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Liu J, Zhao T, Cui H, Tian Y, Miao X, Xing L, Wang X, Huang J, Liu Q, Zhang W, Shi K, Liu Y, Jia B, Kang L, Tian Y, Yuan W, He S, Feng X, Liu S. HMGB1 Encapsulated in Podocyte-Derived Exosomes Plays a Central Role in Glomerular Endothelial Cell Injury in Lupus Nephritis by Regulating TRIM27 Expression. J Transl Med 2025; 105:104096. [PMID: 39848602 DOI: 10.1016/j.labinv.2025.104096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 12/16/2024] [Accepted: 01/09/2025] [Indexed: 01/25/2025] Open
Abstract
Exosomes play a role in cell communication by transporting content between cells. Here, we tested whether renal podocyte-derived exosomes affect the injury of glomerular endothelial cells in lupus nephritis (LN). We found that exosomes containing high levels of high mobility group protein B1 (HMGB1) were released from podocytes in patients with LN, BALB/c mice injected with pristane (which induces lupus-like disease in mice), and cultured human renal glomerular endothelial cells (HRGECs) treated with LN plasma. In vitro, GW4869 (an inhibitor of exosome biogenesis/release) or exosome removal alleviated the injury of HRGECs induced by LN plasma. Additionally, leptomycin B or knockdown of HMGB1 in podocyte-derived exosomes reduced endothelial cell injury and the expression of tripartite motif-containing protein 27 (TRIM27). Knockdown or overexpression of TRIM27 attenuated or promoted the damage of HRGECs treated with LN plasma. In vivo, knockdown of HMGB1 in podocytes ameliorated the injury of glomerular endothelial cells in a mouse model of LN. Furthermore, the injection of podocyte-derived exosomes into mice caused glomerular endothelial cell dysfunction. In conclusion, our study revealed that podocyte-derived exosomes may mediate the injury of glomerular endothelial cells seen in LN.
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Affiliation(s)
- Jinxi Liu
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Tongyu Zhao
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China; Department of Pathology, the First Hospital of Hebei Medical University; Shijiazhuang, China
| | - Huixin Cui
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Yuexin Tian
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Xinyan Miao
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Lingling Xing
- Department of Nephrology, the Second Affiliated Hospital of Hebei Medical University; Shijiazhuang, China
| | - Xiaorong Wang
- Department of Nephrology, the Second Affiliated Hospital of Hebei Medical University; Shijiazhuang, China
| | - Jie Huang
- Department of Pathology, Shijiazhuang Obstetrics and Gynecology Hospital, China
| | - Qingjuan Liu
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Wei Zhang
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Ke Shi
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China; Department of Oncology, the Fourth Hospital of Hebei Medical University; Shijiazhuang, China
| | - Yunhe Liu
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Baiyun Jia
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Lihua Kang
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China
| | - Yu Tian
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Department of Rheumatology, the Second Affiliated Hospital of Hebei Medical University; Shijiazhuang, China
| | - Weicheng Yuan
- Clinical Medicine, Hebei Medical University; Shijiazhuang, China
| | - Shiwei He
- Clinical Medicine, Hebei Medical University; Shijiazhuang, China
| | - Xiaojuan Feng
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China.
| | - Shuxia Liu
- Department of Pathology, Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang, China; Key Laboratory of Kidney Diseases of Hebei Province, Hebei Medical University, Shijiazhuang, China.
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Duan L, Lin W, Zhang Y, Jin L, Xiao J, Wang H, Pang S, Wang H, Sun D, Gong Y, Li H. Exosomes in Autoimmune Diseases: A Review of Mechanisms and Diagnostic Applications. Clin Rev Allergy Immunol 2025; 68:5. [PMID: 39820756 DOI: 10.1007/s12016-024-09013-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2024] [Indexed: 01/19/2025]
Abstract
Exosomes, small extracellular vesicles secreted by various cell types, have emerged as key players in the pathophysiology of autoimmune diseases. These vesicles serve as mediators of intercellular communication, facilitating the transfer of bioactive molecules such as proteins, lipids, and nucleotide. In autoimmune diseases, exosomes have been implicated in modulating immune responses, oxidative stress, autophagy, gut microbes, and the cell cycle, contributing to disease initiation, progression, and immune dysregulation. Recent advancements in exosome isolation techniques and their molecular characterization have paved the way for exploring their clinical potential as biomarkers and therapeutic targets. This review focuses on the mechanisms by which exosomes influence autoimmune disease development and their potential clinical applications, particularly in diagnosis. The role of exosomes in autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes mellitus (T1DM), inflammatory bowel disease (IBD), and Sjögren's syndrome (SS), is discussed in relation to their involvements in antigen presentation, T-cell activation, and the induction of inflammatory pathways. Additionally, exosome-based biomarkers offer promising non-invasive diagnostic tools for early diagnostic, disease monitoring, and therapeutic response assessment. However, challenges such as standardization of exosome isolation protocols and validation of their clinical significance remain. This review highlights the potential of exosomes as both diagnostic biomarkers and therapeutic targets in autoimmune diseases, emphasizing the need for further research to overcome current limitations and fully harness their clinical value.
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Affiliation(s)
- Lina Duan
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Wanying Lin
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Yi Zhang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Lingyue Jin
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Jie Xiao
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Haifang Wang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Shuyin Pang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Hongxia Wang
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China
| | - Dehua Sun
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
| | - Ying Gong
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
| | - Haixia Li
- Department of Laboratory Medicine, Guangdong Provincial Key Laboratory of Precision Medical Diagnostics, Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, People's Republic of China.
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Chopra P, Fatima A, Mohapatra S, Murugaiyan K, Vemuganti GK, Rengan AK, Watson SL, Singh V, Basu S, Singh S. Extracellular vesicles in dry eye disease and Sjögren's syndrome: A systematic review on their diagnostic and therapeutic role. Surv Ophthalmol 2025:S0039-6257(25)00010-4. [PMID: 39818361 DOI: 10.1016/j.survophthal.2025.01.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 01/08/2025] [Accepted: 01/10/2025] [Indexed: 01/18/2025]
Abstract
Extracellular vesicles (EVs), defined as membrane-bound vesicles released from all cells, are being explored for their diagnostic and therapeutic role in dry eye disease (DED). We systematically shortlisted 32 articles on the role of EVs in diagnosing and treating DED. We cover the progress in the last 2 decades on the classification and isolation of EVs and their role in DED. The diagnostic predictability of exosomes was evaluated in Sjögren syndrome (SS) patients' tears, plasma, and saliva, where upregulation of inflammatory proteins was reported uniformly across studies. Also, we evaluate the therapeutic effects of MSC-derived EVs in in vitro and in vivo studies of SS and DED mouse models. A significant response occurs at a functional level with improved tear production and saliva flow rate and at a cellular level with reduced lymphocyte infiltration, improved corneal structural integrity, decreased epithelial cell apoptosis, and dampening of the inflammatory cytokine response. The proposed mechanisms of EV action include PD-L1, PRDM, NLRP-3, and Nf-kb pathways, and an increase in M2 macrophage phenotype. Current use of exosomes in DED is limited due to their cumbersome isolation techniqus. Further research on human subjects is needed, in addition to optimizing exosome isolation and delivery methods.
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Affiliation(s)
- Prakshi Chopra
- Sydney Eye Hospital, Sydney, Australia; The University of Sydney, Australia
| | - Asra Fatima
- School of Medical Sciences, University of Hyderabad, India
| | - Sonali Mohapatra
- Brien Holden Centre for Eye Research (BHERC), L V Prasad Eye Institute, Hyderabad, Telangana, India
| | - Kavipriya Murugaiyan
- Department of Biomedical Engineering, Indian Institute of Technology, Hyderabad, India
| | | | - Aravind Kumar Rengan
- Department of Biomedical Engineering, Indian Institute of Technology, Hyderabad, India
| | | | - Vivek Singh
- Brien Holden Centre for Eye Research (BHERC), L V Prasad Eye Institute, Hyderabad, Telangana, India
| | - Sayan Basu
- Brien Holden Centre for Eye Research (BHERC), L V Prasad Eye Institute, Hyderabad, Telangana, India; Shantilal Shanghvi Cornea Institute, L V Prasad Eye Institute, Hyderabad, Telangana, India
| | - Swati Singh
- Centre for Ocular Regeneration (CORE), L V Prasad Eye Institute, Hyderabad, Telangana, India; Prof. Krothapalli Ravindranath Ophthalmic Research Biorepository, LV Prasad Eye Institute, Hyderabad, Telangana, India.
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Fan X, Zhang Y, Liu W, Shao M, Gong Y, Wang T, Xue S, Nian R. A comprehensive review of engineered exosomes from the preparation strategy to therapeutic applications. Biomater Sci 2024; 12:3500-3521. [PMID: 38828621 DOI: 10.1039/d4bm00558a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024]
Abstract
Exosomes exhibit high bioavailability, biological stability, targeted specificity, low toxicity, and low immunogenicity in shuttling various bioactive molecules such as proteins, lipids, RNA, and DNA. Natural exosomes, however, have limited production, targeting abilities, and therapeutic efficacy in clinical trials. On the other hand, engineered exosomes have demonstrated long-term circulation, high stability, targeted delivery, and efficient intracellular drug release, garnering significant attention. The engineered exosomes bring new insights into developing next-generation drug delivery systems and show enormous potential in therapeutic applications, such as tumor therapies, diabetes management, cardiovascular disease, and tissue regeneration and repair. In this review, we provide an overview of recent advancements associated with engineered exosomes by focusing on the state-of-the-art strategies for cell engineering and exosome engineering. Exosome isolation methods, including traditional and emerging approaches, are systematically compared along with advancements in characterization methods. Current challenges and future opportunities are further discussed in terms of the preparation and application of engineered exosomes.
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Affiliation(s)
- Xiying Fan
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
| | - Yiwen Zhang
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
- University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Beijing 100049, People's Republic of China
| | - Wenshuai Liu
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
| | - Mingzheng Shao
- Research Center on Advanced Chemical Engineering and Energy Materials, China University of Petroleum (East China), Qingdao 266580, P. R. China.
| | - Yibo Gong
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
- University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Beijing 100049, People's Republic of China
| | - Tingya Wang
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
- University of Chinese Academy of Sciences, No. 19(A) Yuquan Road, Beijing 100049, People's Republic of China
| | - Song Xue
- Research Center on Advanced Chemical Engineering and Energy Materials, China University of Petroleum (East China), Qingdao 266580, P. R. China.
| | - Rui Nian
- CAS Key Laboratory of Biobased Materials, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, No. 189, Songling Road, Qingdao 266101, China.
- Shandong Energy Institute, No. 189, Songling Road, Qingdao 266101, China
- Qingdao New Energy Shandong Laboratory, No. 189, Songling Road, Qingdao 266101, China
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Lin Y, Wang Z, Liu S, Liu J, Zhang Z, Ouyang Y, Su Z, Chen D, Guo L, Luo T. Roles of extracellular vesicles on macrophages in inflammatory bone diseases. Mol Cell Biochem 2024; 479:1401-1414. [PMID: 37436653 DOI: 10.1007/s11010-023-04809-w] [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: 04/02/2023] [Accepted: 07/02/2023] [Indexed: 07/13/2023]
Abstract
Inflammatory bone disease is a general term for a series of diseases caused by chronic inflammation, which leads to the destruction of bone homeostasis, that is, the osteolytic activity of osteoclasts increases, and the osteogenic activity of osteoblasts decreases, leading to osteolysis. Macrophages are innate immune cell with plasticity, and their polarization is related to inflammatory bone diseases. The dynamic balance of macrophages between the M1 phenotype and the M2 phenotype affects the occurrence and development of diseases. In recent years, an increasing number of studies have shown that extracellular vesicles existing in the extracellular environment can act on macrophages, affecting the progress of inflammatory diseases. This process is realized by influencing the physiological activity or functional activity of macrophages, inducing macrophages to secrete cytokines, and playing an anti-inflammatory or pro-inflammatory role. In addition, by modifying and editing extracellular vesicles, the potential of targeting macrophages can be used to provide new ideas for developing new drug carriers for inflammatory bone diseases.
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Affiliation(s)
- Yifan Lin
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ziyan Wang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Shirong Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiaohong Liu
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhiyi Zhang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuanting Ouyang
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhikang Su
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ding Chen
- Guangzhou Medical University, Guangzhou, Guangdong, China
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lvhua Guo
- Guangzhou Medical University, Guangzhou, Guangdong, China.
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Tao Luo
- Guangzhou Medical University, Guangzhou, Guangdong, China.
- Department of Prosthodontics, Guangdong Engineering Research Center of Oral Restoration and Reconstruction, Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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Chatterjee A, Jayaprakasan M, Chakrabarty AK, Lakkaniga NR, Bhatt BN, Banerjee D, Narwaria A, Katiyar CK, Dubey SK. Comprehensive insights into rheumatoid arthritis: Pathophysiology, current therapies and herbal alternatives for effective disease management. Phytother Res 2024; 38:2764-2799. [PMID: 38522945 DOI: 10.1002/ptr.8187] [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: 11/01/2023] [Revised: 02/14/2024] [Accepted: 03/01/2024] [Indexed: 03/26/2024]
Abstract
Rheumatoid arthritis is a chronic autoimmune inflammatory disease characterized by immune response overexpression, causing pain and swelling in the synovial joints. This condition is caused by auto-reactive antibodies that attack self-antigens due to their incapacity to distinguish between self and foreign molecules. Dysregulated activity within numerous signalling and immunological pathways supports the disease's development and progression, elevating its complexity. While current treatments provide some alleviation, their effectiveness is accompanied by a variety of adverse effects that are inherent in conventional medications. As a result, there is a deep-rooted necessity to investigate alternate therapeutic strategies capable of neutralizing these disadvantages. Medicinal herbs display a variety of potent bioactive phytochemicals that are effective in the complementary management of disease, thus generating an enormous potency for the researchers to delve deep into the development of novel phytomedicine against autoimmune diseases, although additional evidence and understanding are required in terms of their efficacy and pharmacodynamic mechanisms. This literature-based review highlights the dysregulation of immune tolerance in rheumatoid arthritis, analyses the pathophysiology, elucidates relevant signalling pathways involved, evaluates present and future therapy options and underscores the therapeutic attributes of a diverse array of medicinal herbs in addressing this severe disease.
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Affiliation(s)
- Amrita Chatterjee
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines), Dhanbad, India
| | - Monisha Jayaprakasan
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines), Dhanbad, India
| | | | - Naga Rajiv Lakkaniga
- Department of Chemistry and Chemical Biology, Indian Institute of Technology (Indian School of Mines), Dhanbad, India
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Fang Z, Mao J, Huang J, Sun H, Lu X, Lei H, Dong J, Chen S, Wang X. Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice. Cell Commun Signal 2024; 22:230. [PMID: 38627796 PMCID: PMC11022359 DOI: 10.1186/s12964-024-01610-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 04/10/2024] [Indexed: 04/19/2024] Open
Abstract
OBJECTIVE Recurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models. METHODS Exosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR. RESULTS IFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3' UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity. CONCLUSION Our study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal-fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.
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Affiliation(s)
- Zheng Fang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jiaqin Mao
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jialyu Huang
- Center for Reproductive Medicine, Jiangxi Maternal and Child Health Hospital, Nanchang, China
| | - Huijun Sun
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Xueyan Lu
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Hui Lei
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Jie Dong
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China
| | - Shuqiang Chen
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China.
| | - Xiaohong Wang
- Center for Reproductive Medicine, Department of Gynecology and Obstetrics, Tangdu Hospital, Air Force Medical University, Xi'an, China.
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Zhou S, Huang J, Zhang Y, Yu H, Wang X. Exosomes in Action: Unraveling Their Role in Autoimmune Diseases and Exploring Potential Therapeutic Applications. Immune Netw 2024; 24:e12. [PMID: 38725675 PMCID: PMC11076296 DOI: 10.4110/in.2024.24.e12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/20/2024] [Accepted: 02/07/2024] [Indexed: 05/12/2024] Open
Abstract
Exosomes are double phospholipid membrane vesicles that are synthesized and secreted by a variety of cells, including T cells, B cells, dendritic cells, immune cells, are extracellular vesicles. Recent studies have revealed that exosomes can play a significant role in under both physiological and pathological conditions. They have been implicated in regulation of inflammatory responses, immune response, angiogenesis, tissue repair, and antioxidant activities, particularly in modulating immunity in autoimmune diseases (AIDs). Moreover, variations in the expression of exosome-related substances, such as miRNA and proteins, may not only offer valuable perspectives for the early warning, and prognostic assessment of various AIDs, but may also serve as novel markers for disease diagnosis. This article examines the impact of exosomes on the development of AIDs and explores their potential for therapeutic application.
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Affiliation(s)
- Shuanglong Zhou
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Guizhou 563002, China
| | - Jialing Huang
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Guizhou 563002, China
| | - Yi Zhang
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Guizhou 563002, China
| | - Hongsong Yu
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Guizhou 563002, China
| | - Xin Wang
- School of Basic Medical Sciences, Zunyi Medical University, Guizhou 563002, China
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9
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Ijinu TP, De Lellis LF, Shanmugarama S, Pérez-Gregorio R, Sasikumar P, Ullah H, Buccato DG, Di Minno A, Baldi A, Daglia M. Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability. Nutrients 2023; 15:4152. [PMID: 37836436 PMCID: PMC10574533 DOI: 10.3390/nu15194152] [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: 09/07/2023] [Revised: 09/21/2023] [Accepted: 09/24/2023] [Indexed: 10/15/2023] Open
Abstract
Anthocyanins (ACNs) have attracted considerable attention for their potential to modulate the immune system. Research has revealed their antioxidant and anti-inflammatory properties, which play a crucial role in immune regulation by influencing key immune cells, such as lymphocytes, macrophages, and dendritic cells. Moreover, ACNs contribute towards maintaining a balance between proinflammatory and anti-inflammatory cytokines, thus promoting immune health. Beyond their direct effects on immune cells, ACNs significantly impact gut health and the microbiota, essential factors in immune regulation. Emerging evidence suggests that they positively influence the composition of the gut microbiome, enhancing their immunomodulatory effects. Furthermore, these compounds synergize with other bioactive substances, such as vitamins and minerals, further enhancing their potential as immune-supporting dietary supplements. However, detailed clinical studies must fully validate these findings and determine safe dosages across varied populations. Incorporating these natural compounds into functional foods or supplements could revolutionize the management of immune-related conditions. Personalized nutrition and healthcare strategies may be developed to enhance overall well-being and immune resilience by fully understanding the mechanisms underlying the actions of their components. Recent advancements in delivery methods have focused on improving the bioavailability and effectiveness of ACNs, providing promising avenues for future applications.
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Affiliation(s)
- Thadiyan Parambil Ijinu
- Naturæ Scientific, Kerala University-Business Innovation and Incubation Centre, Kariavattom Campus, University of Kerala, Thiruvananthapuram 695581, India;
- The National Society of Ethnopharmacology, VRA-179, Mannamoola, Peroorkada P.O., Thiruvananthapuram 695005, India
| | - Lorenza Francesca De Lellis
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
| | - Santny Shanmugarama
- Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Rosa Pérez-Gregorio
- Food and Health Omics Group, Institute of Agroecology and Food, Faculty of Sciences, University of Vigo, 32004 Ourense, Spain;
- LAQV-REQUIMTE, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, Portugal
- Department of Analytical and Food Chemistry, Galicia Sur Health Research Institute (IISGS), SERGAS-UVIGO, 32002 Ourense, Spain
| | | | - Hammad Ullah
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
| | - Daniele Giuseppe Buccato
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
| | - Alessandro Di Minno
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
- CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Alessandra Baldi
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
| | - Maria Daglia
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (L.F.D.L.); (D.G.B.); (A.D.M.); (A.B.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
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10
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Yang X, Wang Z, Zhang M, Shuai Z. Differential Expression Profiles of Plasma Exosomal microRNAs in Rheumatoid Arthritis. J Inflamm Res 2023; 16:3687-3698. [PMID: 37663759 PMCID: PMC10473432 DOI: 10.2147/jir.s413994] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/03/2023] [Indexed: 09/05/2023] Open
Abstract
Aim Differential expression maps of microRNAs (miRNAs) are connected to the autoimmune diseases. This study sought to elucidate the expression maps of exosomal miRNA in plasma of rheumatoid arthritis (RA) patients and their potential clinical significance. Methods In the screening phase, small RNA sequencing was performed to characterize dysregulated exosome-derived miRNAs in the plasma samples from six patients with RA and six healthy patients. At the independent verification stage, the candidate plasma exosomal miRNAs were verified in 40 patients with RA and 32 healthy patients by using qRT-PCR. The correlation of miRNA levels and clinical characteristics was tested in patients with RA. The value of these miRNAs in diagnosing RA was assessed with the receiver operating characteristic curve. Results During the screening phase, 177 and 129 miRNAs were increased and decreased in RA patients and healthy controls, respectively. There were 10 candidate plasma exosomal miRNAs selected for the next identification. Compared with the healthy controls, eight plasma exosomal miRNAs (let-7a-5p, let-7b-5p, let-7d-5p, let-7f-5p, let-7g-5p, let-7i-5p, miR-128-3p, and miR-25-3p) were significantly elevated in RA patients, but miR-144-3p and miR-15a-5p expression exhibited no significant changes. The let-7a-5p and miR-25-3p levels were linked to the rheumatoid factor-positive phenotype in RA patients. For the eight miRNAs, the area under the subject work characteristic curve (AUC) is 0.641 to 0.843, and their combination had a high diagnostic accuracy for RA (AUC = 0.916). Conclusion Our study illustrates that novel exosomal miRNAs in the plasma may represent potential noninvasive biomarkers for RA.
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Affiliation(s)
- Xiaoke Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Zhixin Wang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Mingming Zhang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
| | - Zongwen Shuai
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People’s Republic of China
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Chen L, Ou Q, Kou X. Extracellular vesicles and their indispensable roles in pathogenesis and treatment of inflammatory bowel disease: A comprehensive review. Life Sci 2023; 327:121830. [PMID: 37286163 DOI: 10.1016/j.lfs.2023.121830] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/09/2023]
Abstract
Inflammatory bowel disease (IBD) is a global disease with rising incidence worldwide, and its debilitating symptoms and dissatisfactory therapies have brought heavy burdens for patients. Extracellular vesicles (EVs), a heterogeneous population of lipid bilayer membranes containing abundant bioactive molecules, have been indicated to play important roles in the pathogenesis and treatment of many diseases. However, to our knowledge, comprehensive reviews summarizing the various roles of diverse source-derived EVs in the pathogenesis and treatment of IBD are still lacking. This review, not only summarizes the EV characteristics, but also focuses on the multiple roles of diverse EVs in IBD pathogenesis and their treatment potential. In addition, hoping to push forward the research frontiers, we point out several challenges that the researchers are faced, about EVs in current IBD research and future therapeutic applications. We also put forward our prospects on future exploration regarding EVs in IBD treatment, including developing IBD vaccines and paying more attention on apoptotic vesicles. This review is aimed to enrich the knowledge on the indispensable roles of EVs in IBD pathogenesis and treatment, providing ideas and reference for future therapeutic strategy for IBD treatment.
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Affiliation(s)
- Linling Chen
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, 510055 Guangzhou, China
| | - Qianmin Ou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, 510055 Guangzhou, China
| | - Xiaoxing Kou
- Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, South China Center of Craniofacial Stem Cell Research, Guangdong Provincial Key Laboratory of Stomatology, 510055 Guangzhou, China; Key Laboratory of Stem Cells and Tissue Engineering (Sun Yat-sen University), Ministry of Education, Guangzhou, Guangdong 510055, China.
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12
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Yang X, Xia H, Liu C, Wu Y, Liu X, Cheng Y, Wang Y, Xia Y, Yue Y, Cheng X, Jia R. The novel delivery-exosome application for diagnosis and treatment of rheumatoid arthritis. Pathol Res Pract 2023; 242:154332. [PMID: 36696804 DOI: 10.1016/j.prp.2023.154332] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 01/15/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Rheumatoid arthritis (RA) is a chronic degenerative disease characterized by persistent systemic synovitis, with a high risk of stiffness, pain, and swelling. It may affect the other extra-articular tissues. There is no ideal treatment for this disease at present, and it can only be controlled by medication to alleviate the prognosis. Exosomes are small vesicles secreted by various cells in the organism under normal or pathological conditions, and play a role in immune response, antigen presentation, cell migration, cell differentiation, tumor invasion and so on. Due to the adverse effects of conventional drugs and treatments in the treatment of RA, exosomes, as a nanocarrier with many advantages, can have a great impact on the loading of drugs for the treatment of RA. This article reviews the role of exosomes in the pathogenesis of RA and the progress of exosome-based therapy for RA.
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Affiliation(s)
- Xinying Yang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Hongmei Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China.
| | - Chang Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yifang Wu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xinyi Liu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yongfeng Cheng
- Clinical College of Anhui Medical University, Hefei 230031, People's Republic of China; School of Life Science, University of Science and Technology of China, Hefei 230027, People's Republic of China
| | - Yu Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ying Xia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Yan Yue
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Xiaoman Cheng
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
| | - Ruoyang Jia
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, People's Republic of China
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13
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Zhu Y, Liu L, Chu L, Lan J, Wei J, Li W, Xue C. Microscopic polyangiitis plasma-derived exosomal miR-1287-5p induces endothelial inflammatory injury and neutrophil adhesion by targeting CBL. PeerJ 2023; 11:e14579. [PMID: 36726727 PMCID: PMC9885867 DOI: 10.7717/peerj.14579] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 11/28/2022] [Indexed: 01/28/2023] Open
Abstract
Background An inflammatory environment around the vessel wall caused by leukocyte infiltration is one of the characteristic histopathological features of microscopic polyangiitis (MPA); however, the pathogenic mechanisms are not fully understood. Studies have found that circulating microRNA (miRNA) can be used as potential biomarkers for the diagnosis and classification of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV), and the E3 ubiquitin ligase casitas B-lineage lymphoma (CBL) seems to be associated with inflammation. In addition, evidence indicates that miRNA can be tracked into exosomes and transferred into recipient cells to mediate the process of vascular endothelial injury. Herein, we aimed to identify the profiles of exosomal miRNA, and determine the effect of exosomal miR-1287-5p and its target gene CBL on vascular endothelial cells in MPA. Method We isolated plasma exosomes from patients with MPA (MPA-exo) and healthy controls (HC-exo) by ultracentrifugation and conducted exosome small-RNA sequencing to screen differential miRNA expression in MPA-exo (n = 3) compared to HC-exo (n = 3). We measured the expression levels of miR-1303, miR-1287-5p, and miR-129-1-3p using quantitative reverse transcription-polymerase chain reaction (qRT-PCR, n = 6) and performed dual luciferase reporter gene assays to confirm the downstream target gene of miR-1287-5p. In addition, we treated human umbilical vein endothelial cell (HUVEC) with MPA-exo, or transfected them with miR-1287-5p mimic/inhibitor or with CBL-siRNA/CBL-siRNA+ miR-1287-5p inhibitor. After cell culture, we evaluated the effects on vascular endothelial cells by examining the mRNA levels of IL-6, IL-8, MCP-1, ICAM-1 and E-selectin using qRT-PCR and performed neutrophil adhesion assay with haematoxylin staining. Result Transmission electron microscopy, Western blot and nanoparticle tracking analysis showed that we successfully purified exosomes and MPA-exo could be absorbed into HUVEC. We screened a total of 1,077 miRNA by sequencing and observed a high abundance of miR-1287-5p in the exosomes obtained from MPA plasma. The dual luciferase reporter assay identified CBL as a downstream target gene of miR-1287-5p, and the results revealed that MPA-exo decreased CBL protein expression in HUVEC. In addition, treatment with MPA-exo, up-regulating miR-1287-5p or silencing of CBL in HUVEC significantly increased the mRNA expression of inflammatory factors (including IL-6, IL-8, and MCP-1) and adhesion molecules (including ICAM-1 and E-selection) and promoted the adhesion of neutrophils to HUVEC. However, down-regulating miR-1287-5p had the opposite effect. Conclusion Our study revealed that MPA-exo was involved in the intercellular transfer of miR-1287-5p and subsequently promote the development of acute endothelial injury in MPA. MiR-1287-5p and CBL agonists may be promising therapeutic approach for MPA-induced vascular inflammatory injury.
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Affiliation(s)
- Yan Zhu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China,The First Affiliated Hospital, Department of Nephrology, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Liu Liu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Liepeng Chu
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jingjing Lan
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jingsi Wei
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Wei Li
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Chao Xue
- Department of Nephrology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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Tavasolian F, Pastrello C, Ahmed Z, Jurisica I, Inman RD. Vesicular traffic-mediated cell-to-cell signaling at the immune synapse in Ankylosing Spondylitis. Front Immunol 2023; 13:1102405. [PMID: 36741392 PMCID: PMC9889860 DOI: 10.3389/fimmu.2022.1102405] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 12/21/2022] [Indexed: 01/19/2023] Open
Abstract
The chronic inflammatory disease ankylosing spondylitis (AS) is marked by back discomfort, spinal ankylosis, and extra-articular symptoms. In AS, inflammation is responsible for both pain and spinal ankylosis. However, the processes that sustain chronic inflammation remain unknown. Despite the years of research conducted to decipher the intricacy of AS, little progress has been made in identifying the signaling events that lead to the development of this disease. T cells, an immune cell type that initiates and regulates the body's response to infection, have been established to substantially impact the development of AS. T lymphocytes are regarded as a crucial part of adaptive immunity for the control of the immune system. A highly coordinated interaction involving antigen-presenting cells (APCs) and T cells that regulate T cell activation constitutes an immunological synapse (IS). This first phase leads to the controlled trafficking of receptors and signaling mediators involved in folding endosomes to the cellular interface, which allows the transfer of information from T cells to APCs through IS formation. Discrimination of self and nonself antigen is somatically learned in adaptive immunity. In an autoimmune condition such as AS, there is a disturbance of self/nonself antigen discrimination; available findings imply that the IS plays a preeminent role in the adaptive immune response. In this paper, we provide insights into the genesis of AS by evaluating recent developments in the function of vesicular trafficking in IS formation and the targeted release of exosomes enriched microRNAs (miRNA) at the synaptic region in T cells.
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Affiliation(s)
- Fataneh Tavasolian
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada
| | - Chiara Pastrello
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Zuhaib Ahmed
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Igor Jurisica
- Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, and Data Science Discovery Centre for Chronic Diseases, Krembil Research Institute, University Health Network, Toronto, ON, Canada,Departments of Medical Biophysics and Computer Science, and the Faculty of Dentistry, University of Toronto, Toronto, ON, Canada,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Robert D. Inman
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, ON, Canada,Krembil Research Institute, University Health Network, Toronto, ON, Canada,Departments of Medicine and Immunology, University of Toronto, Toronto, ON, Canada,*Correspondence: Robert D. Inman,
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15
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Joseph J, Rahmani B, Cole Y, Puttagunta N, Lin E, Khan ZK, Jain P. Can Soluble Immune Checkpoint Molecules on Exosomes Mediate Inflammation? J Neuroimmune Pharmacol 2022; 17:381-397. [PMID: 34697721 PMCID: PMC10128092 DOI: 10.1007/s11481-021-10018-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/25/2021] [Indexed: 01/13/2023]
Abstract
Immune checkpoints (ICPs) are major co-signaling pathways that trigger effector functions in immune cells, with isoforms that are either membrane bound, engaging in direct cell to cell activation locally, or soluble, acting at distant sites by circulating freely or potentially via extracellular vesicles (EVs). Exosomes are small EVs secreted by a variety of cells carrying various proteins and nucleic acids. They are distributed extensively through biological fluids and have major impacts on infectious diseases, cancer, and neuroinflammation. Similarly, ICPs play key roles in a variety of disease conditions and have been extensively utilized as a prognostic tool for various cancers. Herein, we explored if the association between exosomes and ICPs could be a significant contributor of inflammation, particularly in the setting of cancer, neuroinflammation and viral infections, wherein the up regulation in both exosomal proteins and ICPs correlate with immunosuppressive effects. The detailed literature review of existing data highlights the significance and complexity of these two important pathways in mediating cancer and potentiating neuroinflammation via modulating overall immune response. Cells increasingly secret exosomes in response to intracellular signals from invading pathogens or cancerous transformations. These exosomes can carry a variety of cargo including proteins, nucleic acids, cytokines, and receptors/ligands that have functional consequences on recipient cells. Illustration generated using BioRender software.
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Affiliation(s)
- Julie Joseph
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Benjamin Rahmani
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Yonesha Cole
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Neha Puttagunta
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Edward Lin
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Zafar K Khan
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA
| | - Pooja Jain
- Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA. .,Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA, 19129, USA.
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Abesekara MS, Chau Y. Recent advances in surface modification of micro- and nano-scale biomaterials with biological membranes and biomolecules. Front Bioeng Biotechnol 2022; 10:972790. [PMID: 36312538 PMCID: PMC9597319 DOI: 10.3389/fbioe.2022.972790] [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: 06/19/2022] [Accepted: 09/26/2022] [Indexed: 11/16/2022] Open
Abstract
Surface modification of biomaterial can improve its biocompatibility and add new biofunctions, such as targeting specific tissues, communication with cells, and modulation of intracellular trafficking. Here, we summarize the use of various natural materials, namely, cell membrane, exosomes, proteins, peptides, lipids, fatty acids, and polysaccharides as coating materials on micron- and nano-sized particles and droplets with the functions imparted by coating with different materials. We discuss the applicability, operational parameters, and limitation of different coating techniques, from the more conventional approaches such as extrusion and sonication to the latest innovation seen on the microfluidics platform. Methods commonly used in the field to examine the coating, including its composition, physical dimension, stability, fluidity, permeability, and biological functions, are reviewed.
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Shi R, Jin Y, Zhao S, Yuan H, Shi J, Zhao H. Hypoxic ADSC-derived exosomes enhance wound healing in diabetic mice via delivery of circ-Snhg11 and induction of M2-like macrophage polarization. Biomed Pharmacother 2022; 153:113463. [DOI: 10.1016/j.biopha.2022.113463] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2022] [Revised: 07/16/2022] [Accepted: 07/21/2022] [Indexed: 01/09/2023] Open
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18
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Muñoz C, Carmona M, Luna O, Gómez FA, Cárdenas C, Flores-Herrera P, Belmonte R, Marshall SH. Serum-isolated exosomes from Piscirickettsia salmonis-infected Salmo salar specimens enclose bacterial DnaK, DnaJ and GrpE chaperones. ELECTRON J BIOTECHN 2022. [DOI: 10.1016/j.ejbt.2022.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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Zhang K, Liu L, Shi K, Zhang K, Zheng C, Jin Y. Extracellular Vesicles for Immunomodulation in Tissue Regeneration. Tissue Eng Part C Methods 2022; 28:393-404. [PMID: 35856810 DOI: 10.1089/ten.tec.2022.0000059] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A large number of people suffer from tissue injury and defect worldwide, which constitutes a critical challenge for regenerative medicine. During the complicated process of tissue repair and regeneration, immune response that involves many kinds of immune cells often concurrently exists and plays a significant role, thus providing a promising target for the development of therapeutic strategies. As a critical player in cell-cell communication, extracellular vesicles (EVs) are a cluster of nano-sized vesicles of different categories, which have been reported to possess favorable immunoregulatory potential, and participate in the process of tissue repair and regeneration. Furthermore, EVs can be engineered with genetic or chemical strategies for optimized performance as therapeutic mediators. Here, we provide an outline on the biology of EVs as well as the role of EVs in immune regulation, focusing on exosomes, microvesicles, and apoptotic vesicles. We further summarize the applications of EV-based therapies for tissue regeneration, with particular emphasis on the modulation of immune system. Also, we have discussed the construction strategies of engineered EVs and the immunomodulatory capability of engineered EVs as well as their therapeutic potential in tissue repair. This review will highlight the outstanding potential of EV-based therapeutic strategies for tissue repair and regeneration.
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Affiliation(s)
- Kaichao Zhang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China
| | - Lu Liu
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Ke Shi
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China
| | - Kai Zhang
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Chenxi Zheng
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China
| | - Yan Jin
- State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.,Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China
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20
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Zhao J, An Q, Zhu X, Yang B, Gao X, Niu Y, Zhang L, Xu K, Ma D. Research status and future prospects of extracellular vesicles in primary Sjögren's syndrome. Stem Cell Res Ther 2022; 13:230. [PMID: 35659085 PMCID: PMC9166483 DOI: 10.1186/s13287-022-02912-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/19/2022] [Indexed: 11/23/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is a diffuse connective tissue disease characterized by the invasion of exocrine glands such as lacrimal and salivary glands, abnormal proliferation of T and B lymphocytes, and infiltration of tissue lymphocytes. With the development of modern medicine, although research on the pathogenesis, diagnosis, and treatment of pSS has made significant progress, its pathogenesis has not been fully understood. Meanwhile, in the era of individualized treatment, it remains essential to further explore early diagnosis and treatment methods. Exosomes, small vesicles containing proteins and nucleic acids, are a subtype of extracellular vesicles secreted by various cells and present in various body fluids. Exosomes contribute to a variety of biological functions, including intercellular signal transduction and pathophysiological processes, and may play a role in immune tolerance. Therefore, exosomes are key to understanding the pathogenesis of diseases. Exosomes can also be used as a therapeutic tool for pSS because of their biodegradability, low immunogenicity and toxicity, and the ability to bypass the blood–brain barrier, implying the prospect of a broad application in the context of pSS. Here, we systematically review the isolation, identification, tracing, and mode of action of extracellular vesicles, especially exosomes, as well as the research progress in the pathogenesis, diagnosis, and treatment of pSS.
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Affiliation(s)
- Jingwen Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Qi An
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Xueqing Zhu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Baoqi Yang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Xinnan Gao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Yuhu Niu
- Department of Biochemistry and Molecular Biology, Shanxi Medical University, 56, Xinjian South Rd., Taiyuan, China
| | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Ke Xu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China
| | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, 030032, China.
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21
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Nix C, Ghassemi M, Crommen J, Fillet M. Overview on microfluidics devices for monitoring brain disorder biomarkers. Trends Analyt Chem 2022. [DOI: 10.1016/j.trac.2022.116693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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22
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Liu X, Hu L, Liu F. Mesenchymal stem cell-derived extracellular vesicles for cell-free therapy of ocular diseases. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:102-117. [PMID: 39698446 PMCID: PMC11648472 DOI: 10.20517/evcna.2022.08] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/31/2022] [Accepted: 04/18/2022] [Indexed: 12/20/2024]
Abstract
Mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) have noticeably attracted clinicians' attention in treating ocular diseases. As the paracrine factor of MSCs and an alternative for cell-free therapies, MSC-EVs can be conveniently dropped over the ocular surface or diffused through the retina upon intravitreal injection, without increasing the risks of cellular rejection and tumor formation. For clinical translation, a standardized and scalable production, as well as reprogramming the MSC-EVs, are highly encouraged. This review aims to assess the potential approaches for EV production and functional modification, in addition to summarizing the worldwide clinical trials initiated for various physiological systems and the specific biochemical effects of MSC-EVs on the therapy of eye diseases. Recent advances in the therapy of ocular diseases based on MSC-EVs are reviewed, and the associated challenges and prospects are discussed as well.
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Affiliation(s)
- Xiaoling Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Liang Hu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
| | - Fei Liu
- Eye Hospital, School of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325000, Zhejiang, China
- Wenzhou Institute, University of Chinese Academy of Science, Wenzhou 325000, Zhejiang, China
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23
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Extracellular Vesicles in Type 1 Diabetes: A Versatile Tool. Bioengineering (Basel) 2022; 9:bioengineering9030105. [PMID: 35324794 PMCID: PMC8945706 DOI: 10.3390/bioengineering9030105] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/15/2022] Open
Abstract
Type 1 diabetes is a chronic autoimmune disease affecting nearly 35 million people. This disease develops as T-cells continually attack the β-cells of the islets of Langerhans in the pancreas, which leads to β-cell death, and steadily decreasing secretion of insulin. Lowered levels of insulin minimize the uptake of glucose into cells, thus putting the body in a hyperglycemic state. Despite significant progress in the understanding of the pathophysiology of this disease, there is a need for novel developments in the diagnostics and management of type 1 diabetes. Extracellular vesicles (EVs) are lipid-bound nanoparticles that contain diverse content from their cell of origin and can be used as a biomarker for both the onset of diabetes and transplantation rejection. Furthermore, vesicles can be loaded with therapeutic cargo and delivered in conjunction with a transplant to increase cell survival and long-term outcomes. Crucially, several studies have linked EVs and their cargos to the progression of type 1 diabetes. As a result, gaining a better understanding of EVs would help researchers better comprehend the utility of EVs in regulating and understanding type 1 diabetes. EVs are a composition of biologically active components such as nucleic acids, proteins, metabolites, and lipids that can be transported to particular cells/tissues through the blood system. Through their varied content, EVs can serve as a flexible aid in the diagnosis and management of type 1 diabetes. In this review, we provide an overview of existing knowledge about EVs. We also cover the role of EVs in the pathogenesis, detection, and treatment of type 1 diabetes and the function of EVs in pancreas and islet β-cell transplantation.
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24
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A sandwich-based evanescent wave fluorescent biosensor for simple, real-time exosome detection †. Biosens Bioelectron 2021; 200:113902. [PMID: 34954570 DOI: 10.1016/j.bios.2021.113902] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/17/2021] [Accepted: 12/18/2021] [Indexed: 12/14/2022]
Abstract
Exosomes are regarded as a promising biomarker for the noninvasive diagnosis and treatment of diseases. The value of exosomes for medical research has promoted the search for a fast, efficient, and sensitive detection method. This study reported a sandwich-based evanescent wave fluorescent biosensor (S-EWFB) for exosome detection. A two-step strategy was implemented to take advantages of the simple binding of fluorescent probes with exosomes via the hydrophobic interaction between the cholesteryl and phospholipid bilayer membrane, as well as real-time detection on an evanescent wave liquid-solid interface based on CD63 aptamer-specific capture to form an exosome@fluorescence probe/aptamer sandwich structure. The one-to-many connection between exosomes and signal molecules and the aptamer-modified evanescent wave optical fiber detection platform reduced the detection limit of exosomes to 7.66 particles/mL, with a linear range of 47.5-4.75 × 106 particles/mL. The entire detection process was simple, rapid, and real-time and lasted about 1 h while requiring no separation and purification. Additionally, this platform showed excellent surface regeneration capability and exhibited good performance during the analysis of tumor and non-tumor-derived exosomes.
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25
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Arishe OO, Priviero F, Wilczynski SA, Webb RC. Exosomes as Intercellular Messengers in Hypertension. Int J Mol Sci 2021; 22:ijms222111685. [PMID: 34769116 PMCID: PMC8583750 DOI: 10.3390/ijms222111685] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/23/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
People living with hypertension have a higher risk of developing heart diseases, and hypertension remains a top cause of mortality. In hypertension, some detrimental changes occur in the arterial wall, which include physiological and biochemical changes. Furthermore, this disease is characterized by turbulent blood flow, increased fluid shear stress, remodeling of the blood vessels, and endothelial dysfunction. As a complex disease, hypertension is thought to be caused by an array of factors, its etiology consisting of both environmental and genetic factors. The Mosaic Theory of hypertension states that many factors, including genetics, environment, adaptive, neural, mechanical, and hormonal perturbations are intertwined, leading to increases in blood pressure. Long-term efforts by several investigators have provided invaluable insight into the physiological mechanisms responsible for the pathogenesis of hypertension, and these include increased activity of the sympathetic nervous system, overactivation of the renin-angiotensin-aldosterone system (RAAS), dysfunction of the vascular endothelium, impaired platelet function, thrombogenesis, vascular smooth muscle and cardiac hypertrophy, and altered angiogenesis. Exosomes are extracellular vesicles released by all cells and carry nucleic acids, proteins, lipids, and metabolites into the extracellular environment. They play a role in intercellular communication and are involved in the pathophysiology of diseases. Since the discovery of exosomes in the 1980s, numerous studies have been carried out to understand the biogenesis, composition, and function of exosomes. In this review, we will discuss the role of exosomes as intercellular messengers in hypertension.
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Affiliation(s)
- Olufunke Omolola Arishe
- Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC 29209, USA; (F.P.); (S.A.W.); (R.C.W.)
- Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29209, USA
- Correspondence: ; Tel.: +1-706-394-3582
| | - Fernanda Priviero
- Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC 29209, USA; (F.P.); (S.A.W.); (R.C.W.)
- Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29209, USA
| | - Stephanie A. Wilczynski
- Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC 29209, USA; (F.P.); (S.A.W.); (R.C.W.)
- Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29209, USA
| | - R. Clinton Webb
- Cardiovascular Translational Research Center, University of South Carolina, Columbia, SC 29209, USA; (F.P.); (S.A.W.); (R.C.W.)
- Department of Cell Biology and Anatomy, University of South Carolina, School of Medicine, Columbia, SC 29209, USA
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26
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Claridge B, Lozano J, Poh QH, Greening DW. Development of Extracellular Vesicle Therapeutics: Challenges, Considerations, and Opportunities. Front Cell Dev Biol 2021; 9:734720. [PMID: 34616741 PMCID: PMC8488228 DOI: 10.3389/fcell.2021.734720] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 07/30/2021] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) hold great promise as therapeutic modalities due to their endogenous characteristics, however, further bioengineering refinement is required to address clinical and commercial limitations. Clinical applications of EV-based therapeutics are being trialed in immunomodulation, tissue regeneration and recovery, and as delivery vectors for combination therapies. Native/biological EVs possess diverse endogenous properties that offer stability and facilitate crossing of biological barriers for delivery of molecular cargo to cells, acting as a form of intercellular communication to regulate function and phenotype. Moreover, EVs are important components of paracrine signaling in stem/progenitor cell-based therapies, are employed as standalone therapies, and can be used as a drug delivery system. Despite remarkable utility of native/biological EVs, they can be improved using bio/engineering approaches to further therapeutic potential. EVs can be engineered to harbor specific pharmaceutical content, enhance their stability, and modify surface epitopes for improved tropism and targeting to cells and tissues in vivo. Limitations currently challenging the full realization of their therapeutic utility include scalability and standardization of generation, molecular characterization for design and regulation, therapeutic potency assessment, and targeted delivery. The fields' utilization of advanced technologies (imaging, quantitative analyses, multi-omics, labeling/live-cell reporters), and utility of biocompatible natural sources for producing EVs (plants, bacteria, milk) will play an important role in overcoming these limitations. Advancements in EV engineering methodologies and design will facilitate the development of EV-based therapeutics, revolutionizing the current pharmaceutical landscape.
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Affiliation(s)
- Bethany Claridge
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, VIC, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Jonathan Lozano
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, Australia
| | - Qi Hui Poh
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, VIC, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - David W. Greening
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science (LIMS), La Trobe University, Melbourne, VIC, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
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27
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Altered Proteomic Profile of Adipose Tissue-Derived Mesenchymal Stem Cell Exosomes from Cats with Severe Chronic Gingivostomatitis. Animals (Basel) 2021; 11:ani11082466. [PMID: 34438923 PMCID: PMC8388770 DOI: 10.3390/ani11082466] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/16/2021] [Accepted: 08/19/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Feline chronic gingivostomatitis (FCGS) is a common pathology in cats, related to an aberrant immune response. The cause of FCGS remains elusive, despite extensive investigations. A multitude of conditions and infectious agents have been related, without proof of causation, as follows: virus, bacteria, environmental stress, hypersensitivity, etc. In recent years, therapies based on feline adipose-derived mesenchymal stem cells (fAd-MSC) have become an interesting alternative for the treatment of different complex pathologies in cats. Mesenchymal stem cells secrete a wide variety of therapeutic elements, such as bioactive molecules and extracellular vesicles, such as exosomes. It is essential to characterize these elements, to better understand their mechanisms of action. In this study, we show, for the first time, that the proteomic profile of fAd-MSC-derived exosomes, from calicivirus-positive patients with severe FCGS, is altered. Using bioinformatic tools, we have demonstrated the existence of different proteins in the exosomes from diseased patients, responsible for an altered biological effect. In addition, the exosomes do not only experience changes in their cargo, but are also produced in larger quantities. This study might contribute to the better prediction of the clinical outcomes of mesenchymal stem cell treatments in veterinary patients with immune-mediated diseases, such as FCGS. Abstract Feline chronic gingivostomatitis (FCGS) is a pathology with a complicated therapeutic approach and with a prevalence between 0.7 and 12%. Although the etiology of the disease is diverse, feline calicivirus infection is known to be a predisposing factor. To date, the available treatment helps in controlling the disease, but cannot always provide a cure, which leads to a high percentage of refractory animals. Mesenchymal stem cells (MSCs) play a pivotal role in the homeostasis and reparation of different tissues and have the ability to modulate the immune system responses. This ability is, in part, due to the capacity of exosomes to play a part in intercellular cell communication. However, the precise role of MSC-derived exosomes and their alterations in immunocompromised pathologies remains unknown, especially in veterinary patients. The goal of this work was to analyze the proteomic profile of feline adipose tissue-derived MSCs (fAd-MSCs) from calicivirus-positive FCGS patients, and to detect possible modifications of the exosomal cargo, to gain better knowledge of the disease’s etiopathogenesis. Using high-resolution mass spectrometry and functional enrichment analysis with Gene Ontology, exosomes isolated from the fAd-MSCs of five healthy cats and five calicivirus-positive FCGS patients, were pooled and compared. The results showed that the fAd-MSCs from cats suffering from FCGS not only had a higher exosome production, but also their exosomes showed significant alterations in their proteomic profile. Eight proteins were exclusively found in the exosomes from the FCGS group, and five proteins could only be found in the exosomes from the healthy cats. When comparing the exosomal cargo between the two groups, significant upregulation of 17 and downregulation of 13 proteins were detected in the FCGS group compared to the control group. These findings shed light on new perspectives on the roles of MSCs and their relation to this disease, which may help in identifying new therapeutic targets and selecting specific biomarkers.
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Kronstadt SM, Pottash AE, Levy D, Wang S, Chao W, Jay SM. Therapeutic Potential of Extracellular Vesicles for Sepsis Treatment. ADVANCED THERAPEUTICS 2021; 4:2000259. [PMID: 34423113 PMCID: PMC8378673 DOI: 10.1002/adtp.202000259] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Indexed: 12/14/2022]
Abstract
Sepsis is a deadly condition lacking a specific treatment despite decades of research. This has prompted the exploration of new approaches, with extracellular vesicles (EVs) emerging as a focal area. EVs are nanosized, cell-derived particles that transport bioactive components (i.e., proteins, DNA, and RNA) between cells, enabling both normal physiological functions and disease progression depending on context. In particular, EVs have been identified as critical mediators of sepsis pathophysiology. However, EVs are also thought to constitute the biologically active component of cell-based therapies and have demonstrated anti-inflammatory, anti-apoptotic, and immunomodulatory effects in sepsis models. The dual nature of EVs in sepsis is explored here, discussing their endogenous roles and highlighting their therapeutic properties and potential. Related to the latter component, prior studies involving EVs from mesenchymal stem/stromal cells (MSCs) and other sources are discussed and emerging producer cells that could play important roles in future EV-based sepsis therapies are identified. Further, how methodologies could impact therapeutic development toward sepsis treatment to enhance and control EV potency is described.
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Affiliation(s)
- Stephanie M Kronstadt
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Alex E Pottash
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Daniel Levy
- Fischell Department of Bioengineering, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
| | - Sheng Wang
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Steven M Jay
- Fischell Department of Bioengineering and Program in Molecular and, Cell Biology, University of Maryland, 3102 A. James Clark Hall, College Park, MD 20742, USA
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29
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Grieco GE, Fignani D, Formichi C, Nigi L, Licata G, Maccora C, Brusco N, Sebastiani G, Dotta F. Extracellular Vesicles in Immune System Regulation and Type 1 Diabetes: Cell-to-Cell Communication Mediators, Disease Biomarkers, and Promising Therapeutic Tools. Front Immunol 2021; 12:682948. [PMID: 34177928 PMCID: PMC8219977 DOI: 10.3389/fimmu.2021.682948] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 05/10/2021] [Indexed: 12/16/2022] Open
Abstract
Extracellular vesicles (EVs) are generated by cells of origin through complex molecular mechanisms and released into extracellular environment. Hence, the presence of EVs has been described in multiple biological fluids and in most cases their molecular cargo, which includes non-coding RNAs (ncRNA), messenger RNAs (mRNA), and proteins, has been reported to modulate distinct biological processes. EVs release and their molecular cargo have been demonstrated to be altered in multiple diseases, including autoimmune diseases. Notably, numerous evidence showed a relevant crosstalk between immune system and interacting cells through specific EVs release. The crosstalk between insulin-producing pancreatic β cells and immune system through EVs bidirectional trafficking has yet started to be deciphered, thus uncovering an intricate communication network underlying type 1 diabetes (T1D) pathogenesis. EVs can also be found in blood plasma or serum. Indeed, the assessment of circulating EVs cargo has been shown as a promising advance in the detection of reliable biomarkers of disease progression. Of note, multiple studies showed several specific cargo alterations of EVs collected from plasma/serum of subjects affected by autoimmune diseases, including T1D subjects. In this review, we discuss the recent literature reporting evidence of EVs role in autoimmune diseases, specifically focusing on the bidirectional crosstalk between pancreatic β cells and immune system in T1D and highlight the relevant promising role of circulating EVs as disease biomarkers.
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Affiliation(s)
- Giuseppina Emanuela Grieco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Daniela Fignani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Caterina Formichi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Laura Nigi
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Giada Licata
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Carla Maccora
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy
| | - Noemi Brusco
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Guido Sebastiani
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy
| | - Francesco Dotta
- Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.,Fondazione Umberto Di Mario, c/o Toscana Life Sciences, Siena, Italy.,UOC Diabetologia, Azienda Ospedaliera Universitaria Senese, Siena, Italy.,Tuscany Centre for Precision Medicine (CReMeP), Siena, Italy
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30
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Hu Q, Lyon CJ, Fletcher JK, Tang W, Wan M, Hu TY. Extracellular vesicle activities regulating macrophage- and tissue-mediated injury and repair responses. Acta Pharm Sin B 2021; 11:1493-1512. [PMID: 34221864 PMCID: PMC8245807 DOI: 10.1016/j.apsb.2020.12.014] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/04/2020] [Accepted: 12/09/2020] [Indexed: 02/08/2023] Open
Abstract
Macrophages are typically identified as classically activated (M1) macrophages and alternatively activated (M2) macrophages, which respectively exhibit pro- and anti-inflammatory phenotypes, and the balance between these two subtypes plays a critical role in the regulation of tissue inflammation, injury, and repair processes. Recent studies indicate that tissue cells and macrophages interact via the release of small extracellular vesicles (EVs) in processes where EVs released by stressed tissue cells can promote the activation and polarization of adjacent macrophages which can in turn release EVs and factors that can promote cell stress and tissue inflammation and injury, and vice versa. This review discusses the roles of such EVs in regulating such interactions to influence tissue inflammation and injury in a number of acute and chronic inflammatory disease conditions, and the potential applications, advantage and concerns for using EV-based therapeutic approaches to treat such conditions, including their potential role of drug carriers for the treatment of infectious diseases.
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Key Words
- ADSCs, adipose-derived stem cells
- AKI, acute kidney injury
- ALI, acute lung injury
- AMs, alveolar macrophages
- BMSCs, bone marrow stromal cells
- CLP, cecal ligation and puncture
- DSS, dextran sodium sulphate
- EVs, extracellular vesicles
- Extracellular vesicles
- HSPA12B, heat shock protein A12B
- HUCMSCs, human umbilical cord mesenchymal stem cells
- IBD, inflammatory bowel disease
- ICAM-1, intercellular adhesion molecule 1
- IL-1β, interleukin-1β
- Inflammatory disease
- Interaction loop
- KCs, Kupffer cells
- KLF4, krüppel-like factor 4
- LPS, lipopolysaccharides
- MHC, major histocompatibility complex
- MSCs, mesenchymal stromal cells
- MVs, microvesicles
- Macrophage
- PEG, polyethylene glycol
- PMFA, 5,7,30,40,50-pentamethoxyflavanone
- PPARγ, peroxisome proliferator-activated receptor γ
- SIRPα, signal regulatory protein α
- Sepsis
- Stem cell
- TECs, tubular epithelial cells
- TNF, tumor necrosis factor
- TRAIL, tumor necrosis factor-related apoptosis-inducing ligand
- Targeted therapy
- Tissue injury
- iNOS, inducible nitrogen oxide synthase
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Zhang Y, Zhang R, Ge L, Wang L. Exosome-derived TXNDC5 is Required for the Inflammatory Progression of Rheumatoid Arthritis Fibroblast-like Synoviocytes. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021; 000:000-000. [DOI: 10.14218/erhm.2021.00013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Alzhrani GN, Alanazi ST, Alsharif SY, Albalawi AM, Alsharif AA, Abdel-Maksoud MS, Elsherbiny N. Exosomes: Isolation, characterization, and biomedical applications. Cell Biol Int 2021; 45:1807-1831. [PMID: 33913604 DOI: 10.1002/cbin.11620] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 03/30/2021] [Accepted: 04/18/2021] [Indexed: 12/13/2022]
Abstract
Exosomes are nano-sized bioactive vesicles of 30-150 nm in diameter. They are secreted by exocytosis of nearly all type of cells in to the extracellular fluid. Thereby, they can be found in many biological fluids. Exosomes regulate intracellular communication between cells via delivery of their cargo which include lipids, proteins, and nucleic acid. Many desirable features of exosomes made them promising candidates in several therapeutic applications. In this review, we discuss the use of exosomes as diagnostic tools and their possible biomedical applications. Additionally, current techniques used for isolation, purification, and characterization of exosomes from both biological fluids and in vitro cell cultures were discussed.
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Affiliation(s)
- Ghadi N Alzhrani
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Sarah T Alanazi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Sumayyah Y Alsharif
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Amani M Albalawi
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Anwar A Alsharif
- Pharm D Program, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Mohamed S Abdel-Maksoud
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia
| | - Nehal Elsherbiny
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk, Saudi Arabia.,Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
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Komuro H, Kawai-Harada Y, Aminova S, Pascual N, Malik A, Contag CH, Harada M. Engineering Extracellular Vesicles to Target Pancreatic Tissue In Vivo. Nanotheranostics 2021; 5:378-390. [PMID: 33912378 PMCID: PMC8077969 DOI: 10.7150/ntno.54879] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 03/31/2021] [Indexed: 01/04/2023] Open
Abstract
Extracellular vesicles (EVs) are naturally released, cell-derived vesicles that mediate intracellular communication, in part, by transferring genetic information and, thus, have the potential to be modified for use as a therapeutic gene or drug delivery vehicle. Advances in EV engineering suggest that directed delivery can be accomplished via surface alterations. Here we assess enriched delivery of engineered EVs displaying an organ targeting peptide specific to the pancreas. We first characterized the size, morphology, and surface markers of engineered EVs that were decorated with a recombinant protein specific to pancreatic β-cells. This β-cell-specific recombinant protein consists of the peptide p88 fused to the EV-binding domain of lactadherin (C1C2). These engineered EVs, p88-EVs, specifically bound to pancreatic β-cells in culture and transferred encapsulated plasmid DNA (pDNA) as early as in 10 min suggesting that the internalization of peptide-bearing EVs is a rapid process. Biodistribution of p88-EVs administrated intravenously into mice showed an altered pattern of EV localization and improved DNA delivery to the pancreas relative to control EVs, as well as an accumulation of targeting EVs to the pancreas using luciferase activity as a readout. These findings demonstrate that systemic administration of engineered EVs can efficiently deliver their cargo as gene carriers to targeted organs in live animals.
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Affiliation(s)
- Hiroaki Komuro
- Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, Michigan, USA
| | - Yuki Kawai-Harada
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, Michigan, USA
| | - Shakhlo Aminova
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Lyman Briggs College, Michigan State University, Michigan, USA
| | - Nathaniel Pascual
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Chemical Engineering and Material, Michigan State University, Michigan, USA
| | - Anshu Malik
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, Michigan, USA
| | - Christopher H. Contag
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Microbiology and Molecular Genetics, Michigan State University, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, Michigan, USA
| | - Masako Harada
- Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, Michigan, USA
- Department of Biomedical Engineering, Michigan State University, Michigan, USA
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Askenase PW. Ancient Evolutionary Origin and Properties of Universally Produced Natural Exosomes Contribute to Their Therapeutic Superiority Compared to Artificial Nanoparticles. Int J Mol Sci 2021; 22:1429. [PMID: 33572657 PMCID: PMC7866973 DOI: 10.3390/ijms22031429] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/14/2022] Open
Abstract
Extracellular vesicles (EVs), such as exosomes, are newly recognized fundamental, universally produced natural nanoparticles of life that are seemingly involved in all biologic processes and clinical diseases. Due to their universal involvements, understanding the nature and also the potential therapeutic uses of these nanovesicles requires innovative experimental approaches in virtually every field. Of the EV group, exosome nanovesicles and larger companion micro vesicles can mediate completely new biologic and clinical processes dependent on the intercellular transfer of proteins and most importantly selected RNAs, particularly miRNAs between donor and targeted cells to elicit epigenetic alterations inducing functional cellular changes. These recipient acceptor cells are nearby (paracrine transfers) or far away after distribution via the circulation (endocrine transfers). The major properties of such vesicles seem to have been conserved over eons, suggesting that they may have ancient evolutionary origins arising perhaps even before cells in the primordial soup from which life evolved. Their potential ancient evolutionary attributes may be responsible for the ability of some modern-day exosomes to withstand unusually harsh conditions, perhaps due to unique membrane lipid compositions. This is exemplified by ability of the maternal milk exosomes to survive passing the neonatal acid/enzyme rich stomach. It is postulated that this resistance also applies to their durable presence in phagolysosomes, thus suggesting a unique intracellular release of their contained miRNAs. A major discussed issue is the generally poorly realized superiority of these naturally evolved nanovesicles for therapies when compared to human-engineered artificial nanoparticles, e.g., for the treatment of diseases like cancers.
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Affiliation(s)
- Phillip W Askenase
- Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
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Dasgupta I, Chatterjee A. Recent Advances in miRNA Delivery Systems. Methods Protoc 2021; 4:mps4010010. [PMID: 33498244 PMCID: PMC7839010 DOI: 10.3390/mps4010010] [Citation(s) in RCA: 175] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/27/2022] Open
Abstract
MicroRNAs (miRNAs) represent a family of short non-coding regulatory RNA molecules that are produced in a tissue and time-specific manner to orchestrate gene expression post-transcription. MiRNAs hybridize to target mRNA(s) to induce translation repression or mRNA degradation. Functional studies have demonstrated that miRNAs are engaged in virtually every physiological process and, consequently, miRNA dysregulations have been linked to multiple human pathologies. Thus, miRNA mimics and anti-miRNAs that restore miRNA expression or downregulate aberrantly expressed miRNAs, respectively, are highly sought-after therapeutic strategies for effective manipulation of miRNA levels. In this regard, carrier vehicles that facilitate proficient and safe delivery of miRNA-based therapeutics are fundamental to the clinical success of these pharmaceuticals. Here, we highlight the strengths and weaknesses of current state-of-the-art viral and non-viral miRNA delivery systems and provide perspective on how these tools can be exploited to improve the outcomes of miRNA-based therapeutics.
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Affiliation(s)
- Ishani Dasgupta
- Horae Gene Therapy Center, Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA;
| | - Anushila Chatterjee
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA
- Correspondence:
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Jia YC, Ding YX, Mei WT, Wang YT, Zheng Z, Qu YX, Liang K, Li J, Cao F, Li F. Extracellular vesicles and pancreatitis: mechanisms, status and perspectives. Int J Biol Sci 2021; 17:549-561. [PMID: 33613112 PMCID: PMC7893579 DOI: 10.7150/ijbs.54858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
Comprehensive reviews and large population-based cohort studies have played an important role in the diagnosis and treatment of pancreatitis and its sequelae. The incidence and mortality of pancreatitis have been reduced significantly due to substantial advancements in the pathophysiological mechanisms and clinically effective treatments. The study of extracellular vesicles (EVs) has the potential to identify cell-to-cell communication in diseases such as pancreatitis. Exosomes are a subset of EVs with an average diameter of 50~150 nm. Their diverse and unique constituents include nucleic acids, proteins, and lipids, which can be transferred to trigger phenotypic changes of recipient cells. In recent years, many reports have indicated the role of EVs in pancreatitis, including acute pancreatitis, chronic pancreatitis and autoimmune pancreatitis, suggesting their potential influence on the development and progression of pancreatitis. Plasma exosomes of acute pancreatitis can effectively reach the alveolar cavity and activate alveolar macrophages to cause acute lung injury. Furthermore, upregulated exosomal miRNAs can be used as biomarkers for acute pancreatitis. Here, we summarized the current understanding of EVs in pancreatitis with an emphasis on their biological roles and their potential use as diagnostic biomarkers and therapeutic agents for this disease.
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Affiliation(s)
- Yu-Chen Jia
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Yi-Xuan Ding
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Wen-Tong Mei
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | | | - Zhi Zheng
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Yuan-Xu Qu
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Kuo Liang
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Jia Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China
- Clinical Center for Acute Pancreatitis, Capital Medical University, Beijing, China
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Ortega A, Martinez-Arroyo O, Forner MJ, Cortes R. Exosomes as Drug Delivery Systems: Endogenous Nanovehicles for Treatment of Systemic Lupus Erythematosus. Pharmaceutics 2020; 13:pharmaceutics13010003. [PMID: 33374908 PMCID: PMC7821934 DOI: 10.3390/pharmaceutics13010003] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Exosomes, nanometer-sized lipid-bilayer-enclosed extracellular vesicles (EVs), have attracted increasing attention due to their inherent ability to shuttle proteins, lipids and genes between cells and their natural affinity to target cells. Their intrinsic features such as stability, biocompatibility, low immunogenicity and ability to overcome biological barriers, have prompted interest in using exosomes as drug delivery vehicles, especially for gene therapy. Evidence indicates that exosomes play roles in both immune stimulation and tolerance, regulating immune signaling and inflammation. To date, exosome-based nanocarriers delivering small molecule drugs have been developed to treat many prevalent autoimmune diseases. This review highlights the key features of exosomes as drug delivery vehicles, such as therapeutic cargo, use of targeting peptide, loading method and administration route with a broad focus. In addition, we outline the current state of evidence in the field of exosome-based drug delivery systems in systemic lupus erythematosus (SLE), evaluating exosomes derived from various cell types and engineered exosomes.
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Affiliation(s)
- Ana Ortega
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (A.O.); (O.M.-A.); (M.J.F.)
| | - Olga Martinez-Arroyo
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (A.O.); (O.M.-A.); (M.J.F.)
| | - Maria J. Forner
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (A.O.); (O.M.-A.); (M.J.F.)
- Internal Medicine Unit, Hospital Clinico Universitario, 46010 Valencia, Spain
| | - Raquel Cortes
- Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, 46010 Valencia, Spain; (A.O.); (O.M.-A.); (M.J.F.)
- Correspondence: ; Tel.: +34-96398-3916; Fax: +34-96398-7860
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Wu X, Zhu D, Tian J, Tang X, Guo H, Ma J, Xu H, Wang S. Granulocytic Myeloid-Derived Suppressor Cell Exosomal Prostaglandin E2 Ameliorates Collagen-Induced Arthritis by Enhancing IL-10 + B Cells. Front Immunol 2020; 11:588500. [PMID: 33329572 PMCID: PMC7734343 DOI: 10.3389/fimmu.2020.588500] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 11/02/2020] [Indexed: 01/22/2023] Open
Abstract
The results of recent studies have shown that granulocytic-myeloid derived suppressor cells (G-MDSCs) can secrete exosomes that transport various biologically active molecules with regulatory effects on immune cells. However, their roles in autoimmune diseases such as rheumatoid arthritis remain to be further elucidated. In the present study, we investigated the influence of exosomes from G-MDSCs on the humoral immune response in murine collagen-induced arthritis (CIA). G-MDSCs exosomes-treated mice showed lower arthritis index values and decreased inflammatory cell infiltration. Treatment with G-MDSCs exosomes promoted splenic B cells to secrete IL-10 both in vivo and in vitro. In addition, a decrease in the proportion of plasma cells and follicular helper T cells was observed in drainage lymph nodes from G-MDSCs exosomes-treated mice. Moreover, lower serum levels of IgG were detected in G-MDSCs exosomes-treated mice, indicating an alteration of the humoral environment. Mechanistic studies showed that exosomal prostaglandin E2 (PGE2) produced by G-MDSCs upregulated the phosphorylation levels of GSK-3β and CREB, which play a key role in the production of IL-10+ B cells. Taken together, our findings demonstrated that G-MDSC exosomal PGE2 attenuates CIA in mice by promoting the generation of IL-10+ Breg cells.
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Affiliation(s)
- Xinyu Wu
- 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
| | - Dongwei Zhu
- 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
| | - Jie Tian
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Xinyi Tang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
| | - Hongye Guo
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jie Ma
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, 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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39
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Pang H, Luo S, Xiao Y, Xia Y, Li X, Huang G, Xie Z, Zhou Z. Emerging Roles of Exosomes in T1DM. Front Immunol 2020; 11:593348. [PMID: 33324409 PMCID: PMC7725901 DOI: 10.3389/fimmu.2020.593348] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/02/2020] [Indexed: 12/17/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a complex autoimmune disorder that mainly affects children and adolescents. The elevated blood glucose level of patients with T1DM results from absolute insulin deficiency and leads to hyperglycemia and the development of life-threatening diabetic complications. Although great efforts have been made to elucidate the pathogenesis of this disease, the precise underlying mechanisms are still obscure. Emerging evidence indicates that small extracellular vesicles, namely, exosomes, take part in intercellular communication and regulate interorgan crosstalk. More importantly, many findings suggest that exosomes and their cargo are associated with the development of T1DM. Therefore, a deeper understanding of exosomes is beneficial for further elucidating the pathogenic process of T1DM. Exosomes are promising biomarkers for evaluating the risk of developingty T1DM, monitoring the disease state and predicting related complications because their number and composition can reflect the status of their parent cells. Additionally, since exosomes are natural carriers of functional proteins, RNA and DNA, they can be used as therapeutic tools to deliver these molecules and drugs. In this review, we briefly introduce the current understanding of exosomes. Next, we focus on the relationship between exosomes and T1DM from three perspectives, i.e., the pathogenic role of exosomes in T1DM, exosomes as novel biomarkers of T1DM and exosomes as therapeutic tools for T1DM.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yang Xiao
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Ying Xia
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Hejrati A, Hasani B, Esmaili M, Bashash D, Tavakolinia N, Zafari P. Role of exosome in autoimmunity, with a particular emphasis on rheumatoid arthritis. Int J Rheum Dis 2020; 24:159-169. [PMID: 33159418 DOI: 10.1111/1756-185x.14021] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 10/01/2020] [Accepted: 10/15/2020] [Indexed: 12/13/2022]
Abstract
Cell-derived exosomes are identified as carriers of lipids, proteins, and genetic materials that participate in cell-cell signal communication, biological process, and cell signaling. Also, their involvement has been reported in a vast array of disorders and inflammatory conditions such as autoimmune diseases. Rheumatoid arthritis (RA), a common cause of joint disorder, is an inflammation-based disease in which the precise understanding of its pathogenesis needs to be further investigated. Also, there is only a palliative care approach for the alleviation of RA symptoms. This paper discusses the recent advances in the biology of exosomes in autoimmune disorders especially in RA, and also provides a new line of research for arthritis therapy using exosomes.
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Affiliation(s)
- Alireza Hejrati
- Department of Internal Medicine, Hazrate-Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Bahare Hasani
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mozhgan Esmaili
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naeimeh Tavakolinia
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
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41
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Deb A, Gupta S, Mazumder PB. Exosomes: A new horizon in modern medicine. Life Sci 2020; 264:118623. [PMID: 33096118 DOI: 10.1016/j.lfs.2020.118623] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 12/11/2022]
Abstract
Exosomes are a type of extracellular vesicles belonging to endocytic origin. These vesicles carry different biological cargo that play numerous physiological roles and is also indicative of different diseased state. Exosomes are considered as promising tools for therapeutic drug delivery, owing to their intrinsic features like stability, biocompatibility and a capacity of stealth. A clearer understanding of the composition, biogenesis and biology of exosomes can provide us with better insights into the pathophysiological, diagnostic, and therapeutic roles of these extracellular vesicles. In this review we have summarize existing literature regarding the production, efficacy, action mechanism, and potential therapeutic roles of exosomes in the contexts of various diseases such as cancer, renal disease, neurological disorders, cardio-vascular diseases, inflammatory diseases and some of the auto-immune diseases.
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Affiliation(s)
- Ananya Deb
- Natural Product & Biomedicine Research Laboratory, Department of Biotechnology, Assam University, Silchar 788011, Assam, India
| | - Shweta Gupta
- Natural Product & Biomedicine Research Laboratory, Department of Biotechnology, Assam University, Silchar 788011, Assam, India.
| | - P B Mazumder
- Natural Product & Biomedicine Research Laboratory, Department of Biotechnology, Assam University, Silchar 788011, Assam, India.
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42
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Wang JH, Liu XL, Sun JM, Yang JH, Xu DH, Yan SS. Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review. World J Stem Cells 2020; 12:879-896. [PMID: 32952864 PMCID: PMC7477661 DOI: 10.4252/wjsc.v12.i8.879] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/02/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been reported to possess immune regulatory effects in innate and adaptive immune reactions. MSCs can mediate intercellular communications by releasing extracellular vesicles (EVs), which deliver functional molecules to targeted cells. MSC derived EVs (MSC-EVs) confer altering effects on many immune cells, including T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages. A large number of studies have suggested that MSC-EVs participate in regulating autoimmunity related diseases. This characteristic of MSC-EVs makes them be potential biomarkers for the diagnosis and treatment of autoimmunity related diseases.
AIM To verify the potential of MSC-EVs for molecular targeted therapy of autoimmunity related diseases.
METHODS Literature search was conducted in PubMed to retrieve the articles published between 2010 and 2020 in the English language. The keywords, such as “MSCs,” “EVs,” “exosome,” “autoimmunity,” “tumor immunity,” and “transplantation immunity,” and Boolean operator “AND” and “NOT” coalesced admirably to be used for searching studies on the specific molecular mechanisms of MSC-EVs in many immune cell types and many autoimmunity related diseases. Studies that did not investigate the molecular mechanisms of MSC-EVs in the occurrence and development of autoimmune diseases were excluded.
RESULTS A total of 96 articles were chosen for final reference lists. After analyzing those publications, we found that it had been well documented that MSC-EVs have the ability to induce multiple immune cells, like T lymphocytes, B lymphocytes, natural killer cells, dendritic cells, and macrophages, to regulate immune responses in innate immunity and adaptive immunity. Many validated EVs-delivered molecules have been identified as key biomarkers, such as proteins, lipids, and nucleotides. Some EVs-encapsulated functional molecules can serve as promising therapeutic targets particularly for autoimmune disease.
CONCLUSION MSC-EVs play an equally important part in the differentiation, activation, and proliferation of immune cells, and they may become potential biomarkers for diagnosis and treatment of autoimmunity related diseases.
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Affiliation(s)
- Jing-Hua Wang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Xiao-Ling Liu
- Department of Emergency Medicine, Yantai Shan Hospital, Yantai 264001, Shandong Province, China
| | - Jian-Mei Sun
- Department of Chemistry, School of Applied Chemistry, Food and Drug, Weifang Engineering Vocational College, Qingzhou 262500, Shandong Province, China
| | - Jing-Han Yang
- Clinical Medicine College, Weifang Medical University, Weifang 261000, Shandong Province, China
| | - Dong-Hua Xu
- Department of Rheumatology of the First Affiliated Hospital, Weifang Medical University, Central Laboratory of the First Affiliated Hospital, Weifang 261000, Shandong Province, China
| | - Shu-Shan Yan
- Department of Gastrointestinal and Anal Diseases Surgery of the Affiliated Hospital, Weifang Medical University, Weifang 261000, Shandong Province, China
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Wermuth PJ, Jimenez SA. Molecular characteristics and functional differences of anti-PM/Scl autoantibodies and two other distinct and unique supramolecular structures known as "EXOSOMES". Autoimmun Rev 2020; 19:102644. [PMID: 32801042 DOI: 10.1016/j.autrev.2020.102644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
The term "exosome" has been applied to three distinct supramolecular entities, namely the PM/Scl autoantibodies or "RNA exosomes", transforming DNA fragments termed "DNA exosomes", and small size extracellular vesicles knows as "exosomes". Some of the molecular components of the "PM/Scl exosome complex" or "RNA exosome" are recognized by specific autoantibodies present in the serum from some Systemic Sclerosis (SSc), polymyositis (PM) and polymyositis SSc (PM/Scl) overlap syndrome patients. On the other hand, one of the most active focuses of laboratory investigation in the last decade has been the biogenesis and role of extracellular vesicles known as "exosomes". The remarkable ability of these "exosome" vesicles to alter the cellular phenotype following fusion with target cells and the release of their macromolecular cargo has revealed a possible role in the pathogenesis of numerous diseases, including malignant, inflammatory, and autoimmune disorders and may allow them to serve as theranostic agents for personalized and precision medicine. The indiscriminate use of the term "exosome" to refer to these three distinct molecular entities has engendered great confusion in the scientific literature. Here, we review the molecular characteristics and functional differences between the three molecular structures identified as "exosomes". Given the rapidly growing scientific interest in extravesicular exosomes, unless a solution is found the confusion in the literature resulting from the use of the term "exosomes" will markedly increase.
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Affiliation(s)
- Peter J Wermuth
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
| | - Sergio A Jimenez
- Jefferson Institute of Molecular Medicine and Scleroderma Center, Thomas Jefferson University, Philadelphia, PA 19107, USA
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Huang Y, Li R, Ye S, Lin S, Yin G, Xie Q. Recent Advances in the Use of Exosomes in Sjögren's Syndrome. Front Immunol 2020; 11:1509. [PMID: 32903777 PMCID: PMC7438915 DOI: 10.3389/fimmu.2020.01509] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 06/09/2020] [Indexed: 02/05/2023] Open
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disorder of the exocrine glands mediated by lymphocytic infiltrates damaging the body tissues and affecting the life quality of patients. Although traditional methods of diagnosis and treatment for SS are effective, in the time of personalized medicine, new biomarkers, and novel approaches are required for the detection and treatment of SS. Exosomes represent an emerging field in the discovery of biomarkers and the management of SS. Exosomes, a subtype of extracellular vesicles, are secreted by various cell types and can be found in most bodily fluids. Exosomes are packed with cytokines and other proteins, bioactive lipids, and nucleic acids (mRNA, circular RNA, non-coding RNA, tRNA, microRNA, genomic DNA, and ssDNA), and transport such cargo between cells. Evidence has indicated that exosomes may play roles in processes such as the modulation of the immune response and activation of inflammation. Moreover, due to features such as stability, low immunogenicity and toxicity, long half-life, and the capacity to penetrate the blood-brain barrier, exosomes have also emerged as therapeutic tools for SS. In this review, we summarize existing literature regarding the biogenesis, isolation, and function of exosomes, specifically focusing on exosomes as novel biomarkers and their potential therapeutic uses in SS.
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Affiliation(s)
- Yupeng Huang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Ruicen Li
- Health Management Center, West China Hospital, Sichuan University, Chengdu, China
| | - Sheng Ye
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Sang Lin
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Geng Yin
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Qibing Xie
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
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Mitsis T, Pierouli K, Diakou KL, Papakonstantinou E, Bacopoulou F, Chrousos GP, Vlachakis D. Exosomics. ACTA ACUST UNITED AC 2020; 26. [PMID: 32832420 PMCID: PMC7440046 DOI: 10.14806/ej.26.0.934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Extracellular vesicles have been the focus of a large number of studies in the past five years. Exosomes, a subgroup of extracellular vesicles, are of particularly high interest because they partake in a wide number of biological pathways. Produced by a variety of cells, exosomes have an important role in both physiological and pathological conditions. Exosome cargo heavily defines the vesicles’ unique characteristics, and the cargo with the most intriguing prospects in its’ biomedical applications is the non-coding RNAs. Non-coding RNAs, and specifically microRNAs are implicated in the regulation of many biological processes and have been associated with numerous diseases. Exosomes containing such important cargo can be used as biomarkers, therapeutic biomaterials, or even drug carriers. The potential media use of exosomes seems promising. However, some obstacles should be overcome before their clinical application. Synthetic exosome-like biomolecules may be a solution, but their production is still in their beginning stages. This review provides concise information regarding the current trends in exosome studies.
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Affiliation(s)
- Thanasis Mitsis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology & Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Katerina Pierouli
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology & Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Kalliopi Lo Diakou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology & Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Eleni Papakonstantinou
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology & Biotechnology, Agricultural University of Athens, Athens, Greece
| | - Flora Bacopoulou
- University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - George P Chrousos
- University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Dimitrios Vlachakis
- Laboratory of Genetics, Department of Biotechnology, School of Applied Biology & Biotechnology, Agricultural University of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health & Precision Medicine, and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
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Shang Y, Sun Y, Xu J, Ge X, Hu Z, Xiao J, Ning Y, Dong Y, Bai C. Exosomes from mmu_circ_0001359-Modified ADSCs Attenuate Airway Remodeling by Enhancing FoxO1 Signaling-Mediated M2-like Macrophage Activation. MOLECULAR THERAPY-NUCLEIC ACIDS 2020; 19:951-960. [PMID: 32018116 PMCID: PMC6997502 DOI: 10.1016/j.omtn.2019.10.049] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Revised: 10/03/2019] [Accepted: 10/23/2019] [Indexed: 02/07/2023]
Abstract
Asthma is the most common chronic disease and is characterized by airway remodeling and chronic inflammation. Increasingly, studies have found that the activation and M1 phenotypic transformation of macrophages play important roles in asthma progress, including airway remodeling. However, the reversal of M1 macrophages to the M2 phenotype has been shown to attenuate airway remodeling. Exosomes are nano-sized extracellular vesicles derived from endosomes; they play direct roles in governing physiological and pathological conditions by the intracellular transfer of bioactive cargo, such as proteins, enzymes, nucleic acids (microRNA [miRNA], mRNA, DNA), and metabolites. However, transfer mechanisms are unclear. To uncover potential therapeutic mechanisms, we constructed an ovalbumin-induced asthma mouse model and lipopolysaccharide-induced RAW264.7 macrophages cells. High-throughput sequencing showed that mmu_circ_0001359 was downregulated in asthmatic mice when compared with normal mice. Adipose-derived stem cell (ADSC)-exosome treatment suppressed inflammatory cytokine expression by the conversion of M1 macrophages to the M2 phenotype, under lipopolysaccharide-induced conditions. Exosomes from mmu_circ_0001359 overexpression in ADSCs increased therapeutic effects, in terms of cytokine expression, when compared with wild-type exosomes. Luciferase reporter assays confirmed that exosomes from mmu_circ_0001359-modified ADSCs attenuated airway remodeling by enhancing FoxO1 signaling-mediated M2-like macrophage activation, via sponging miR-183-5p. In conclusion, mmu_circ_0001359-enriched exosomes attenuated airway remodeling by promoting M2-like macrophages.
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Affiliation(s)
- Yan Shang
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China.
| | - Yahong Sun
- Department of Respiratory Medicine, Haining People's Hospital of Zhejiang Province, Zhejiang 314400, China
| | - Jing Xu
- Department of Respiratory Medicine, Seventh People's Hospital of Shanghai University of TCM, Shanghai 200137, China
| | - Xiahui Ge
- Department of Respiratory Medicine, Seventh People's Hospital of Shanghai University of TCM, Shanghai 200137, China
| | - Zhenli Hu
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Jiang Xiao
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Yunye Ning
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Yuchao Dong
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
| | - Chong Bai
- Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China.
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Rapid and sensitive exosome detection with CRISPR/Cas12a. Anal Bioanal Chem 2020; 412:601-609. [PMID: 31897558 DOI: 10.1007/s00216-019-02211-4] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 10/08/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023]
Abstract
Numerous studies have shown that exosomes are closely related to the pathogenesis of various diseases, especially cancers. Therefore, a rapid and sensitive method for exosome detection will be of great importance for the diagnosis and prognosis of diseases. We report here a method for exosome detection based on the CD63 aptamer and clustered regular interspaced short palindromic repeats (CRISPR)/Cas12a system. This method consists mainly of exosomal membrane protein recognition based on the CD63 aptamer and signal amplification based on CRISPR/Cas12a. The CD63 aptamer, as an easily adaptable nucleic acid strand, is responsible for the conversion of the amounts of exosomes into nucleic acid detection, whereas CRISPR/Cas12a is responsible for highly specific nucleic acid signal amplification. The detection range of the method was determined as 3 × 103-6 × 107 particles per microliter. Additionally, we successfully applied this method to detect exosomes in clinical samples from both healthy individuals and patients with lung cancer, and the results were highly consistent with those obtained by nanoparticle tracking analysis. In general, this method provides a highly sensitive and specific method for the detection of exosomes and offers an avenue toward future exosome-based diagnosis of diseases.
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Tsai CY, Hsieh SC, Lu CS, Wu TH, Liao HT, Wu CH, Li KJ, Kuo YM, Lee HT, Shen CY, Yu CL. Cross-Talk between Mitochondrial Dysfunction-Provoked Oxidative Stress and Aberrant Noncoding RNA Expression in the Pathogenesis and Pathophysiology of SLE. Int J Mol Sci 2019; 20:ijms20205183. [PMID: 31635056 PMCID: PMC6829370 DOI: 10.3390/ijms20205183] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/10/2019] [Accepted: 10/14/2019] [Indexed: 12/16/2022] Open
Abstract
Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disease involving almost every organ. Polygenic predisposition and complicated epigenetic regulations are the upstream factors to elicit its development. Mitochondrial dysfunction-provoked oxidative stress may also play a crucial role in it. Classical epigenetic regulations of gene expression may include DNA methylation/acetylation and histone modification. Recent investigations have revealed that intracellular and extracellular (exosomal) noncoding RNAs (ncRNAs), including microRNAs (miRs), and long noncoding RNAs (lncRNAs), are the key molecules for post-transcriptional regulation of messenger (m)RNA expression. Oxidative and nitrosative stresses originating from mitochondrial dysfunctions could become the pathological biosignatures for increased cell apoptosis/necrosis, nonhyperglycemic metabolic syndrome, multiple neoantigen formation, and immune dysregulation in patients with SLE. Recently, many authors noted that the cross-talk between oxidative stress and ncRNAs can trigger and perpetuate autoimmune reactions in patients with SLE. Intracellular interactions between miR and lncRNAs as well as extracellular exosomal ncRNA communication to and fro between remote cells/tissues via plasma or other body fluids also occur in the body. The urinary exosomal ncRNAs can now represent biosignatures for lupus nephritis. Herein, we’ll briefly review and discuss the cross-talk between excessive oxidative/nitrosative stress induced by mitochondrial dysfunction in tissues/cells and ncRNAs, as well as the prospect of antioxidant therapy in patients with SLE.
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Affiliation(s)
- Chang-Youh Tsai
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec.2, Shih-Pai Road, Taipei 11217, Taiwan.
| | - Song-Chou Hsieh
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Cheng-Shiun Lu
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Tsai-Hung Wu
- Division of Nephrology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec. 2, Shih-Pai Road, Taipei 11217, Taiwan.
| | - Hsien-Tzung Liao
- Division of Allergy, Immunology & Rheumatology, Taipei Veterans General Hospital & National Yang-Ming University, #201 Sec.2, Shih-Pai Road, Taipei 11217, Taiwan.
| | - Cheng-Han Wu
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Ko-Jen Li
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Yu-Min Kuo
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Hui-Ting Lee
- Section of Allergy, Immunology & Rheumatology, Mackay Memorial Hospital, #92 Sec. 2, Chung-Shan North Road, Taipei 10449, Taiwan.
| | - Chieh-Yu Shen
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
- Institute of Clinical Medicine, National Taiwan University College of Medicine, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
| | - Chia-Li Yu
- Department of Internal Medicine, National Taiwan University Hospital, #7 Chung-Shan South Road, Taipei 10002, Taiwan.
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Jayaseelan VP, Arumugam P. Dissecting the theranostic potential of exosomes in autoimmune disorders. Cell Mol Immunol 2019; 16:935-936. [PMID: 31619771 DOI: 10.1038/s41423-019-0310-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 02/05/2023] Open
Affiliation(s)
- Vijayashree Priyadharsini Jayaseelan
- Biomedical Research Unit and Laboratory Animal Centre-Dental Research Cell, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, 600077, India.
| | - Paramasivam Arumugam
- Biomedical Research Unit and Laboratory Animal Centre-Dental Research Cell, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamil Nadu, 600077, India
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