectile function, enhance smooth muscle and endothelial content, restore neuronal nitric oxide synthase (nNOS) expression, and attenuate cell apoptosis in penile tissue. Moreover, penile fibrosis was significantly alleviated after hGMSC administration. In addition, potential mechanism exploration indicated that hGMSCs might exert its functions via skewed macrophage polarity from M1 toward M2 anti-inflammatory phenotype. In conclusion, this study found that transplantation of hGMSCs significantly improved CNI-related ED, which might provide new clues to evaluate their pre-clinical application.
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Affiliation(s)
- Juekun Wu
- Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Zehong Chen
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fuyan Zhong
- Central Laboratory, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wende Yang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xi Ouyang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaolei Ma
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Songguo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, United States
| | - Hongbo Wei
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
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33
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Liu H, Zhao J, Su M, Tian X, Lai L. Recombinant CD300c-Fc fusion protein attenuates collagen-induced arthritis in mice. Rheumatology (Oxford) 2021; 61:1255-1264. [PMID: 34021311 DOI: 10.1093/rheumatology/keab450] [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: 02/11/2021] [Revised: 05/13/2021] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVES Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and tissue destruction. Immune responses mediated by T cells and autoantibodies are known to play critical roles in RA. Collagen type II (CII)-induced arthritis (CIA) is a commonly used animal model of human RA. We have previously reported the identification of a new T cell inhibitory molecule CD300c. Here we investigate the ability of recombinant CD300c-IgG2a Fc (CD300c-Ig) fusion protein to prevent and treat CIA. METHODS Mice were induced to develop CIA by CII and injected with CD300c-Ig or control Ig protein before or after CIA symptoms occur. The mice were examined for CIA clinical and pathological scores, and analyzed for the expression of proinflammatory cytokines, the percentage and activation of CD4 T cells and regulatory T cells, CII-specific T cell proliferation and cytokine production, and CII-specific autoantibody production. RESULTS In a prevention model, CD300c-Ig significantly decreases CIA incidence, and reduces clinical and pathological arthritis scores. In the treatment model, CD300c-Ig ameliorates established CIA. The beneficial effects of CD300c-Ig are related to decreased expansion and activation of T cells in the spleen and reduced expression of proinflammatory cytokines in the joints. CD300c-Ig also inhibits CII-specific T cell proliferation and Th1 and Th17 cytokine production. In addition, CD300c-Ig treatment reduced the production of CII autoantibodies in the serum. Furthermore, CD300c-Ig inhibits the proliferation and activation of T cells from RA patients in vitro. CONCLUSION CD300c-Ig protein has the potential to be used in the treatment of patients with RA.
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Affiliation(s)
- Haiyan Liu
- Shandong Provincial Hospital, Shandong First Medical University, Jinan, 250021, ChinaAffiliated to.,Department of Allied Health Sciences, University of Connecticut, Storrs, CT, U.S.A
| | - Jin Zhao
- Department of Allied Health Sciences, University of Connecticut, Storrs, CT, U.S.A
| | - Min Su
- Department of Allied Health Sciences, University of Connecticut, Storrs, CT, U.S.A.,Department of Human Histology and Embryology, Tissue Engineering and Stem Cell Research Center, Guizhou Medical University, Guiyang, 550004, China
| | - Xiaohong Tian
- Department of Tissue Engineering, School of Fundamental Science, China Medical University, Shenyang, 110122, China
| | - Laijun Lai
- Department of Allied Health Sciences, University of Connecticut, Storrs, CT, U.S.A.,University of Connecticut Stem Cell Institute, University of Connecticut, Storrs, CT, U.S.A
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34
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Kim D, Lee AE, Xu Q, Zhang Q, Le AD. Gingiva-Derived Mesenchymal Stem Cells: Potential Application in Tissue Engineering and Regenerative Medicine - A Comprehensive Review. Front Immunol 2021; 12:667221. [PMID: 33936109 PMCID: PMC8085523 DOI: 10.3389/fimmu.2021.667221] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/30/2021] [Indexed: 12/15/2022] Open
Abstract
A unique subpopulation of mesenchymal stem cells (MSCs) has been isolated and characterized from human gingival tissues (GMSCs). Similar to MSCs derived from other sources of tissues, e.g. bone marrow, adipose or umbilical cord, GMSCs also possess multipotent differentiation capacities and potent immunomodulatory effects on both innate and adaptive immune cells through the secretion of various types of bioactive factors with immunosuppressive and anti-inflammatory functions. Uniquely, GMSCs are highly proliferative and have the propensity to differentiate into neural cell lineages due to the neural crest-origin. These properties have endowed GMSCs with potent regenerative and therapeutic potentials in various preclinical models of human disorders, particularly, some inflammatory and autoimmune diseases, skin diseases, oral and maxillofacial disorders, and peripheral nerve injuries. All types of cells release extracellular vesicles (EVs), including exosomes, that play critical roles in cell-cell communication through their cargos containing a variety of bioactive molecules, such as proteins, nucleic acids, and lipids. Like EVs released by other sources of MSCs, GMSC-derived EVs have been shown to possess similar biological functions and therapeutic effects on several preclinical diseases models as GMSCs, thus representing a promising cell-free platform for regenerative therapy. Taken together, due to the easily accessibility and less morbidity of harvesting gingival tissues as well as the potent immunomodulatory and anti-inflammatory functions, GMSCs represent a unique source of MSCs of a neural crest-origin for potential application in tissue engineering and regenerative therapy.
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Affiliation(s)
- Dane Kim
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Alisa E Lee
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Qilin Xu
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Qunzhou Zhang
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Anh D Le
- Department of Oral & Maxillofacial Surgery & Pharmacology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States.,Center of Innovation & Precision Dentistry, School of Dental Medicine, School of Engineering and Applied Sciences, University of Pennsylvania, Philadelphia, PA, United States.,Department of Oral & Maxillofacial Surgery, Penn Medicine Hospital of the University of Pennsylvania, Philadelphia, PA, United States
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35
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Diar-Bakirly S, El-Bialy T. Human gingival fibroblasts: Isolation, characterization, and evaluation of CD146 expression. Saudi J Biol Sci 2021; 28:2518-2526. [PMID: 33911963 PMCID: PMC8071911 DOI: 10.1016/j.sjbs.2021.01.053] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 12/31/2020] [Accepted: 01/21/2021] [Indexed: 01/31/2023] Open
Abstract
Gingival fibroblasts (GFs) that exhibit adult stem cell-like characteristics are known as gingival mesenchymal stem cells (GMSCs). Specific mesenchymal stem cell (MSC) markers have not been identified to distinguish GMSCs from GFs. Recently, the cell surface molecule known as cluster of differentiation (CD) 146 has been identified as a potential MSC surface marker. In the present study, we investigated the differentiation potential of GMSCs based on CD146 expression. GFs were isolated by two techniques: tissue explants or enzymatic digestion. GFs were cultured and expanded then magnetically sorted according to CD146 expression. CD146low and CD146high cells were collected, expanded, and then tested for stem cell markers by flow cytometry as well as osteogenic and chondrogenic differentiation potential. The differentiation of these cells was analyzed after 21 days using histology, immunofluorescence, real-time quantitative PCR (qPCR), and glycosaminoglycan (GAG) to DNA ratio (GAG/DNA) assays. Positive histological staining indicated osteogenic differentiation of all groups regardless of the isolation techniques utilized. However, none of the groups demonstrated chondrogenic differentiation, confirmed by the lack of collagen type II in the extracellular matrix (ECM) of GF aggregates. Our data suggest that identification of gingival stem cells based solely on CD146 is not sufficient to properly carry out translational research using gingival fibroblasts for novel therapeutic methods of treating oral disease.
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Affiliation(s)
- Samira Diar-Bakirly
- Faculty of Medicine and Dentistry - University of Alberta, Mohammed Bin Rashid University of Medicine and Health Sciences, United Arab Emirates
| | - Tarek El-Bialy
- Faculty of Medicine and Dentistry, University of Alberta, 7-020D Katz Group Centre for Pharmacy and Health Research, Canada
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36
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Galgaro BC, Beckenkamp LR, van den M Nunnenkamp M, Korb VG, Naasani LIS, Roszek K, Wink MR. The adenosinergic pathway in mesenchymal stem cell fate and functions. Med Res Rev 2021; 41:2316-2349. [PMID: 33645857 DOI: 10.1002/med.21796] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/02/2021] [Accepted: 02/17/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) play an important role in tissue homeostasis and damage repair through their ability to differentiate into cells of different tissues, trophic support, and immunomodulation. These properties made them attractive for clinical applications in regenerative medicine, immune disorders, and cell transplantation. However, despite multiple preclinical and clinical studies demonstrating beneficial effects of MSCs, their native identity and mechanisms of action remain inconclusive. Since its discovery, the CD73/ecto-5'-nucleotidase is known as a classic marker for MSCs, but its role goes far beyond a phenotypic characterization antigen. CD73 contributes to adenosine production, therefore, is an essential component of purinergic signaling, a pathway composed of different nucleotides and nucleosides, which concentrations are finely regulated by the ectoenzymes and receptors. Thus, purinergic signaling controls pathophysiological functions such as proliferation, migration, cell fate, and immune responses. Despite the remarkable progress already achieved in considering adenosinergic pathway as a therapeutic target in different pathologies, its role is not fully explored in the context of the therapeutic functions of MSCs. Therefore, in this review, we provide an overview of the role of CD73 and adenosine-mediated signaling in the functions ascribed to MSCs, such as homing and proliferation, cell differentiation, and immunomodulation. Additionally, we will discuss the pathophysiological role of MSCs, via CD73 and adenosine, in different diseases, as well as in tumor development and progression. A better understanding of the adenosinergic pathway in the regulation of MSCs functions will help to provide improved therapeutic strategies applicable in regenerative medicine.
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Affiliation(s)
- Bruna C Galgaro
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Liziane R Beckenkamp
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Martha van den M Nunnenkamp
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Vitória G Korb
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Liliana I S Naasani
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
| | - Katarzyna Roszek
- Department of Biochemistry, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Toruń, Poland
| | - Márcia R Wink
- Laboratório de Biologia Celular, Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil
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Villarroel V, Fagalde P, Reininger D. Potential therapeutic uses of intraoral mesenchymal stem cells in other tissues of the body: A review. J Clin Exp Dent 2021; 13:e259-e267. [PMID: 33680328 PMCID: PMC7920563 DOI: 10.4317/jced.56809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 08/10/2020] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Over the last few years, there has been a great advance in regenerative medicine, with various studies that have observed the ability to repair or regenerate dysfunctional tissues with the patient's own cells, such as with mesenchymal cells. In this area, mesenchymal stem cells (MSCs) from the oral cavity have attracted attention because of their easy access and multiple cellular differentiations. Multiple studies have shown the various clinical applications at the intraoral level, especially at the level of bone regeneration, but the potential applications of oral MSC at a systemic level have been scarcely described. Objective: The objective of this review was to describe the potential therapeutic uses of intraoral MSCs in other tissues of the organism. MATERIAL AND METHODS A review of the literature between 2000 and 2019. Only included those studies done on animals or humans. RESULTS Twenty five articles were selected, all performed on animals. The donor site most used were the temporary teeth exfoliated from humans, representing 56% of the total articles, followed by the dental pulp with 28% of the total articles included. Transplantation of intraoral mesenchymal cells in animals with neural tissue illness was the most studied therapy. CONCLUSIONS Although obtaining MSC of intraoral origin has proven to be a good alternative in regenerative medicine, achieving therapeutic uses in bone tissue, nervous tissue, liver tissue, skin tissue, ocular tissue, reperfusion of tissues and in autoimmune diseases, there is a lack of clinical studies that allow its safe use in humans. Key words:Mesenchymal stem cells, stem cell transplantation, regenerative medicine, dental component.
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Affiliation(s)
| | | | - David Reininger
- DDS, PhD, Master in Oral Surgery and Implantology, Assistant Professor, Universidad Mayor, Santiago, Chile
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38
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Huang Z, Li W, Su W. Tregs in Autoimmune Uveitis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:205-227. [PMID: 33523450 DOI: 10.1007/978-981-15-6407-9_11] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Uveitis is a chronic disease with relapsing and remitting ocular attack, which requires corticosteroids and systemic immunosuppression to prevent severe vision loss. Classically, uveitis is referred to an autoimmune disease, mediated by pro-inflammatory Th17 cells and immunosuppressive CD4+CD25+FoxP3+ T-regulatory cells (Tregs). More and more evidence indicates that Tregs are involved in development, resolution, and remission of uveitis. Clinically, many researchers have conducted quantitative and functional analyses of peripheral blood from patients with different subtypes of uveitis, in an attempt to find the changing rules of Tregs. Consistently, using the experimental autoimmune uveitis (EAU) model, researchers have explored the development and resolution mechanism of uveitis in many aspects. In addition, many drug and Tregs therapy investigations have yielded encouraging results. In this chapter, we introduced the current understanding of Tregs, summarized the clinical changes in the number and function of patients with uveitis and the immune mechanism of Tregs involved in EAU model, as well as discussed the progress and shortcomings of Tregs-related drug therapy and Tregs therapy. Although the exact mechanism of Tregs-mediated uveitis protection remains to be elucidated, the strategy of Tregs regulation may provide a specific and meaningful way for the prevention and treatment of uveitis.
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Affiliation(s)
- Zhaohao Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenli Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
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Abstract
Mucosal surfaces are distinctive sites exposed to environmental, dietary, and microbial antigens. Particularly in the gut, the host continuously actively adapts via complex interactions between the microbiota and dietary compounds and immune and other tissue cells. Regulatory T cells (Tregs) are critical for tuning the intestinal immune response to self- and non-self-antigens in the intestine. Its importance in intestinal homeostasis is illustrated by the onset of overt inflammation caused by deficiency in Treg generation, function, or stability in the gut. A substantial imbalance in Tregs has been observed in intestinal tissue during pathogenic conditions, when a tightly regulated and equilibrated system becomes dysregulated and leads to unimpeded and chronic immune responses. In this chapter, we compile and critically discuss the current knowledge on the key factors that promote Treg-mediated tolerance in the gut, such as those involved in intestinal Treg differentiation, specificity and suppressive function, and their immunophenotype during health and disease. We also discuss the current state of knowledge on Treg dysregulation in human intestine during pathological states such as inflammatory bowel disease (IBD), necrotizing enterocolitis (NEC), graft-versus-host disease (GVHD), and colorectal cancer (CRC), and how that knowledge is guiding development of Treg-targeted therapies to treat or prevent intestinal disorders.
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Du Y, Fang Q, Zheng SG. Regulatory T Cells: Concept, Classification, Phenotype, and Biological Characteristics. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:1-31. [PMID: 33523440 DOI: 10.1007/978-981-15-6407-9_1] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Regulatory T cells (Treg) play an indispensable role in maintaining the body's immune nonresponse to self-antigens and suppressing the body's unwarranted and potentially harmful immune responses. Their absence, reduction, dysfunction, transformation, and instability can lead to numerous autoimmune diseases. There are several distinct subtypes of the Treg cells, although they share certain biological characteristics and have unique phenotypes with different regulatory functions, as well as mechanistic abilities. In this book chapter, we introduce the latest advances in Treg cell subtypes pertaining to classification, phenotype, biological characteristics, and mechanisms. We also highlight the relationship between Treg cells and various diseases, including autoimmune, infectious, as well as tumors and organ transplants.
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Affiliation(s)
- Yang Du
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin, Guangxi, China.,Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, Guangxi, China
| | - Qiannan Fang
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Song-Guo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH, USA.
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Tian J, Hong Y, Zhu Q, Zhou H, Zhang Y, Shen Z, Guo H, Zhang Y, Ai X, Zhao F, Rui K, Xu H, Wang S. Mesenchymal Stem Cell Enhances the Function of MDSCs in Experimental Sjögren Syndrome. Front Immunol 2020; 11:604607. [PMID: 33414787 PMCID: PMC7782428 DOI: 10.3389/fimmu.2020.604607] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 11/20/2020] [Indexed: 12/18/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is a progressive systemic autoimmune disease characterized by lymphocytic infiltrates in exocrine glands, leading to the injury of salivary and lachrymal glands. Mesenchymal stem cells (MSCs) have been demonstrated to exert great potential in the treatment of various autoimmune diseases. Although MSCs have provide an effective therapeutic approach for SS treatment, the underlying mechanisms are still elusive. Our previous study has shown the reduced suppressive capacity of myeloid-derived suppressor cells (MDSCs) advanced the progression of experimental Sjögren’s syndrome (ESS). In this study, we found that BM-MSCs significantly enhanced the suppressive function of MDSCs with high levels of Arginase and NO, decreased the levels of CD40, CD80, CD86, and MHC-II expression on MDSCs, thus attenuating the disease progression in ESS mice. Furthermore, the enhanced suppressive function of MDSCs was mediated by BM-MSC-secreted TGF-β, and the therapeutic effect of BM-MSCs in inhibiting ESS was almost abolished after silencing TGF-β in BM-MSCs. Taken together, our results demonstrated that BM-MSCs alleviated the ESS progression by up-regulating the immunosuppressive effect of MDSCs through TGF-β/Smad pathway, offering a novel mechanism for MSCs in the treatment of pSS.
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Affiliation(s)
- Jie Tian
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yue Hong
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Qiugang Zhu
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Huimin Zhou
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yidan Zhang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Ziwei Shen
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Hongye Guo
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yue Zhang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Xiangyan Ai
- Department of Rheumatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Futao Zhao
- Department of Rheumatology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Huaxi Xu
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.,Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
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An updated advance of autoantibodies in autoimmune diseases. Autoimmun Rev 2020; 20:102743. [PMID: 33333232 DOI: 10.1016/j.autrev.2020.102743] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 08/06/2020] [Indexed: 12/18/2022]
Abstract
Autoantibodies are abnormal antibodies which are generated by pathogenic B cells when targeting an individual's own tissue. Autoantibodies have been identified as a symbol of autoimmune disorders and are frequently considered a clinical marker of these disorders. Autoimmune diseases, including system lupus erythematosus and rheumatoid arthritis, consist of a series of disorders that share some similarities and differences. They are characterized by chronic, systemic, excessive immune activation and inflammation and involve in almost all body tissues. Autoimmune diseases occur more frequently in women than men due to hormonal impacts. In this review we systemically introduce and summarize the latest advances of various autoantibodies in multiple autoimmune diseases.
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Sun H, Zhao Y, Wang K, Zhu L, Dong J, Zhao J, Wang Y, Li H, Sun X, Lu Y. Low dose IL-2 suppress osteoclastogenesis in collagen-induced arthritis via JNK dependent pathway. IMMUNITY INFLAMMATION AND DISEASE 2020; 8:727-735. [PMID: 33098626 PMCID: PMC7654429 DOI: 10.1002/iid3.364] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/20/2020] [Accepted: 10/11/2020] [Indexed: 01/08/2023]
Abstract
Background Rheumatoid arthritis (RA) is one of the most common chronic immune joint diseases, mainly involving blood vessels and small joints. The complex pathogenesis of RA greatly increases the difficulty of treatment. At present, the common hormone and immunosuppressive therapy are not effective, while low‐dose interleukin‐2 (IL‐2) recently has been found to possess some advantages for immunotherapy. However, its related signal pathway remains to be elucidated. Methods We fabricated the model of arthritis in mice, and then low‐dose IL‐2 was injected at a fixed time point to observe the changes of related vascular and organ pathology, inflammatory factors, and signal pathway proteins, which were verified by statistical analysis. Results Low dose IL‐2 can reduce the severity of vascular and bone lesions in collagen‐induced arthritis immune model, and inhibit osteoclast formation in vitro by phosphorylation of nuclear factor‐κB (NF‐κB), which inhibits the receptor activator of NF‐κB ligand effect through c‐Jun N‐terminal kinase (JNK) pathway, and its immunotherapeutic effect depends on the activation of JNK. Conclusion It is the first time for us to prove that low dose IL‐2 can inhibit osteoclast formation in collagen‐induced arthritis through the JNK dependent pathway, which will provide the angle and theoretical basis for future immunotherapy of IL‐2.
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Affiliation(s)
- Han Sun
- The Third Affiliated Hospital of Soochow University, Changzhou, China.,Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Yong Zhao
- Department of Hepatobiliary Surgery, The people's hospital of Jinsha County, China
| | - Kun Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Li Zhu
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jian Dong
- Department of Sports Medicine and Adult Reconstructive Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, China
| | - Jie Zhao
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yimin Wang
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Huan Li
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xiaoliang Sun
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Yunjie Lu
- The Third Affiliated Hospital of Soochow University, Changzhou, China
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44
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Liu Y, Cao F, Sun B, Bellanti JA, Zheng SG. Magnetic nanoparticles: A new diagnostic and treatment platform for rheumatoid arthritis. J Leukoc Biol 2020; 109:415-424. [PMID: 32967052 DOI: 10.1002/jlb.5mr0420-008rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/19/2020] [Accepted: 04/21/2020] [Indexed: 12/30/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory condition characterized by articular synovitis that eventually leads to the destruction of cartilage and bone in the joints with resulting pain and disability. The current therapies for RA are divided into 4 categories: non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, nonbiological disease-modifying anti-rheumatic drugs (DMARDs), and biological DMARDs. Each drug grouping is beset with significant setbacks that not only include limited drug bioavailability and high clearance, but also varying degrees of drug toxicity to normal tissues. Recently, nanotechnology has provided a promising tool for the development of novel therapeutic and diagnostic systems in the area of malignant and inflammatory diseases. Among these, magnetic nanoparticles (MNPs) have provided an attractive carrier option for delivery of therapeutic agents. Armed with an extra magnetic probe, MNPs are capable of more accurately targeting the local lesion with avoidance of unpleasant systemic side effects. This review aims to provide an introduction to the applications of magnetic nanoparticles in RA, focusing on the latest advances, challenges, and opportunities for future development.
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Affiliation(s)
- Yan Liu
- Institute of Clinical Immunology Center, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Fenglin Cao
- Department of Internal Medicine, the First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Baoqing Sun
- Department of Allergy and Clinical Immunology, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Medical University, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Joseph A Bellanti
- Department of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center, Washington, District of Columbia, United States
| | - Song Guo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, Ohio, United States
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Stefańska K, Mehr K, Wieczorkiewicz M, Kulus M, Angelova Volponi A, Shibli JA, Mozdziak P, Skowroński MT, Antosik P, Jaśkowski JM, Piotrowska-Kempisty H, Kempisty B, Dyszkiewicz-Konwińska M. Stemness Potency of Human Gingival Cells-Application in Anticancer Therapies and Clinical Trials. Cells 2020; 9:cells9081916. [PMID: 32824702 PMCID: PMC7464983 DOI: 10.3390/cells9081916] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/01/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Gingivae, as the part of periodontium, are involved in tooth support and possess the ability to heal rapidly, without scar formation. Recently, dental tissues have been identified as a potential source of mesenchymal stem cells (MSCs) and several populations of MSCs were isolated from the orofacial region, including gingival mesenchymal stem cells (GMSCs). GMSCs exhibit robust immunomodulatory and differentiation potential and are easily obtainable, which make them promising candidates for cellular therapies. Apart from being tested for application in immunologic- and inflammatory-related disorders and various tissue regeneration, GMSCs promise to be a valuable tool in cancer treatment, especially in tongue squamous cell carcinoma (TSCC) with the use of targeted therapy, since GMSCs are able to selectively migrate towards the cancerous cells both in vitro and in vivo. In addition to their ability to uptake and release anti-neoplastic drugs, GMSCs may be transduced with apoptosis-inducing factors and used for cancer growth inhibition. Moreover, GMSCs, as most mammalian cells, secrete exosomes, which are a subset of extracellular vesicles with a diameter of 40–160 nm, containing DNA, RNA, lipids, metabolites, and proteins. Such GMSCs-derived exosomes may be useful therapeutic tool in cell-free therapy, as well as their culture medium. GMSCs exhibit molecular and stem-cell properties that make them well suited in preclinical and clinical studies.
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Affiliation(s)
- Katarzyna Stefańska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 6 Święcickiego St., 60-781 Poznan, Poland;
| | - Katarzyna Mehr
- Department of Gerostomatology and Pathology of Oral Cavity, Poznan University of Medical Sciences, 70 Bukowska St., 60-812 Poznan, Poland;
| | - Maria Wieczorkiewicz
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland; (M.W.); (M.T.S.)
| | - Magdalena Kulus
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland; (M.K.); (P.A.)
| | - Ana Angelova Volponi
- Centre for Craniofacial and Regenerative Biology, Dental Institute, King’s College London, Strand, London WC2R 2LS, UK;
| | - Jamil A. Shibli
- Department of Periodontology and Oral Implantology, Dental Research Division, Guarulhos University, Guarulhos, R. Eng. Prestes Maia, 88-Centro, São Paulo 07023-070, Brazil;
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Campus Box 7608, Raleigh, NC 27695-7608, USA;
| | - Mariusz T. Skowroński
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland; (M.W.); (M.T.S.)
| | - Paweł Antosik
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland; (M.K.); (P.A.)
| | - Jędrzej M. Jaśkowski
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland;
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd St., 60-631 Poznan, Poland;
| | - Bartosz Kempisty
- Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 7 Gagarina St., 87-100 Torun, Poland; (M.K.); (P.A.)
- Department of Anatomy, Poznan University of Medical Sciences, 6 Święcickiego St., 60-781 Poznan, Poland;
- Correspondence: ; Tel./Fax: +48-61-8546565
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 6 Święcickiego St., 60-781 Poznan, Poland;
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 70 Bukowska St., 60-812 Poznan, Poland
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Mesenchymal Stem/Stromal Cells for Rheumatoid Arthritis Treatment: An Update on Clinical Applications. Cells 2020; 9:cells9081852. [PMID: 32784608 PMCID: PMC7465092 DOI: 10.3390/cells9081852] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/29/2020] [Accepted: 08/05/2020] [Indexed: 02/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects the lining of the synovial joints leading to stiffness, pain, inflammation, loss of mobility, and erosion of joints. Its pathogenesis is related to aberrant immune responses against the synovium. Dysfunction of innate and adaptive immunity, including dysregulated cytokine networks and immune complex-mediated complement activation, are involved in the progression of RA. At present, drug treatments, including corticosteroids, antirheumatic drugs, and biological agents, are used in order to modulate the altered immune responses. Chronic use of these drugs may cause adverse effects to a significant number of RA patients. Additionally, some RA patients are resistant to these therapies. In recent years, mesenchymal stem/stromal cell (MSCs)-based therapies have been largely proposed as a novel and promising stem cell therapeutic approach in the treatment of RA. MSCs are multipotent progenitor cells that have immunomodulatory properties and can be obtained and expanded easily. Today, nearly one hundred studies in preclinical models of RA have shown promising trends for clinical application. Proof-of-concept clinical studies have demonstrated satisfactory safety profile of MSC therapy in RA patients. The present review discusses MSC-based therapy approaches with a focus on published clinical data, as well as on clinical trials, for treatment of RA that are currently underway.
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Chen Y, Xu Z, Liang R, Wang J, Xu A, Na N, Li B, Wang R, Joseph M, Olsen N, Hsueh W, Zheng SG. CD4 +CD126 low/- Foxp3 + Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases. Mol Ther 2020; 28:2406-2416. [PMID: 32738192 DOI: 10.1016/j.ymthe.2020.07.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/11/2020] [Accepted: 07/10/2020] [Indexed: 01/17/2023] Open
Abstract
CD4+Foxp3+ regulatory T (Treg) cells are crucial for maintaining homeostasis and preventing autoimmune diseases. Nonetheless, we and others have previously reported that natural Treg cells are unstable and dysfunctional in the inflamed environment with a high-salt diet, limiting the Treg function in disease control. In this study, we made an innovative observation showing a high degree of heterogeneity within the Treg pool. We identified that CD126, interleukin (IL)-6 receptor alpha chain, contributed to Treg cell instability. Using a series of in vitro and in vivo experimental approaches, we demonstrated that CD126Lo/- Treg cells presented greater function and were more stable than CD126Hi nTreg cells, even in the presence of IL-6 and inflammation. Blockade of programmed death-1 (PD-1) interrupted CD126Lo/- nTreg cell stability. Additionally, CD126Lo/- Treg cells can treat colitis and established collagen-induced arthritis, while the CD126Hi cell population failed to do this. Moreover, we noted that CD126 expression of Treg cells had a positive correlation to rheumatoid arthritis (RA) severity and the stability of Treg cells. Our results strongly suggest that the manipulation of CD126Lo/- nTreg cells could be a novel strategy for the treatment of autoimmune diseases and for other conditions associated with a deficit of Treg cells.
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Affiliation(s)
- Ye Chen
- Department of Clinical Immunology, Third Hospital at Sun Yat-sen University, 510630 Guangzhou, China; Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA; Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA
| | - Zhenjian Xu
- Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA; Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Rongzhen Liang
- Department of Clinical Immunology, Third Hospital at Sun Yat-sen University, 510630 Guangzhou, China
| | - Julie Wang
- Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA
| | - Anping Xu
- Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China
| | - Ning Na
- Department of Clinical Immunology, Third Hospital at Sun Yat-sen University, 510630 Guangzhou, China
| | - Bin Li
- Department of Immunology, Shanghai Jiaotong University School of Medicine, Shanghai 200021, China
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Disease, Abigail Wexner Research Institute, Nationwide Children's Hospital and Department of Pediatrics, The Ohio State University School of Medicine, Columbus, OH 43205, USA
| | - Miller Joseph
- Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA
| | - Nancy Olsen
- Division of Rheumatology, Penn State College of Medicine and Milton S. Hershey Medical Center, Hershey, PA 17033, USA
| | - Willa Hsueh
- Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA
| | - Song Guo Zheng
- Division of Rheumatology and Immunology, Department of Internal Medicine, College of Medicine, The Ohio State University, Wexner Medical Center, Columbus, OH 43201, USA.
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Wu W, Xiao ZX, Zeng D, Huang F, Wang J, Liu Y, Bellanti JA, Olsen N, Zheng SG. B7-H1 Promotes the Functional Effect of Human Gingiva-Derived Mesenchymal Stem Cells on Collagen-Induced Arthritis Murine Model. Mol Ther 2020; 28:2417-2429. [PMID: 32707035 PMCID: PMC7646216 DOI: 10.1016/j.ymthe.2020.07.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 03/20/2020] [Accepted: 06/28/2020] [Indexed: 02/06/2023] Open
Abstract
Recent studies found that mesenchymal stem cells (MSCs), by virtue of their tissue recovery and immunoregulatory properties, have shown a broad prospect for applications in various autoimmune and degenerative diseases. Although the potential therapeutic use of MSCs is considerable, studies and clinical treatment efficacy are preliminary due to the heterogeneity of MSCs. Herein, based on RNA-sequencing (RNA-seq) and single cell sequence properties, we demonstrated that B7-H1 plays an important role in the immunosuppressive function of human gingiva-derived mesenchymal stem cells (GMSCs) in a collagen-induced arthritis murine model that is dependent on STAT3 signaling. Our data offer convincing evidence that B7-H1 expression by GMSCs helps to identify a new subpopulation of MSCs with a greater immunosuppressive property. The approach provides a unique and additional strategy for stem cells-based therapies of autoimmune and other inflammatory diseases.
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Affiliation(s)
- Wenbin Wu
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ze Xiu Xiao
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Donglan Zeng
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Feng Huang
- Department of Clinical Immunology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Julie Wang
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA
| | - Yanying Liu
- Department of Rheumatology & Immunology, Peking University People's Hospital, Beijing 100044, China
| | - Joseph A Bellanti
- Departments of Pediatrics and Microbiology-Immunology and the International Center for Interdisciplinary Studies of Immunology (ICISI), Georgetown University Medical Center, Washington, DC 20057, USA
| | - Nancy Olsen
- Department of Medicine, Penn State University Hershey Medical Center, Hershey, PA 17033, USA
| | - Song Guo Zheng
- Department of Internal Medicine, Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA.
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49
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Dang J, Xu Z, Xu A, Liu Y, Fu Q, Wang J, Huang F, Zheng Y, Qi G, Sun B, Bellanti JA, Kandalam U, Emam HA, Jarjour W, Zheng SG. Human gingiva-derived mesenchymal stem cells are therapeutic in lupus nephritis through targeting of CD39 -CD73 signaling pathway. J Autoimmun 2020; 113:102491. [PMID: 32565049 DOI: 10.1016/j.jaut.2020.102491] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 04/30/2020] [Accepted: 05/18/2020] [Indexed: 12/21/2022]
Abstract
Cell specific and cytokine targeted therapeutics have underperformed in systemic lupus erythematosus (SLE). Mesenchymal stem cells (MSCs) have emerged as a novel therapy to address the dysregulation in autoimmune diseases but also have limitations. Human gingiva derived MSCs (GMSCs) are superior in regulating immune responses. Here, we demonstrate that the adoptive transfer of GMSCs homes to and maintains in the kidney and has a robust therapeutic effect in a spontaneous lupus nephritis model. Specifically, GMSCs limits the development of autoantibodies as well as proteinuria, decreases the frequency of plasma cells and lupus nephritis histopathological scores by directly suppressing B cells activation, proliferation and differentiation. The blockage of CD39-CD73 pathway dramatically abrogates the suppressive capacities of GMSCs in vitro and in vivo and highlights the significance of this signaling pathway in SLE. Collectively, manipulation of GMSCs provides a promising strategy for the treatment of patients with SLE and other autoimmune diseases.
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Affiliation(s)
- Junlong Dang
- Department of Clinical Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China; Division of Rheumatology, Department of Medicine, Penn State College of Medicine, Hershey, PA, USA
| | - Zhenjian Xu
- Division of Rheumatology, Department of Medicine, Penn State College of Medicine, Hershey, PA, USA; Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Anping Xu
- Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yan Liu
- Department of Clinical Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Qingling Fu
- Otorhinolaryngology Department, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Julie Wang
- Division of Immunology and Rheumatology, Department of Internal Medicine, Ohio State University College of Medicine, USA
| | - Feng Huang
- Department of Clinical Immunology, Third Affiliated Hospital at Sun Yat-sen University, Guangzhou, China
| | - Yuejuan Zheng
- Center for Traditional Chinese Medicine and Immunology Research, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Guangying Qi
- Guangxi State Key Lab, Guilin College of Medicine, Guilin, China
| | - Boqing Sun
- Department of Allergy and Clinical Immunology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Joseph A Bellanti
- Departments of Pediatrics and Microbiology-Immunology, Georgetown University Medical Center, Washington DC, USA
| | - Umadevi Kandalam
- Department of Pediatric Dentistry, College of Dental Medicine, Nova Southeastern University, Davie, FL, USA
| | - Hany A Emam
- Department of Oral & Maxillofacial Surgery, The Ohio State University, Columbus, USA
| | - Wael Jarjour
- Division of Immunology and Rheumatology, Department of Internal Medicine, Ohio State University College of Medicine, USA
| | - Song Guo Zheng
- Division of Immunology and Rheumatology, Department of Internal Medicine, Ohio State University College of Medicine, USA.
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Chang Q, Li C, Lu Y, Geng R, Wei J, Hu J. Adipose‐derived mesenchymal stromal cells suppress osteoclastogenesis and bone erosion in collagen‐induced arthritis. Scand J Immunol 2020; 92:e12877. [PMID: 32145090 DOI: 10.1111/sji.12877] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 02/22/2020] [Accepted: 03/02/2020] [Indexed: 01/10/2023]
Affiliation(s)
- Qing Chang
- Department of Orthopaedics Zhongda Hospital Medical School Southeast University Nanjing China
| | - Chao Li
- Department of Orthopaedics Zhongda Hospital Medical School Southeast University Nanjing China
| | - Yunjie Lu
- The First People's Hospital of Changzhou the Third Hospital Affiliated to Soochow University Changzhou China
| | - Rui Geng
- Department of Orthopaedics Zhongda Hospital Medical School Southeast University Nanjing China
| | - Ji‐nan Wei
- Department of Orthopaedics Zhongda Hospital Medical School Southeast University Nanjing China
| | - Jun‐zheng Hu
- Department of Orthopaedics Zhongda Hospital Medical School Southeast University Nanjing China
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