|
1
|
Tao K, Tao K, Wang J. The potential mechanisms of extracellular vesicles in transfusion-related adverse reactions: Recent advances. Transfus Clin Biol 2025; 32:205-227. [PMID: 40180029 DOI: 10.1016/j.tracli.2025.03.006] [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: 01/15/2025] [Revised: 03/15/2025] [Accepted: 03/25/2025] [Indexed: 04/05/2025]
Abstract
Blood transfusion is an irreplaceable clinical treatment. Blood components are differentiated and stored according to specific guidelines. Storage temperatures and times vary depending on the blood component, but they all release extracellular vesicles (EVs) during storage. Although blood transfusions can be life-saving, they can also cause many adverse transfusion reactions, among which the effects of EVs are of increasing interest to researchers. EVs are submicron particles that vary in size, composition, and surface biomarkers, are encapsulated by a lipid bilayer, and are not capable of self-replication. EVs released by blood cells are important contributors to pathophysiologic states through proinflammatory, coagulant, and immunosuppressive effects, which in turn promote or inhibit the associated disease phenotype. Therefore, this review explores the potential mechanisms of hematopoietic-derived EVs in transfusion-associated adverse reactions and discusses the potential of the latest proteomics tools to be applied to the analysis of EVs in the field of transfusion medicine with a view to reducing the risk of blood transfusion.
Collapse
Affiliation(s)
- Keyi Tao
- Panzhihua University, Panzhihua 617000 Sichuan, China
| | - Keran Tao
- Institute of Medicine and Nursing, Hubei University of Medicine, Shiyan 442000 Hubei, China
| | - Jing Wang
- Southwest Medical University, Luzhou 646000 Sichuan, China; Department of Blood Transfusion, The Affiliated Hospital of Southwest Medical University, Luzhou Sichuan, 646000 China.
| |
Collapse
|
|
2
|
Tandon R, Srivastava N. Unravelling exosome paradigm: Therapeutic, diagnostic and theranostics application and regulatory consideration. Life Sci 2025; 366-367:123472. [PMID: 39956185 DOI: 10.1016/j.lfs.2025.123472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2024] [Revised: 01/13/2025] [Accepted: 02/13/2025] [Indexed: 02/18/2025]
Abstract
In the recent decade, extracellular vesicles (EVs) have been released from nearly all the kingdoms, modulating intercellular communication and maintaining the human body's homeostasis by regulating different cellular processes. Among EVs, exosomes are the emerging field in biopharmaceuticals. They have lipid bilayer ranging from 30 to 150 nm in size and encompass DNA, RNA, protein lipids, etc. Their sources are widespread, easy to acquire, and cost-effective in manufacturing. This review focuses on the detailed classification of exosomes existing in nature, knowledge and application of omics, therapeutic, diagnostic and theranostic application of exosomes. It covers diseases such as cancer, infectious diseases (viral, bacterial, fungal infections), neurodegenerative diseases, metabolic diseases, lifestyle diseases (diabetes, cardiovascular, gastric disorder (IBD)), autoimmune disorders and their biodistribution. This article unfolds the recent progress in the exosomes arena and covers all the regulatory considerations (FDA, EMA, and other nations) involved with it. Moreover, a detailed discussion about clinical trials and its manifestation with exosomes and challenges associated with their isolation procedures, reproducibility, and safety concerns.
Collapse
Affiliation(s)
- Reetika Tandon
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India
| | - Nidhi Srivastava
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow 226002, India.
| |
Collapse
|
|
3
|
Chen Y, Liu H, He Y, Yang B, Lu W, Dai Z. Roles for Exosomes in the Pathogenesis, Drug Delivery and Therapy of Psoriasis. Pharmaceutics 2025; 17:51. [PMID: 39861699 PMCID: PMC11768235 DOI: 10.3390/pharmaceutics17010051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/18/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Psoriasis is a chronic, recurrent and inflammatory skin disease. Although conventional immunosuppressants can ameliorate psoriatic symptoms, it tends to relapse over time. Previous studies have shown that exosomes from both immune and non-immune cells participate in psoriatic immunopathology. The biologically active cargoes in exosomes accelerate psoriasis progression by altering gene profiles and signaling pathways of neighboring cells. On the other hand, exosomes can be utilized as drug delivery platforms for psoriasis treatment. Especially, engineered exosomes may serve as drug delivery systems for effective delivery of proteins, nucleic acids or other drugs due to their low immunogenicity, good stability and ability to fuse with target cells. Therefore, investigation into the mechanisms underlying intercellular communications mediated by exosomes in skin lesions likely helps design drugs for therapy of psoriasis. In this review, we have summarized recent advances in the biogenesis of exosomes and their potential roles in the pathogenesis and treatment of psoriasis and further discussed their challenges and future directions in psoriasis treatment. In particular, this review highlights the immunoregulatory function of exosomes derived from immune or non-immune cells and exosome-based therapeutic applications in psoriasis, including their drug delivery systems. Thus, this review may help accelerate applications of exosomes for drug delivery and treatment of psoriasis.
Collapse
Affiliation(s)
- Yuchao Chen
- Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, 55 Nei Huan Xi Lu, College Town, Guangzhou 510006, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Huazhen Liu
- Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, 55 Nei Huan Xi Lu, College Town, Guangzhou 510006, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Yuming He
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Bin Yang
- Department of Cardiovascular Sciences, College of Life Sciences, University of Leicester, Leicester LE1 9HN, UK
| | - Weihui Lu
- Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, 55 Nei Huan Xi Lu, College Town, Guangzhou 510006, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| | - Zhenhua Dai
- Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, 55 Nei Huan Xi Lu, College Town, Guangzhou 510006, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510006, China
| |
Collapse
|
|
4
|
Dai Z, Cai R, Zeng H, Zhu H, Dou Y, Sun S. Exosome may be the next generation of promising cell-free vaccines. Hum Vaccin Immunother 2024; 20:2345940. [PMID: 38714324 PMCID: PMC11086043 DOI: 10.1080/21645515.2024.2345940] [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: 01/12/2024] [Accepted: 04/18/2024] [Indexed: 05/09/2024] Open
Abstract
Traditional vaccines have limits against some persistent infections and pathogens. The development of novel vaccine technologies is particularly critical for the future. Exosomes play an important role in physiological and pathological processes. Exosomes present many advantages, such as inherent capacity being biocompatible, non-toxic, which make them a more desirable candidate for vaccines. However, research on exosomes are in their infancy and the barriers of low yield, low purity, and weak targeting of exosomes limit their applications in vaccines. Accordingly, further exploration is necessary to improve these problems and subsequently facilitate the functional studies of exosomes. In this study, we reviewed the origin, classification, functions, modifications, separation and purification, and characterization methods of exosomes. Meanwhile, we focused on the role and mechanism of exosomes for cancer and COVID-19 vaccines.
Collapse
Affiliation(s)
- Zelan Dai
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Ruiru Cai
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Hong Zeng
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Hailian Zhu
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Youwei Dou
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
| |
Collapse
|
|
5
|
Boysen AT, Whitehead B, Revenfeld ALS, Gupta D, Petersen T, Nejsum P. Urine-derived stem cells serve as a robust platform for generating native or engineered extracellular vesicles. Stem Cell Res Ther 2024; 15:288. [PMID: 39256816 PMCID: PMC11389316 DOI: 10.1186/s13287-024-03903-0] [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: 07/01/2024] [Accepted: 08/26/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Mesenchymal stromal cell (MSC) therapy holds great potential yet efficacy and safety concerns with cell therapy persist. The beneficial effects of MSCs are often attributed to their secretome that includes extracellular vesicles (EVs). EVs carry biologically active molecules, protected by a lipid bilayer. However, several barriers hinder large-scale MSC EV production. A serum-free culturing approach is preferred for producing clinical-grade MSC-derived EVs but this can affect both yield and purity. Consequently, new strategies have been explored, including genetically engineering MSCs to alter EV compositions to enhance potency, increase circulation time or mediate targeting. However, efficient transfection of MSCs is challenging. Typical sources of MSC include adipose tissue and bone marrow, which both require invasive extraction procedures. Here, we investigate the use of urine-derived stem cells (USCs) as a non-invasive and inexhaustible source of MSCs for EV production. METHODS We isolated, expanded, and characterized urine-derived stem cells (USCs) harvested from eight healthy donors at three different time points during the day. We evaluated the number of clones per urination, proliferation capacity and conducted flow cytometry to establish expression of surface markers. EVs were produced in chemically defined media and characterized. PEI/DNA transfection was used to genetically engineer USCs using transposon technology. RESULTS There were no differences between time points for clone number, doubling time or viability. USCs showed immunophenotypic characteristics of MSCs, such as expression of CD73, CD90 and CD105, with no difference at the assessed time points, however, male donors had reduced CD73 + cells. Expanded USCs were incubated without growth factors or serum for 72 h without a loss in viability and EVs were isolated. USCs were transfected with high efficiency and after 10 days of selection, pure engineered cell cultures were established. CONCLUSIONS Isolation and expansion of MSCs from urine is non-invasive, robust, and without apparent sex-related differences. The sampling time point did not affect any measured markers or USC isolation potential. USCs offer an attractive production platform for EVs, both native and engineered.
Collapse
Affiliation(s)
- Anders Toftegaard Boysen
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.
| | - Bradley Whitehead
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark
| | - Anne Louise S Revenfeld
- Center for Gene and Cellular Therapy, Department of Clinical Immunology, Aarhus University Hospital, Aarhus N, Denmark
| | - Dhanu Gupta
- Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
- Department of Paediatrics, University of Oxford, Oxford, OX3 7TY, UK
| | - Thor Petersen
- Department of Regional Health Research, Southern Danish University, Sønderborg, Denmark
| | - Peter Nejsum
- Department of Clinical Medicine, Aarhus University, Aarhus N, Denmark.
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus N, Denmark.
| |
Collapse
|
|
6
|
Li X, Zhang C, Yue W, Jiang Y. Modulatory effects of cancer stem cell-derived extracellular vesicles on the tumor immune microenvironment. Front Immunol 2024; 15:1362120. [PMID: 38962016 PMCID: PMC11219812 DOI: 10.3389/fimmu.2024.1362120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
Cancer stem cells (CSCs), accounting for only a minor cell proportion (< 1%) within tumors, have profound implications in tumor initiation, metastasis, recurrence, and treatment resistance due to their inherent ability of self-renewal, multi-lineage differentiation, and tumor-initiating potential. In recent years, accumulating studies indicate that CSCs and tumor immune microenvironment act reciprocally in driving tumor progression and diminishing the efficacy of cancer therapies. Extracellular vesicles (EVs), pivotal mediators of intercellular communications, build indispensable biological connections between CSCs and immune cells. By transferring bioactive molecules, including proteins, nucleic acids, and lipids, EVs can exert mutual influence on both CSCs and immune cells. This interaction plays a significant role in reshaping the tumor immune microenvironment, creating conditions favorable for the sustenance and propagation of CSCs. Deciphering the intricate interplay between CSCs and immune cells would provide valuable insights into the mechanisms of CSCs being more susceptible to immune escape. This review will highlight the EV-mediated communications between CSCs and each immune cell lineage in the tumor microenvironment and explore potential therapeutic opportunities.
Collapse
Affiliation(s)
- Xinyu Li
- Department of Animal Science, College of Animal Science, Hebei North University, Zhangjiakou, Hebei, China
- Department of Gynecology and Obstetrics, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Cuilian Zhang
- Reproductive Medicine Center, Henan Provincial People’s Hospital, Zhengzhou University, Zhengzhou, China
| | - Wei Yue
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
| | - Yuening Jiang
- State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China
- Key Laboratory of Assisted Reproduction, Peking University, Ministry of Education, Beijing, China
| |
Collapse
|
|
7
|
Samavati SF, Yarani R, Kiani S, HoseinKhani Z, Mehrabi M, Levitte S, Primavera R, Chetty S, Thakor AS, Mansouri K. Therapeutic potential of exosomes derived from mesenchymal stem cells for treatment of systemic lupus erythematosus. J Inflamm (Lond) 2024; 21:20. [PMID: 38867277 PMCID: PMC11170788 DOI: 10.1186/s12950-024-00381-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 03/14/2024] [Indexed: 06/14/2024] Open
Abstract
Autoimmune diseases are caused by an imbalance in the immune system, producing autoantibodies that cause inflammation leading to tissue damage and organ dysfunction. Systemic Lupus Erythematosus (SLE) is one of the most common autoimmune diseases and a major contributor to patient morbidity and mortality. Although many drugs manage the disease, curative therapy remains elusive, and current treatment regimens have substantial side effects. Recently, the therapeutic potential of exosomes has been extensively studied, and novel evidence has been demonstrated. A direct relationship between exosome contents and their ability to regulate the immune system, inflammation, and angiogenesis. The unique properties of extracellular vesicles, such as biomolecule transportation, biodegradability, and stability, make exosomes a promising treatment candidate for autoimmune diseases, particularly SLE. This review summarizes the structural features of exosomes, the isolation/purification/quantification method, their origin, effect, immune regulation, a critical consideration for selecting an appropriate source, and their therapeutic mechanisms in SLE.
Collapse
Affiliation(s)
- Shima Famil Samavati
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Reza Yarani
- Translational Type 1 Diabetes Research, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Sara Kiani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zohreh HoseinKhani
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Masomeh Mehrabi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Steven Levitte
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Rosita Primavera
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Shashank Chetty
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Kamran Mansouri
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| |
Collapse
|
|
8
|
Tiwari P, Yadav K, Shukla RP, Bakshi AK, Panwar D, Das S, Mishra PR. Extracellular vesicles-powered immunotherapy: Unleashing the potential for safer and more effective cancer treatment. Arch Biochem Biophys 2024; 756:110022. [PMID: 38697343 DOI: 10.1016/j.abb.2024.110022] [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: 03/20/2024] [Revised: 04/29/2024] [Accepted: 04/29/2024] [Indexed: 05/04/2024]
Abstract
Cancer treatment has seen significant advancements with the introduction of Onco-immunotherapies (OIMTs). Although some of these therapies have received approval for use, others are either undergoing testing or are still in the early stages of development. Challenges persist in making immunotherapy widely applicable to cancer treatment. To maximize the benefits of immunotherapy and minimize potential side effects, it's essential to improve response rates across different immunotherapy methods. A promising development in this area is the use of extracellular vesicles (EVs) as novel delivery systems. These small vesicles can effectively deliver immunotherapies, enhancing their effectiveness and reducing harmful side effects. This article discusses the importance of integrating nanomedicines into OIMTs, highlighting the challenges with current anti-OIMT methods. It also explores key considerations for designing nanomedicines tailored for OIMTs, aiming to improve upon existing immunotherapy techniques. Additionally, the article looks into innovative approaches like biomimicry and the use of natural biomaterial-based nanocarriers (NCs). These advancements have the potential to transform the delivery of immunotherapy. Lastly, the article addresses the challenges of moving OIMTs from theory to clinical practice, providing insights into the future of using advanced nanotechnology in cancer treatment.
Collapse
Affiliation(s)
- Pratiksha Tiwari
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Jawaharlal Nehru University, New Delhi, India
| | - Krishna Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Ravi Prakash Shukla
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Avijit Kumar Bakshi
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Dilip Panwar
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Sweety Das
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Prabhat Ranjan Mishra
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, 201002, U.P., India.
| |
Collapse
|
|
9
|
Jonoush ZA, Mahdavi R, Farahani M, Zeinali F, Shayan E, Amari A. The implications of exosomes in psoriasis: disease: emerging as new diagnostic markers and therapeutic targets. Mol Biol Rep 2024; 51:465. [PMID: 38551769 DOI: 10.1007/s11033-024-09449-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 03/14/2024] [Indexed: 04/02/2024]
Abstract
As the largest human organ, the skin is continuously exposed to various external and internal triggers that affect body homeostasis. Psoriasis is a persistent inflammatory skin condition that has a major bearing on patients' physiological functioning as well as their mental well-being. It is an autoimmune disorder and has been the focus of extensive research efforts in recent years. Cells secrete exosomes into the environment surrounding them, which comprises a lipid bilayer. The movement of cellular components like microRNAs, mRNAs, DNA, lipids, metabolites, and cell-surface proteins is mediated by exosomes. Exosomes are crucial for inducing communication between cells. There has been extensive study of exosomes, both preclinical and clinical, looking at their potential role in autoimmune diseases. Besides the role that they play in the body's basic processes, exosomes are also considered an increasingly essential part as diagnostic and therapeutic agents. In the following article, we conduct a literature review of current studies related to molecular and structural aspects of exosomes. We emphasis on the function of exosomes in pathogenesis, as well as the possibility of their usage in medicinal applications and as biomarkers.
Collapse
Affiliation(s)
- Zahra Akbari Jonoush
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Roya Mahdavi
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Masoumeh Farahani
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Zeinali
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Elahe Shayan
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Afshin Amari
- Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
|
10
|
Guan XL, Guan XY, Zhang ZY. Roles and application of exosomes in the development, diagnosis and treatment of gastric cancer. World J Gastrointest Oncol 2024; 16:630-642. [PMID: 38577463 PMCID: PMC10989387 DOI: 10.4251/wjgo.v16.i3.630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 12/18/2023] [Accepted: 01/15/2024] [Indexed: 03/12/2024] Open
Abstract
As important messengers of intercellular communication, exosomes can regulate local and distant cellular communication by transporting specific exosomal contents and can also promote or suppress the development and progression of gastric cancer (GC) by regulating the growth and proliferation of tumor cells, the tumor-related immune response and tumor angiogenesis. Exosomes transport bioactive molecules including DNA, proteins, and RNA (coding and noncoding) from donor cells to recipient cells, causing reprogramming of the target cells. In this review, we will describe how exosomes regulate the cellular immune response, tumor angiogenesis, proliferation and metastasis of GC cells, and the role and mechanism of exosome-based therapy in human cancer. We will also discuss the potential application value of exosomes as biomarkers in the diagnosis and treatment of GC and their relationship with drug resistance.
Collapse
Affiliation(s)
- Xiao-Li Guan
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Xiao-Ying Guan
- Department of Pathology, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| | - Zheng-Yi Zhang
- Department of General Medicine, The Second Hospital of Lanzhou University, Lanzhou 730030, Gansu Province, China
| |
Collapse
|
|
11
|
Miron RJ, Estrin NE, Sculean A, Zhang Y. Understanding exosomes: Part 2-Emerging leaders in regenerative medicine. Periodontol 2000 2024; 94:257-414. [PMID: 38591622 DOI: 10.1111/prd.12561] [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: 02/04/2024] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 04/10/2024]
Abstract
Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.
Collapse
Affiliation(s)
- Richard J Miron
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Nathan E Estrin
- Advanced PRF Education, Venice, Florida, USA
- School of Dental Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, Florida, USA
| | - Anton Sculean
- Department of Periodontology, University of Bern, Bern, Switzerland
| | - Yufeng Zhang
- Department of Oral Implantology, University of Wuhan, Wuhan, China
| |
Collapse
|
|
12
|
de Carvalho TG, Lara P, Jorquera-Cordero C, Aragão CFS, de Santana Oliveira A, Garcia VB, de Paiva Souza SV, Schomann T, Soares LAL, da Matta Guedes PM, de Araújo Júnior RF. Inhibition of murine colorectal cancer metastasis by targeting M2-TAM through STAT3/NF-kB/AKT signaling using macrophage 1-derived extracellular vesicles loaded with oxaliplatin, retinoic acid, and Libidibia ferrea. Biomed Pharmacother 2023; 168:115663. [PMID: 37832408 DOI: 10.1016/j.biopha.2023.115663] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/05/2023] [Accepted: 10/05/2023] [Indexed: 10/15/2023] Open
Abstract
Colorectal cancer is still unmanageable despite advances in target therapy. However, extracellular vesicles (EVs) have shown potential in nanomedicine as drug delivery systems, especially for modulating the immune cells in the tumor microenvironment (TME). In this study, M1 Macrophage EVs (M1EVs) were used as nanocarriers of oxaliplatin (M1EV1) associated with retinoic acid (M1EV2) and Libidibia ferrea (M1EV3), alone or in combination (M1EV4) to evaluate their antiproliferative and immunomodulatory potential on CT-26 and MC-38 colorectal cancer cell lines and prevent metastasis in mice of allograft and peritoneal colorectal cancer models. Tumors were evaluated by qRT-PCR and immunohistochemistry. The cell death profile and epithelial-mesenchymal transition process (EMT) were analyzed in vitro in colorectal cancer cell lines. Polarization of murine macrophages (RAW264.7 cells) was also carried out. M1EV2 and M1EV3 used alone or particularly M1EV4 downregulated the tumor progression by TME immunomodulation, leading to a decrease in primary tumor size and metastasis in the peritoneum, liver, and lungs. STAT3, NF-kB, and AKT were the major genes downregulated by of M1EV systems. Tumor-associated macrophages (TAMs) shifted from an M2 phenotype (CD163) to an M1 phenotype (CD68) reducing levels of IL-10, TGF-β and CCL22. Furthermore, malignant cells showed overexpression of FADD, APAF-1, caspase-3, and E-cadherin, and decreased expression of MDR1, survivin, vimentin, and PD-L1 after treatment with systems of M1EVs. The study shows that EVs from M1 antitumor macrophages can transport drugs and enhance their immunomodulatory and antitumor activity by modulating pathways associated with cell proliferation, migration, survival, and drug resistance.
Collapse
Affiliation(s)
- Thaís Gomes de Carvalho
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
| | - Pablo Lara
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands.
| | - Carla Jorquera-Cordero
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands
| | - Cícero Flávio Soares Aragão
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Medicines Quality Control Laboratory (LCQMed), Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Artur de Santana Oliveira
- Postgraduate Program in Pharmaceutical Sciences, Department of Pharmacology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Medicines Quality Control Laboratory (LCQMed), Department of Pharmacy, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Vinicius Barreto Garcia
- Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
| | - Shirley Vitória de Paiva Souza
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil
| | - Timo Schomann
- Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Luiz Alberto Lira Soares
- Post Graduation Program in Therapeutic Innovation, Department of Pharmaceutical Sciences, Federal University of Pernambuco (UFPE), Recife, PE, Brazil
| | - Paulo Marcos da Matta Guedes
- Department of Parasitology and Microbiology and Post-Graduation Program in Parasite Biology, Federal University of Rio Grande do Norte, Natal, RN, Brazil
| | - Raimundo Fernandes de Araújo Júnior
- Postgraduate Program in Health Science, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil; Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands; Inflammation and Cancer Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal, RN, Brazil.
| |
Collapse
|
|
13
|
Barnwal A, Gaur V, Sengupta A, Tyagi W, Das S, Bhattacharyya J. Tumor Antigen-Primed Dendritic Cell-Derived Exosome Synergizes with Colony Stimulating Factor-1 Receptor Inhibitor by Modulating the Tumor Microenvironment and Systemic Immunity. ACS Biomater Sci Eng 2023; 9:6409-6424. [PMID: 37870457 DOI: 10.1021/acsbiomaterials.3c00469] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2023]
Abstract
Dendritic cell-derived exosomes (Dex) have overcome the disadvantages associated with dendritic cell (DC) vaccines, such as cost effectiveness, stability, and sensitivity to the systemic microenvironment. However, in clinical trials, Dex failed to provide satisfactory results because of many reasons, including inadequate maturation of DC as well as the immunosuppressive tumor microenvironment (TME). Hence, culturing DCs in the presence of a maturation cocktail showed an induced expression of MHCs and co-stimulatory molecules. Additionally, targeting the colony stimulating factor-1 (CSF-1)/CSF-1 receptor (CSF-1R) signaling pathway by a CSF-1R inhibitor could deplete tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) which are responsible for immunosuppressive TME. Hence, in this study, mDexTA were isolated from bone marrow-derived DC cultured in the presence of a novel maturation cocktail and tumor antigen. mDexTA showed elevated expression of major histocompatibility complexes (MHCs) and co-stimulatory molecules and was found capable of activating naïve DC and T cells in vitro more efficiently when compared to imDexTA isolated from immature DCs. In addition, PLX-3397, a small molecule inhibitor of CSF-1/CSF-1R, was used in combination to enhance the antitumor efficacy of mDexTA. PLX-3397 showed dose-dependent toxicity against bone marrow-derived macrophages (BMDMs). In the B16-F10 murine melanoma model, we found that the combination treatment delayed tumor growth and improved survival compared to the mice treated with mDexTA alone by enhancing the CD8 T cells infiltration in TME. mDexTA when combined with PLX-3397 modulated the TME by shifting the Th1/Th2 toward a dominant Th1 population and depleting the TAMs and MDSCs. Interestingly, PLX-3397-induced FoxP3 expression was diminished when it was used in combination with mDexTA. Combination treatment also induced favorable systemic antitumor immunity in the spleen and lymph node. In conclusion, our findings provide insights into the synergy between mDexTA-based immunotherapy and PLX-3397 as the combination overcame the disadvantages associated with monotherapy and offer a therapeutic strategy for the treatment of solid tumors including melanoma.
Collapse
Affiliation(s)
- Anjali Barnwal
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi 110029, India
| | - Vidit Gaur
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi 110029, India
| | - Anindita Sengupta
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi 110029, India
| | - Witty Tyagi
- National Institute of Immunology, Delhi 110067, India
| | - Sanjeev Das
- National Institute of Immunology, Delhi 110067, India
| | - Jayanta Bhattacharyya
- Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India
- Department of Biomedical Engineering, All India Institute of Medical Science, Delhi 110029, India
| |
Collapse
|
|
14
|
Jafari MM, Azimzadeh Tabrizi Z, Dayer MS, Kazemi-Sefat NA, Mohtashamifard M, Mohseni R, Bagheri A, Bahadory S, Karimipour-Saryazdi A, Ghaffarifar F. Immune system roles in pathogenesis, prognosis, control, and treatment of Toxoplasma gondii infection. Int Immunopharmacol 2023; 124:110872. [PMID: 37660595 DOI: 10.1016/j.intimp.2023.110872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 08/25/2023] [Accepted: 08/27/2023] [Indexed: 09/05/2023]
Abstract
Toxoplasma gondii is the protozoan causative agent of toxoplasmosis in humans and warm-blooded animals. Recent studies have illustrated that the immune system plays a pivotal role in the pathogenesis of toxoplasmosis by triggering immune cytokines like IL-12, TNF-α, and IFN-γ and immune cells like DCs, Th1, and Th17. On the other hand, some immune components can serve as prognosis markers of toxoplasmosis. In healthy people, the disease is often asymptomatic, but immunocompromised people and newborns may suffer severe symptoms and complications. Therefore, the immune prognostic markers may provide tools to measure the disease progress and help patients to avoid further complications. Immunotherapies using monoclonal antibody, cytokines, immune cells, exosomes, novel vaccines, and anti-inflammatory molecules open new horizon for toxoplasmosis treatment. In this review article, we discussed the immunopathogenesis, prognosis, and immunotherapy of Toxoplasma gondii infection.
Collapse
Affiliation(s)
- Mohammad Mahdi Jafari
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zahra Azimzadeh Tabrizi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Mohammad Saaid Dayer
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Mahshid Mohtashamifard
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Rahimeh Mohseni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Atefeh Bagheri
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Saeed Bahadory
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Amir Karimipour-Saryazdi
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Ghaffarifar
- Department of Parasitology and Medical Entomology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
|
15
|
Lee KW, Yam JWP, Mao X. Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations. Cells 2023; 12:2147. [PMID: 37681880 PMCID: PMC10486560 DOI: 10.3390/cells12172147] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
Collapse
Affiliation(s)
- Kyu-Won Lee
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
| |
Collapse
|
|
16
|
Luo S, Chen J, Xu F, Chen H, Li Y, Li W. Dendritic Cell-Derived Exosomes in Cancer Immunotherapy. Pharmaceutics 2023; 15:2070. [PMID: 37631284 PMCID: PMC10457773 DOI: 10.3390/pharmaceutics15082070] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Exosomes are nanoscale vesicles released by diverse types of cells for complex intercellular communication. Numerous studies have shown that exosomes can regulate the body's immune response to tumor cells and interfere with the tumor microenvironment (TME). In clinical trials on dendritic cell (DC)-based antitumor vaccines, no satisfactory results have been achieved. However, recent studies suggested that DC-derived exosomes (DEXs) may be superior to DC-based antitumor vaccines in avoiding tumor cell-mediated immunosuppression. DEXs contain multiple DC-derived surface markers that capture tumor-associated antigens (TAAs) and promote immune cell-dependent tumor rejection. These findings indicate the necessity of the further development and improvement of DEX-based cell-free vaccines to complement chemotherapy, radiotherapy, and other immunotherapies. In this review, we highlighted the recent progress of DEXs in cancer immunotherapy, particularly by concentrating on landmark studies and the biological characterization of DEXs, and we summarized their important role in the tumor immune microenvironment (TIME) and clinical application in targeted cancer immunotherapy. This review could enhance comprehension of advances in cancer immunotherapy and contribute to the elucidation of how DEXs regulate the TIME, thereby providing a reference for utilizing DEX-based vaccines in clinical practice.
Collapse
Affiliation(s)
- Shumin Luo
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Jing Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Fang Xu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Huan Chen
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;
| | - Yiru Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Weihua Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| |
Collapse
|
|
17
|
Jiang W, Xu Y, Chen JC, Lee YH, Hu Y, Liu CH, Chen E, Tang H, Zhang H, Wu D. Role of extracellular vesicles in nonalcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1196831. [PMID: 37534206 PMCID: PMC10392952 DOI: 10.3389/fendo.2023.1196831] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/21/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that affects approximately one-quarter of the global population and is becoming increasingly prevalent worldwide. The lack of current noninvasive tools and efficient treatment is recognized as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) are nanoscale vesicles released by various cells and deliver bioactive molecules to target cells, thereby mediating various processes, including the development of NAFLD. SCOPE OF REVIEW There is still a long way to actualize the application of EVs in NAFLD diagnosis and treatment. Herein, we summarize the roles of EVs in NAFLD and highlight their prospects for clinical application as a novel noninvasive diagnostic tool as well as a promising therapy for NAFLD, owing to their unique physiochemical characteristics. We summarize the literatures on the mechanisms by which EVs act as mediators of intercellular communication by regulating metabolism, insulin resistance, inflammation, immune response, intestinal microecology, and fibrosis in NAFLD. We also discuss future challenges that must be resolved to improve the therapeutic potential of EVs. MAJOR CONCLUSIONS The levels and contents of EVs change dynamically at different stages of diseases and this phenomenon may be exploited for establishing sensitive stage-specific markers. EVs also have high application potential as drug delivery systems with low immunogenicity and high biocompatibility and can be easily engineered. Research on the mechanisms and clinical applications of EVs in NAFLD is in its initial phase and the applicability of EVs in NAFLD diagnosis and treatment is expected to grow with technological progress.
Collapse
Affiliation(s)
- Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Youhui Xu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jou-Chen Chen
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yi-Hung Lee
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yushin Hu
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| |
Collapse
|
|
18
|
Cieślik M, Bryniarski K, Nazimek K. Biodelivery of therapeutic extracellular vesicles: should mononuclear phagocytes always be feared? Front Cell Dev Biol 2023; 11:1211833. [PMID: 37476156 PMCID: PMC10354279 DOI: 10.3389/fcell.2023.1211833] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 06/26/2023] [Indexed: 07/22/2023] Open
Abstract
At present, extracellular vesicles (EVs) are considered key candidates for cell-free therapies, including treatment of allergic and autoimmune diseases. However, their therapeutic effectiveness, dependent on proper targeting to the desired cells, is significantly limited due to the reduced bioavailability resulting from their rapid clearance by the cells of the mononuclear phagocyte system (MPS). Thus, developing strategies to avoid EV elimination is essential when applying them in clinical practice. On the other hand, malfunctioning MPS contributes to various immune-related pathologies. Therapeutic reversal of these effects with EVs would be beneficial and could be achieved, for example, by modulating the macrophage phenotype or regulating antigen presentation by dendritic cells. Additionally, intended targeting of EVs to MPS macrophages for replication and repackaging of their molecules into new vesicle subtype can allow for their specific targeting to appropriate populations of acceptor cells. Herein, we briefly discuss the under-explored aspects of the MPS-EV interactions that undoubtedly require further research in order to accelerate the therapeutic use of EVs.
Collapse
Affiliation(s)
| | | | - Katarzyna Nazimek
- Department of Immunology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
|
19
|
Teo KYW, Zhang S, Loh JT, Lai RC, Hey HWD, Lam KP, Lim SK, Toh WS. Mesenchymal Stromal Cell Exosomes Mediate M2-like Macrophage Polarization through CD73/Ecto-5'-Nucleotidase Activity. Pharmaceutics 2023; 15:pharmaceutics15051489. [PMID: 37242732 DOI: 10.3390/pharmaceutics15051489] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/06/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
Mesenchymal stem/stromal cell (MSC) exosomes have been shown to alleviate immune dysfunction and inflammation in preclinical animal models. This therapeutic effect is attributed, in part, to their ability to promote the polarization of anti-inflammatory M2-like macrophages. One polarization mechanism has been shown to involve the activation of the MyD88-mediated toll-like receptor (TLR) signaling pathway by the presence of extra domain A-fibronectin (EDA-FN) within the MSC exosomes. Here, we uncovered an additional mechanism where MSC exosomes mediate M2-like macrophage polarization through exosomal CD73 activity. Specifically, we observed that polarization of M2-like macrophages by MSC exosomes was abolished in the presence of inhibitors of CD73 activity, adenosine receptors A2A and A2B, and AKT/ERK phosphorylation. These findings suggest that MSC exosomes promote M2-like macrophage polarization by catalyzing the production of adenosine, which then binds to adenosine receptors A2A and A2B to activate AKT/ERK-dependent signaling pathways. Thus, CD73 represents an additional critical attribute of MSC exosomes in mediating M2-like macrophage polarization. These findings have implications for predicting the immunomodulatory potency of MSC exosome preparations.
Collapse
Affiliation(s)
- Kristeen Ye Wen Teo
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Shipin Zhang
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
| | - Jia Tong Loh
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Hwee Weng Dennis Hey
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Kong-Peng Lam
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Singapore 138648, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road, Singapore 119228, Singapore
- Faculty of Dentistry, National University of Singapore, 9 Lower Kent Ridge Road, Singapore 119085, Singapore
- Tissue Engineering Program, Life Sciences Institute, National University of Singapore, 27 Medical Drive, Singapore 117510, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, National University of Singapore, 21 Lower Kent Ridge Road, Singapore 119077, Singapore
| |
Collapse
|
|
20
|
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.
Collapse
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
| |
Collapse
|
|
21
|
Ye Q, Li Z, Li Y, Li Y, Zhang Y, Gui R, Cui Y, Zhang Q, Qian L, Xiong Y, Yu Y. Exosome-Derived microRNA: Implications in Melanoma Progression, Diagnosis and Treatment. Cancers (Basel) 2022; 15:cancers15010080. [PMID: 36612077 PMCID: PMC9818028 DOI: 10.3390/cancers15010080] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 12/19/2022] [Indexed: 12/25/2022] Open
Abstract
Melanoma is a malignant and aggressive cancer, and its progression is greatly affected by interactions between melanoma cells and their surroundings. Exploration on mechanism of melanoma and improved diagnostic and therapeutic strategies are becoming increasingly important. Unlike extracellular messengers that mainly work on targeted cells through corresponding receptors, exosomes are essential intercellular messengers that deliver biologically active substances such as nucleic acids and proteins to target cells for cell-cell communication. Of them, microRNAs (miRNAs) are common and important exosomal components that can regulate the expression of a wide range of target genes. Accordingly, exosome-derived miRNAs play a significant role in melanoma progression, including invasion and metastasis, microenvironment establishment, angiogenesis, and immune escape. MiRNA signatures of exosomes are specific in melanoma patients compared to healthy controls, thus circulating miRNAs, especially exosomal miRNAs, become potential diagnostic markers and therapeutic targets for melanoma. This review aims to summarize recent studies on the role of exosomal miRNAs in melanoma as well as ongoing efforts in melanoma treatment.
Collapse
Affiliation(s)
- Qiang Ye
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Zi Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yang Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yirong Li
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yan Zhang
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Runlin Gui
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Yue Cui
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Qi Zhang
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
| | - Lu Qian
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Department of Endocrinology, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Xi’an 710069, China
| | - Yuyan Xiong
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
- Correspondence: (Y.X.); (Y.Y.)
| | - Yi Yu
- Xi’an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi’an No. 3 Hospital, The Affiliated Hospital of Northwest University, Faculty of Life Sciences and Medicine, Northwest University, Xi’an 710069, China
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, School of Medicine, Northwest University, Xi’an 710069, China
- Correspondence: (Y.X.); (Y.Y.)
| |
Collapse
|
|
22
|
Feng S, Lou K, Luo C, Zou J, Zou X, Zhang G. Obesity-Related Cross-Talk between Prostate Cancer and Peripheral Fat: Potential Role of Exosomes. Cancers (Basel) 2022; 14:5077. [PMID: 36291860 PMCID: PMC9600017 DOI: 10.3390/cancers14205077] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/06/2022] [Accepted: 10/13/2022] [Indexed: 11/17/2022] Open
Abstract
The molecular mechanisms of obesity-induced cancer progression have been extensively explored because of the significant increase in obesity and obesity-related diseases worldwide. Studies have shown that obesity is associated with certain features of prostate cancer. In particular, bioactive factors released from periprostatic adipose tissues mediate the bidirectional communication between periprostatic adipose tissue and prostate cancer. Moreover, recent studies have shown that extracellular vesicles have a role in the relationship between tumor peripheral adipose tissue and cancer progression. Therefore, it is necessary to investigate the feedback mechanisms between prostate cancer and periglandular adipose and the role of exosomes as mediators of signal exchange to understand obesity as a risk factor for prostate cancer. This review summarizes the two-way communication between prostate cancer and periglandular adipose and discusses the potential role of exosomes as a cross-talk and the prospect of using adipose tissue as a means to obtain exosomes in vitro. Therefore, this review may provide new directions for the treatment of obesity to suppress prostate cancer.
Collapse
Affiliation(s)
- Shangzhi Feng
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Kecheng Lou
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Cong Luo
- The First Clinical College, Gannan Medical University, Ganzhou 341000, China
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Junrong Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou 341000, China
- Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou 341000, China
| | - Xiaofeng Zou
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou 341000, China
- Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou 341000, China
| | - Guoxi Zhang
- Department of Urology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
- Institute of Urology, The First Affiliated Hospital of Ganna Medical University, Ganzhou 341000, China
- Jiangxi Engineering Technology Research Center of Calculi Prevention, Ganzhou 341000, China
| |
Collapse
|
|
23
|
Shi Y, Lu Y, You J. Antigen transfer and its effect on vaccine-induced immune amplification and tolerance. Am J Cancer Res 2022; 12:5888-5913. [PMID: 35966588 PMCID: PMC9373810 DOI: 10.7150/thno.75904] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/15/2022] [Indexed: 12/13/2022] Open
Abstract
Antigen transfer refers to the process of intercellular information exchange, where antigenic components including nucleic acids, antigen proteins/peptides and peptide-major histocompatibility complexes (p-MHCs) are transmitted from donor cells to recipient cells at the thymus, secondary lymphoid organs (SLOs), intestine, allergic sites, allografts, pathological lesions and vaccine injection sites via trogocytosis, gap junctions, tunnel nanotubes (TNTs), or extracellular vesicles (EVs). In the context of vaccine inoculation, antigen transfer is manipulated by the vaccine type and administration route, which consequently influences, even alters the immunological outcome, i.e., immune amplification and tolerance. Mainly focused on dendritic cells (DCs)-based antigen receptors, this review systematically introduces the biological process, molecular basis and clinical manifestation of antigen transfer.
Collapse
Affiliation(s)
- Yingying Shi
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Yichao Lu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, Zhejiang, China
| |
Collapse
|
|
24
|
Nguyen PH, Le AH, Pek JSQ, Pham TT, Jayasinghe MK, Do DV, Phung CD, Le MT. Extracellular vesicles and lipoproteins - Smart messengers of blood cells in the circulation. JOURNAL OF EXTRACELLULAR BIOLOGY 2022; 1:e49. [PMID: 38938581 PMCID: PMC11080875 DOI: 10.1002/jex2.49] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 06/12/2022] [Accepted: 06/19/2022] [Indexed: 06/29/2024]
Abstract
Blood cell-derived extracellular vesicles (BCEVs) and lipoproteins are the major circulating nanoparticles in blood that play an important role in intercellular communication. They have attracted significant interest for clinical applications, given their endogenous characteristics which make them stable, biocompatible, well tolerated, and capable of permeating biological barriers efficiently. In this review, we describe the basic characteristics of BCEVs and lipoproteins and summarize their implications in both physiological and pathological processes. We also outline well accepted workflows for the isolation and characterization of these circulating nanoparticles. Importantly, we highlight the latest progress and challenges associated with the use of circulating nanoparticles as diagnostic biomarkers and therapeutic interventions in multiple diseases. We spotlight novel engineering approaches and designs to facilitate the development of these nanoparticles by enhancing their stability, targeting capability, and delivery efficiency. Therefore, the present work provides a comprehensive overview of composition, biogenesis, functions, and clinical translation of circulating nanoparticles from the bench to the bedside.
Collapse
Affiliation(s)
- Phuong H.D. Nguyen
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Anh Hong Le
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Jonetta Shi Qi Pek
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Thach Tuan Pham
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Migara Kavishka Jayasinghe
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Immunology ProgrammeCancer Programme and Nanomedicine Translational ProgrammeYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Department of SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Dang Vinh Do
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Cao Dai Phung
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| | - Minh T.N. Le
- Department of Pharmacology and Institute for Digital MedicineYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Immunology ProgrammeCancer Programme and Nanomedicine Translational ProgrammeYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
- Department of SurgeryYong Loo Lin School of MedicineNational University of SingaporeSingaporeSingapore
| |
Collapse
|
|
25
|
Keshtkar S, Soleimanian S, Kaviani M, Sarvestani FS, Azarpira N, Asvar Z, Pakbaz S. Immune Cell-Derived Extracellular Vesicles in the Face of Pathogenic Infections. Front Immunol 2022; 13:906078. [PMID: 35844564 PMCID: PMC9279736 DOI: 10.3389/fimmu.2022.906078] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/31/2022] [Indexed: 11/22/2022] Open
Abstract
Extracellular Vesicles (EVs) are a collection of vesicles released from cells that play an important role in intercellular communication. Microbial infections are known as one of the major problems in the medical field. Considering the increasing resistance of strains to routine drug treatments, the need for new therapies seems to be more than ever. Recent studies have shown that the EVs released from immune cells during microbial infections had anti-microbial effects or were able to induce neighbouring cells to display anti-microbial effects. This mini-review aimed to explore the latest studies on immune cell-derived EVs in viral, bacterial, fungal, and parasitic infections. Review of the literature demonstrated that specific cargos in EVs were involved in the fight against pathogenic infections. Additionally, the transport of appropriate bioactive molecules including miRNAs, mRNAs, and proteins via EVs could mediate the anti-microbial process. Thus, it could be a proof-of-principle that therapeutic approaches based on EVs derived from immune cells could offer a promising path forward, which is still in early stages and needs further assessments.
Collapse
Affiliation(s)
- Somayeh Keshtkar
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Molecular Dermatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeede Soleimanian
- Allergy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Negar Azarpira
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Asvar
- Nanotechnology School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sara Pakbaz
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine & Pathobiology, Mount Sinai Hospital, Toronto, ON, Canada
| |
Collapse
|
|
26
|
Liu H, Huang Y, Huang M, Huang Z, Wang Q, Qing L, Li L, Xu S, Jia B. Current Status, Opportunities, and Challenges of Exosomes in Oral Cancer Diagnosis and Treatment. Int J Nanomedicine 2022; 17:2679-2705. [PMID: 35733418 PMCID: PMC9208818 DOI: 10.2147/ijn.s365594] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/01/2022] [Indexed: 12/13/2022] Open
Abstract
Oral cancer is one of the most common cancers in the world, with more than 300,000 cases diagnosed each year, of which oral squamous cell carcinoma accounts for more than 90%, with a 5-year survival rate of only 40–60%, and poor prognosis. Exploring new strategies for the early diagnosis and treatment of oral cancer is key to improving the survival rate. Exosomes are nanoscale lipid bilayer membrane vesicles that are secreted by almost all cell types. During the development of oral cancer, exosomes can transport their contents (DNA, RNA, proteins, etc) to target cells and promote or inhibit the proliferation, invasion, and metastasis of oral cancer cells by influencing the host immune response, drug-resistant metastasis, and tumour angiogenesis. Therefore, exosomes have great potential and advantages as biomarkers for oral cancer diagnosis, and as drug delivery vehicles or targets for oral cancer therapy. In this review, we first describe the biogenesis, biological functions, and isolation methods of exosomes, followed by their relationship with oral cancer. Here, we focused on the potential of exosomes as oral cancer biomarkers, drug carriers, and therapeutic targets. Finally, we provide an insightful discussion of the opportunities and challenges of exosome application in oral cancer diagnosis and treatment, intending to offer new ideas for the clinical management of oral cancer.
Collapse
Affiliation(s)
- Hongyu Liu
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Yisheng Huang
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Mingshu Huang
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhijie Huang
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Qin Wang
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Ling Qing
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Li Li
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Shuaimei Xu
- Department of Endodontics, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Bo Jia
- Department of Oral Surgery, Stomatological Hospital, Southern Medical University, Guangzhou, People's Republic of China
| |
Collapse
|
|
27
|
Bahmani L, Ullah M. Different Sourced Extracellular Vesicles and Their Potential Applications in Clinical Treatments. Cells 2022; 11:1989. [PMID: 35805074 PMCID: PMC9265969 DOI: 10.3390/cells11131989] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/19/2022] [Accepted: 06/20/2022] [Indexed: 12/12/2022] Open
Abstract
Extracellular vesicles (EVs) include a heterogeneous group of natural cell-derived nanostructures that are increasingly regarded as promising biotherapeutic agents and drug delivery vehicles in human medicine. Desirable intrinsic properties of EVs including the ability to bypass natural membranous barriers and to deliver their unique biomolecular cargo to specific cell populations position them as fiercely competitive alternatives for currently available cell therapies and artificial drug delivery platforms. EVs with distinct characteristics can be released from various cell types into the extracellular environment as a means of transmitting bioactive components and altering the status of the target cell. Despite the existence of a large number of preclinical studies confirming the therapeutic efficacy of different originated EVs for treating several pathological conditions, in this review, we first provide a brief overview of EV biophysical properties with an emphasis on their intrinsic therapeutic benefits over cell-based therapies and synthetic delivery systems. Next, we describe in detail different EVs derived from distinct cell sources, compare their advantages and disadvantages, and recapitulate their therapeutic effects on various human disorders to highlight the progress made in harnessing EVs for clinical applications. Finally, knowledge gaps and concrete hurdles that currently hinder the clinical translation of EV therapies are debated with a futuristic perspective.
Collapse
Affiliation(s)
- Leila Bahmani
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Mujib Ullah
- Institute for Immunity and Transplantation, Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Palo Alto, CA 94304, USA;
- Molecular Medicine Department of Medicine, Stanford University, Palo Alto, CA 94304, USA
| |
Collapse
|
|
28
|
Shen J, Zhang M, Peng M. Progress of exosome research in systemic lupus erythematosus. Cytokine X 2022; 4:100066. [PMID: 35656386 PMCID: PMC9151726 DOI: 10.1016/j.cytox.2022.100066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 04/27/2022] [Accepted: 05/14/2022] [Indexed: 02/08/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a global chronic autoimmune disease that invades most organs of the body, with kidney injury being the most prominent feature. Exosomes are extracellular vesicles that carry a variety of proteins, lipids and genetic material, participate in the exchange of local and intersystem information, and play an important immunoregulatory role in a variety of autoimmune diseases. At the same time, the use of exosomes as disease biomarkers and drug delivery carriers also shows great application prospects. This article reviews current progress in the application of exosomes in the pathogenesis, diagnosis and treatment of SLE.
Collapse
Key Words
- CfDNA, Circulating free DNA
- Diagnostic role
- Exosomes
- HMGB1, High mobility group box 1
- Immunomodulation
- LN, Lupus nephritis
- MSC, Mesenchymal stem cells (MSC)
- MiRNAs, Microribonucleic acids
- Microribonucleic acid
- PAMPs, Pathogen-associated molecular patterns
- PDCs, Plasmacytoid dendritic cells
- SLE, Systemic lupus erythematosus
- Systemic lupus erythematosus
- TLR, Recombinant Toll Like Receptor
- Therapeutic potential
- Treg, Regulatory T cells
Collapse
Affiliation(s)
- Jie Shen
- Weifang Medical University, Weifang 261053, China
| | - Mengyu Zhang
- Weifang Medical University, Weifang 261053, China
| | - Meiyu Peng
- Weifang Medical University, Weifang 261053, China
- Department of Immunology, School of Basic Medical Sciences, Weifang Medical University, Weifang 261053, China
| |
Collapse
|
|
29
|
Jorquera-Cordero C, Lara P, Cruz LJ, Schomann T, van Hofslot A, de Carvalho TG, Guedes PMDM, Creemers L, Koning RI, Chan AB, de Araujo Junior RF. Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer. Pharmaceutics 2022; 14:pharmaceutics14051068. [PMID: 35631654 PMCID: PMC9143936 DOI: 10.3390/pharmaceutics14051068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/21/2022] Open
Abstract
One of the main reasons for cancer’s low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the β-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-κB was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-β. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer.
Collapse
Affiliation(s)
- Carla Jorquera-Cordero
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (C.J.-C.); (L.C.); (A.B.C.)
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
| | - Pablo Lara
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
- Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (L.J.C.); (A.v.H.)
- Correspondence: (P.L.); (R.F.d.A.J.); Tel.: +31-06-21180677 (P.L.); +31-65-562-0247 (R.F.d.A.J.)
| | - Luis J. Cruz
- Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (L.J.C.); (A.v.H.)
| | - Timo Schomann
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
- Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (L.J.C.); (A.v.H.)
| | - Anna van Hofslot
- Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (L.J.C.); (A.v.H.)
| | - Thaís Gomes de Carvalho
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
- Postgraduate Program in Health Science, Health Science Department, Federal University of Rio Grande do Norte (UFRN), Natal 59078 970, RN, Brazil
- Cancer and Inflammation Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte, Natal 59078 970, RN, Brazil
| | - Paulo Marcos Da Matta Guedes
- Department of Microbiology and Parasitology, Federal University of Rio Grande do Norte, Natal 59078 970, RN, Brazil;
| | - Laura Creemers
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (C.J.-C.); (L.C.); (A.B.C.)
| | - Roman I. Koning
- Electron Microscopy, Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands;
| | - Alan B. Chan
- Department of Orthopedics, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; (C.J.-C.); (L.C.); (A.B.C.)
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
| | - Raimundo Fernandes de Araujo Junior
- Percuros B.V., 2333 CL Leiden, The Netherlands; (T.S.); (T.G.d.C.)
- Translational Nanobiomaterials and Imaging (TNI) Group, Radiology Department, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands; (L.J.C.); (A.v.H.)
- Postgraduate Program in Health Science, Health Science Department, Federal University of Rio Grande do Norte (UFRN), Natal 59078 970, RN, Brazil
- Cancer and Inflammation Research Laboratory, Department of Morphology, Federal University of Rio Grande do Norte, Natal 59078 970, RN, Brazil
- Postgraduate Program in Functional and Structural Biology, Department of Morphology, Federal University of Rio Grande do Norte (UFRN), Natal 59078 970, RN, Brazil
- Correspondence: (P.L.); (R.F.d.A.J.); Tel.: +31-06-21180677 (P.L.); +31-65-562-0247 (R.F.d.A.J.)
| |
Collapse
|
|
30
|
Yang L, Patel KD, Rathnam C, Thangam R, Hou Y, Kang H, Lee KB. Harnessing the Therapeutic Potential of Extracellular Vesicles for Biomedical Applications Using Multifunctional Magnetic Nanomaterials. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2022; 18:e2104783. [PMID: 35132796 PMCID: PMC9344859 DOI: 10.1002/smll.202104783] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/12/2022] [Indexed: 04/14/2023]
Abstract
Extracellular vesicles (e.g., exosomes) carrying various biomolecules (e.g., proteins, lipids, and nucleic acids) have rapidly emerged as promising platforms for many biomedical applications. Despite their enormous potential, their heterogeneity in surfaces and sizes, the high complexity of cargo biomolecules, and the inefficient uptake by recipient cells remain critical barriers for their theranostic applications. To address these critical issues, multifunctional nanomaterials, such as magnetic nanomaterials, with their tunable physical, chemical, and biological properties, may play crucial roles in next-generation extracellular vesicles (EV)-based disease diagnosis, drug delivery, tissue engineering, and regenerative medicine. As such, one aims to provide cutting-edge knowledge pertaining to magnetic nanomaterials-facilitated isolation, detection, and delivery of extracellular vesicles and their associated biomolecules. By engaging the fields of extracellular vesicles and magnetic nanomaterials, it is envisioned that their properties can be effectively combined for optimal outcomes in biomedical applications.
Collapse
Affiliation(s)
- Letao Yang
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Kapil D. Patel
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Christopher Rathnam
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Ramar Thangam
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Yannan Hou
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Piscataway, NJ 08854, USA
| | - Heemin Kang
- Department of Materials Science and Engineering, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
| | - Ki-Bum Lee
- Department of Chemistry and Chemical Biology, Rutgers-the State University of New Jersey, 123 Bevier Road, Pis cataway, NJ 08854, USA
| |
Collapse
|
|
31
|
Kowalczyk A, Wrzecińska M, Czerniawska-Piątkowska E, Kupczyński R. Exosomes - Spectacular role in reproduction. Biomed Pharmacother 2022; 148:112752. [PMID: 35220028 DOI: 10.1016/j.biopha.2022.112752] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/21/2022] [Accepted: 02/23/2022] [Indexed: 11/28/2022] Open
Abstract
Exosomes are nano-sized structures that are found in semen, epididymal -fluid, endometrium, as well as in follicular fluid. They are responsible for transporting bioactive cargo- proteins, lipids, and nucleic acids. Exosomes have been proven to influence processes in both female and male reproductive systems, including gametogenesis, acrosomal reaction, sperm capacitation, and embryo implantation in the endometrium. Exosomes are made of the same particles as the cells they come from and are secreted by normal and pathological cells. Therefore, exosomes can reflect the physiological state of cells. Moreover, due to the transportation of biomolecules, they participate in intercellular communication and can be used as biomarkers of many diseases, including ovarian, endometrial and prostate cancer. Identification of exosomes as biomarkers could contribute to a better understanding of genital dysfunction and fertility disorders.
Collapse
Affiliation(s)
- Alicja Kowalczyk
- Department of Environment Hygiene and Animal Welfare, Wrocław University of Environmental and Life Sciences, Chełmońskiego 38C, Wrocław, Poland.
| | - Marcjanna Wrzecińska
- Department of Ruminant Science, West Pomeranian University of Technology, ul. Klemensa Janickiego 29, 71-270 Szczecin, Poland.
| | - Ewa Czerniawska-Piątkowska
- Department of Ruminant Science, West Pomeranian University of Technology, ul. Klemensa Janickiego 29, 71-270 Szczecin, Poland.
| | - Robert Kupczyński
- Department of Environment Hygiene and Animal Welfare, Wrocław University of Environmental and Life Sciences, Chełmońskiego 38C, Wrocław, Poland.
| |
Collapse
|
|
32
|
Kumar P, Boyne C, Brown S, Qureshi A, Thorpe P, Synowsky SA, Shirran S, Powis SJ. Tumour-associated antigenic peptides are present in the HLA class I ligandome of cancer cell line derived extracellular vesicles. Immunology 2022; 166:249-264. [PMID: 35318648 DOI: 10.1111/imm.13471] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/16/2021] [Accepted: 01/17/2022] [Indexed: 12/12/2022] Open
Abstract
The recent success of monoclonal antibody checkpoint inhibitor therapies that enhance the ability of CD8+ T cells to detect cancer-related antigenic peptides has refocused the need to fully understand the repertoire of peptides being presented to the immune system. Whilst the peptide ligandome presented by cell surface human leucocyte antigen class I (HLA-I) molecules on cancer cells has been studied extensively, the ligandome of extracellular vesicles (EVs) remains poorly defined. Here, we report the HLA-I ligandome of both the cell surface and EVs from eight breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-361, MDA-MB-415, MDA-MB-453, HCC 1806, HCC 1395, and HCC 1954), and additionally the melanoma cell line ESTDAB-056 and the multiple myeloma line RPMI 8226. Utilizing HLA-I immunoisolation and mass spectrometry, we detected a total of 6574 peptides from the cell surface and 2461 peptides from the EVs of the cell lines studied. Within the EV HLA-I ligandome, we identified 150 peptides derived from tumour associated antigenic proteins, of which 19 peptides have been shown to elicit T-cell responses in previous studies. Our data thus show the prevalence of clinically relevant tumour-associated antigenic peptides in the HLA-I ligandome presented on EV.
Collapse
Affiliation(s)
- Pankaj Kumar
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Caitlin Boyne
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Sydney Brown
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Ayesha Qureshi
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Peter Thorpe
- School of Medicine, University of St Andrews, St Andrews, UK
| | - Silvia A Synowsky
- School of Biology, University of St Andrews, St Andrews, UK.,Biomedical Sciences Research Complex, University of St Andrews, St Andrews, UK
| | - Sally Shirran
- School of Biology, University of St Andrews, St Andrews, UK.,Biomedical Sciences Research Complex, University of St Andrews, St Andrews, UK
| | - Simon J Powis
- School of Medicine, University of St Andrews, St Andrews, UK.,Biomedical Sciences Research Complex, University of St Andrews, St Andrews, UK
| |
Collapse
|
|
33
|
Zheng C, Xie L, Qin H, Liu X, Chen X, Lv F, Wang L, Zhu X, Xu J. The Role of Extracellular Vesicles in Systemic Lupus Erythematosus. Front Cell Dev Biol 2022; 10:835566. [PMID: 35309937 PMCID: PMC8924487 DOI: 10.3389/fcell.2022.835566] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/07/2022] [Indexed: 12/19/2022] Open
Abstract
Extracellular Vesicles (EVs) are small vesicles that can be actively secreted by most cell types into the extracellular environment. Evidence indicates that EVs can carry microRNAs (miRNAs), long non-coding RNAs (lncRNAs), tRNA-derived small RNAs (tsRNAs), proteins, and lipids to target cells or tissue organizations. Latest studies show that EVs play a vital role in the immune modulation and may contribute to the pathogenesis of autoimmune diseases. Systemic lupus erythematosus (SLE) is a common autoimmune disease characterized by abnormal T cell activation and sustained production of autoantibodies against self-antigens, resulting in inflammation and damage to multiple systems. Pathogenic mechanisms of SLE, however, are still not well understood. In this review, we summarize the latest research advances on the functions and mechanisms of EVs, and its role in the pathogenesis, diagnosis, and treatment of SLE.
Collapse
Affiliation(s)
| | - Lin Xie
- *Correspondence: Lin Xie, ; Xiaohua Zhu, ; Jinhua Xu,
| | | | | | | | | | | | - Xiaohua Zhu
- *Correspondence: Lin Xie, ; Xiaohua Zhu, ; Jinhua Xu,
| | - Jinhua Xu
- *Correspondence: Lin Xie, ; Xiaohua Zhu, ; Jinhua Xu,
| |
Collapse
|
|
34
|
Immunomodulatory Activity of Extracellular Vesicles of Kimchi-Derived Lactic Acid Bacteria ( Leuconostoc mesenteroides, Latilactobacillus curvatus, and Lactiplantibacillus plantarum). Foods 2022; 11:foods11030313. [PMID: 35159463 PMCID: PMC8834128 DOI: 10.3390/foods11030313] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/21/2022] [Accepted: 01/21/2022] [Indexed: 12/12/2022] Open
Abstract
Lactic acid bacteria present in Kimchi, such as Leuconostoc mesenteroides (Lm), Latilactobacillus curvatus (Lc), and Lactiplantibacillus plantarum (Lp) produce extracellular vesicles (ECVs) that modulate immune responses. The ECVs of probiotic Kimchi bacteria are abbreviated as LmV, LcV, and LpV. Treatment of macrophages (RAW264.7) with ECVs (LmV, LcV, and LpV) increased the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and interleukin-6 (IL-6). Immunostimulatory effects exerted on the RAW264.7 cells were stronger after treatments with LmV and LcV than with LpV. Treatment of mice with LcV (1 mg/kg, orally) induced splenocyte proliferation and subsequent production of both NO and cytokines (INF-γ, TNF-α, IL-4, and IL-10). Furthermore, pre-treatment of macrophages and microglial cells with ECVs prior to LPS stimulation significantly attenuated the production of NO and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6). Therefore, ECVs (LmV, LcV, and LpV) prevent inflammatory responses in the LPS-stimulated microglial cells by blocking the extracellular signal-regulated kinase (Erk) and p38 signaling pathways. These results showed that LmV, LcV, and LpV from Kimchi probiotic bacteria safely exert immunomodulatory effects.
Collapse
|
|
35
|
Ciullo A, Li C, Li L, Ungerleider KC, Peck K, Marbán E, Ibrahim AG. Biodistribution of unmodified cardiosphere-derived cell extracellular vesicles using single RNA tracing. J Extracell Vesicles 2022; 11:e12178. [PMID: 35005847 PMCID: PMC8743874 DOI: 10.1002/jev2.12178] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 12/25/2022] Open
Abstract
Extracellular vesicles (EVs) are potent signalling mediators. Although interest in EV translation is ever-increasing, development efforts are hampered by the inability to reliably assess the uptake of EVs and their RNA cargo. Here, we establish a novel qPCR-based method for the detection of unmodified EVS using an RNA Tracer (DUST). In this proof-of-concept study we use a human-specific Y RNA-derived small RNA (YsRNA) we dub "NT4" that is enriched in cardiosphere-derived cell small EVs (CDC-sEVs). The assay is robust, sensitive, and reproducible. Intravenously administered CDC-sEVs accumulated primarily in the heart on a per mg basis. Cardiac injury enhanced EV uptake in the heart, liver, and brain. Inhibition of EV docking by heparin suppressed uptake variably, while inhibition of endocytosis attenuated uptake in all organs. In vitro, EVs were uptaken more efficiently by macrophages, endothelial cells, and cardiac fibroblasts compared to cardiomyocytes. These findings demonstrate the utility of DUST to assess uptake of EVs in vivo and in vitro.
Collapse
Affiliation(s)
- Alessandra Ciullo
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Chang Li
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Liang Li
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | | | - Kiel Peck
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Eduardo Marbán
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| | - Ahmed G.E. Ibrahim
- Smidt Heart InstituteCedars‐Sinai Medical CenterLos AngelesCaliforniaUSA
| |
Collapse
|
|
36
|
Small Extracellular Vesicles Loaded with Immunosuppressive miRNAs Leads to an Inhibition of Dendritic Cell Maturation. Arch Immunol Ther Exp (Warsz) 2022; 70:27. [PMID: 36318344 PMCID: PMC9626419 DOI: 10.1007/s00005-022-00664-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 09/15/2022] [Indexed: 11/22/2022]
Abstract
In particular conditions, inhibition of an immune response is required to prevent tissue damage. Among these conditions are diseases caused by an over-reactive immune response, such as autoimmune or allergic disorders, or imminent organ rejection after transplantation. To avoid tissue damage, drug-mediated systemic immune suppression is an option, but it comes with high costs in the form of susceptibility to viral and bacterial infections. Thus, the induction of antigen-specific tolerance is preferable. Extracellular vesicles (EVs) are capable of delivering antigen together with immunosuppressive signals and may be used to specifically induce antigen-specific tolerance. However, naturally occurring EVs are heterogeneous and not all of them show immunosuppressive character. In our trials to engineer cell culture derived EVs to increase their tolerogenic potential, we equipped them with immunosuppressive miRNA mimics. Small EVs (sEVs) were isolated and purified from the human monocytic THP-1 cell line or from healthy donor peripheral blood mononuclear cells, and electroporated with miR-494 and miR-146a mimics. The acquired immunosuppressive potential of the modified sEVs was demonstrated by their ability to alter the major histocompatibility complex molecules and co-stimulatory receptors present on dendritic cells (DCs). To avoid allogeneic responses, the same cells that produced the sEVs served also as recipient cells. In contrast to the treatment with unmodified sEVs, the tolerogenic sEVs impeded lipopolysaccharide-induced maturation and kept DCs in a more immature developmental stage. Our experiments show that simple manipulations of sEVs using immunosuppressive cargo can lead to the inhibition of DC maturation.
Collapse
|
|
37
|
Nazimek K, Bryniarski K. Increasing the Therapeutic Efficacy of Extracellular Vesicles From the Antigen-Specific Antibody and Light Chain Perspective. Front Cell Dev Biol 2021; 9:790722. [PMID: 34901032 PMCID: PMC8652241 DOI: 10.3389/fcell.2021.790722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/05/2021] [Indexed: 12/12/2022] Open
Abstract
Due to their exceptional properties, extracellular vesicles (EVs) receive special attention as next generation biotherapeutics and vehicles for drug delivery. However, despite having many advantages over cell-based therapies, EVs usually exert lower therapeutic efficacy. This results from a number of hurdles that are faced by the EV-based approaches. Administered EVs could be rapidly cleared by the mononuclear phagocytes as well as can randomly distribute within various tissues, making tissue penetration and cell targeting insufficient. However, recent research findings imply that these limitations could be overcome with the use of antigen-specific antibodies and light chains. Major histocompatibility complex (MHC) class II-expressing EVs have been shown to form aggregates after co-incubation with antigen-specific antibodies, which greatly enhanced their biological efficacy. On the other hand, EVs could be coated with antibody light chains of chosen specificity to direct them towards desired target cell population. Both findings open up a promising perspective to achieve the highest efficacy of the EV-based approaches. Herein we discuss the opportunities for enhancing extracellular vesicle’s biological activity by using specific antibodies and light chains in the context of the challenges faced by such therapeutic approach.
Collapse
Affiliation(s)
- Katarzyna Nazimek
- Department of Immunology, Jagiellonian University Medical College, Krakow, Poland
| | - Krzysztof Bryniarski
- Department of Immunology, Jagiellonian University Medical College, Krakow, Poland
| |
Collapse
|
|
38
|
Di Silvestre D, Garavelli S, Procaccini C, Prattichizzo F, Passignani G, De Rosa V, Mauri P, Matarese G, de Candia P. CD4 + T-Cell Activation Prompts Suppressive Function by Extracellular Vesicle-Associated MicroRNAs. Front Cell Dev Biol 2021; 9:753884. [PMID: 34778265 PMCID: PMC8580371 DOI: 10.3389/fcell.2021.753884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 09/23/2021] [Indexed: 12/14/2022] Open
Abstract
MicroRNAs (miRNAs), small non-coding molecules targeting messenger RNAs and inhibiting protein translation, modulate key biological processes, including cell growth and development, energy utilization, and homeostasis. In particular, miRNAs control the differentiation, survival, and activation of CD4 + T conventional (Tconv) cells, key players of the adaptive immunity, and regulate the physiological response to infections and the pathological loss of immune homeostasis in autoimmunity. Upon T-cell receptor (TCR) stimulation, the described global miRNA quantitative decrease occurring in T cells is believed to promote the acquisition of effector functions by relaxing the post-transcriptional repression of genes associated with proliferation and cell activity. MiRNAs were initially thought to get downregulated uniquely by intracellular degradation; on the other hand, miRNA secretion via extracellular vesicles (EVs) represents an additional mechanism of rapid downregulation. By focusing on molecular interactions by means of graph theory, we have found that miRNAs released by TCR-stimulated Tconv cells are significantly enriched for targeting transcripts upregulated upon stimulation, including those encoding for crucial proteins associated with Tconv cell activation and function. Based on this computational approach, we present our perspective based on the following hypothesis: a stimulated Tconv cell will release miRNAs targeting genes associated with the effector function in the extracellular space in association with EVs, which will thus possess a suppressive potential toward other Tconv cells in the paracrine environment. We also propose possible future directions of investigation aimed at taking advantage of these phenomena to control Tconv cell effector function in health and autoimmunity.
Collapse
Affiliation(s)
- Dario Di Silvestre
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy
| | - Silvia Garavelli
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy
| | - Claudio Procaccini
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.,Unitá di Neuroimmunologia, IRCCS Fondazione Santa Lucia, Roma, Italy
| | | | - Giulia Passignani
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy
| | - Veronica De Rosa
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.,Unitá di Neuroimmunologia, IRCCS Fondazione Santa Lucia, Roma, Italy
| | - Pierluigi Mauri
- Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche (ITB-CNR), Milan, Italy
| | - Giuseppe Matarese
- Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples, Italy.,Treg Cell Laboratory, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá Degli Studi di Napoli "Federico II", Naples, Italy
| | | |
Collapse
|
|
39
|
Shao T, Verma HK, Pande B, Costanzo V, Ye W, Cai Y, Bhaskar LVKS. Physical Activity and Nutritional Influence on Immune Function: An Important Strategy to Improve Immunity and Health Status. Front Physiol 2021; 12:751374. [PMID: 34690818 PMCID: PMC8531728 DOI: 10.3389/fphys.2021.751374] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/13/2021] [Indexed: 12/11/2022] Open
Abstract
Physical activity (PA) and nutrition are the essential components of a healthy lifestyle, as they can influence energy balance, promote functional ability of various systems and improve immunity. Infections and their associated symptoms are the common and frequent challenges to human health that are causing severe economic and social consequences around the world. During aging, human immune system undergoes dramatic aging-related changes/dysfunctions known as immunosenescence. Clinically, immunosenescence refers to the gradual deterioration of immune system that increases exposure to infections, and reduces vaccine efficacy. Such phenomenon is linked to impaired immune responses that lead to dysfunction of multiple organs, while lack of physical activity, progressive loss of muscle mass, and concomitant decline in muscle strength facilitate immunosenescence and inflammation. In the present review, we have discussed the role of nutrition and PA, which can boost the immune system alone and synergistically. Evidence suggests that long-term PA is beneficial in improving immune system and preventing various infections. We have further discussed several nutritional strategies for improving the immune system. Unfortunately, the available evidence shows conflicting results. In terms of interaction with food intake, PA does not tend to increase energy intake during a short time course. However, overcoming nutritional deficiencies appears to be the most practical recommendation. Through the balanced nutritious diet intake one can fulfill the bodily requirement of optimal nutrition that significantly impacts the immune system. Supplementation of a single nutrient as food is generally not advisable. Rather incorporating various fruits and vegetables, whole grains, proteins and probiotics may ensure adequate nutrient intake. Therefore, multi-nutrient supplements may benefit people having deficiency in spite of sufficient diet. Along with PA, supplementation of probiotics, bovine colostrum, plant-derived products and functional foods may provide additional benefits in improving the immune system.
Collapse
Affiliation(s)
- Tianyi Shao
- College of Teacher Education, Zhejiang Normal University, Jinhua, China
| | - Henu Kumar Verma
- Department of Immunopathology, Institute of lungs Biology and Disease, Comprehensive Pneumology Center, Helmholtz Zentrum, Munich, Germany
| | - Babita Pande
- Department of Physiology, All India Institute of Medical Science, Raipur, India
| | - Vincenzo Costanzo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Weibing Ye
- College of Physical Education and Health Sciences, Zhejiang Normal University, Jinhua, China
| | - Yuyan Cai
- Department of Physical Education, Guangdong University of Technology, Guangzhou, China
| | | |
Collapse
|
|
40
|
Xu M, Feng T, Liu B, Qiu F, Xu Y, Zhao Y, Zheng Y. Engineered exosomes: desirable target-tracking characteristics for cerebrovascular and neurodegenerative disease therapies. Theranostics 2021; 11:8926-8944. [PMID: 34522219 PMCID: PMC8419041 DOI: 10.7150/thno.62330] [Citation(s) in RCA: 142] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 07/22/2021] [Indexed: 12/12/2022] Open
Abstract
As extracellular vesicles secreted by cells, exosomes are intercellular signalosomes for cell communication and pharmacological effectors. Because of their special properties, including low toxicity and immunogenicity, biodegradability, ability to encapsulate endogenous biologically active molecules and cross the blood-brain barrier (BBB), exosomes have great therapeutic potential in cerebrovascular and neurodegenerative diseases. However, the poor targeting ability of natural exosomes greatly reduces the therapeutic effect. Using engineering technology, exosomes can obtain active targeting ability to accumulate in specific cell types and tissues by attaching targeting units to the membrane surface or loading them into cavities. In this review, we outline the improved targeting functions of bioengineered exosomes, tracing and imaging techniques, administration methods, internalization in the BBB, and therapeutic effects of exosomes in cerebrovascular and neurodegenerative diseases and further evaluate the clinical opportunities and challenges in this research field.
Collapse
Affiliation(s)
- Meng Xu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Tao Feng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Bowen Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Fen Qiu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Youhua Xu
- Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao, China
| | - Yonghua Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| |
Collapse
|
|
41
|
Zhang E, Geng X, Shan S, Li P, Li S, Li W, Yu M, Peng C, Wang S, Shao H, Du Z. Exosomes derived from bone marrow mesenchymal stem cells reverse epithelial-mesenchymal transition potentially via attenuating Wnt/β-catenin signaling to alleviate silica-induced pulmonary fibrosis. Toxicol Mech Methods 2021; 31:655-666. [PMID: 34225584 DOI: 10.1080/15376516.2021.1950250] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Pulmonary fibrosis induced by silica dust is an irreversible, chronic, and fibroproliferative lung disease with no effective treatment at present. BMSCs-derived exosomes (BMSCs-Exo) possess similar functions to their parent cells. In this study, we investigated the therapeutic potential and underlying molecular mechanism for BMSCs-Exo in the treatment of silica-induced pulmonary fibrosis. The rat model of experimental silicosis pulmonary fibrosis was induced with 1.0 mL of one-off infusing silica suspension using the non-exposed intratracheal instillation (50 mg/mL/rat). In vivo transplantation of BMSCs-Exo effectively alleviated silica-induced pulmonary fibrosis, including a reduction in collagen accumulation, inhibition of TGF-β1, and decreased HYP content. Treatment of BMSCs-Exo increased the expression of epithelial marker proteins including E-cadherin (E-cad) and cytokeratin19 (CK19) and reduced the expression of fibrosis marker proteins including α-Smooth muscle actin (α-SMA) after exposure to silica suspension. Furthermore, we found that BMSCs-Exo inhibited the expression of Wnt/β-catenin pathway components (P-GSK3β, β-catenin, Cyclin D1) in pulmonary fibrosis tissue. BMSCs-Exo is involved in the alleviation of silica-induced pulmonary fibrosis by reducing the level of profibrotic factor TGF-β1 and inhibiting the progression of epithelial-mesenchymal transition (EMT). Additionally, attenuation of the Wnt/β-catenin signaling pathway closely related to EMT may be one of the mechanisms involved in anti-fibrotic effects of exosomes.
Collapse
Affiliation(s)
- Enguo Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.,Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Xiao Geng
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Shan Shan
- School of Public Health, Shandong University, Jinan, People's Republic of China
| | - Peng Li
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Shumin Li
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Wentao Li
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Meili Yu
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Cheng Peng
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China.,Queensland Alliance for Environmental Health Sciences (QAEHS), The University of Queensland, Brisbane, Australia
| | - Shijun Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Hua Shao
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| | - Zhongjun Du
- Department of Toxicology, Shandong Academy of Occupational Health and Occupational Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, People's Republic of China
| |
Collapse
|
|
42
|
Odobasic D, Holdsworth SR. Emerging Cellular Therapies for Anti-myeloperoxidase Vasculitis and Other Autoimmune Diseases. Front Immunol 2021; 12:642127. [PMID: 34394071 PMCID: PMC8358391 DOI: 10.3389/fimmu.2021.642127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 07/08/2021] [Indexed: 11/26/2022] Open
Abstract
Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.
Collapse
Affiliation(s)
- Dragana Odobasic
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, VIC, Australia
| | - Stephen R Holdsworth
- Centre for Inflammatory Diseases, Department of Medicine, Monash University, Monash Medical Centre, Clayton, VIC, Australia.,Department of Nephrology, Monash Health, Clayton, VIC, Australia.,Department of Immunology, Monash Health, Clayton, VIC, Australia
| |
Collapse
|
|
43
|
Yao Y, Fu C, Zhou L, Mi QS, Jiang A. DC-Derived Exosomes for Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13153667. [PMID: 34359569 PMCID: PMC8345209 DOI: 10.3390/cancers13153667] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 12/18/2022] Open
Abstract
As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.
Collapse
Affiliation(s)
- Yi Yao
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Chunmei Fu
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
| | - Li Zhou
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Qing-Sheng Mi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
- Correspondence: (Q.-S.M.); (A.J.); Tel.: +313-876-1017 (Q.-S.M.); +313-876-7292 (A.J.)
| | - Aimin Jiang
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
- Correspondence: (Q.-S.M.); (A.J.); Tel.: +313-876-1017 (Q.-S.M.); +313-876-7292 (A.J.)
| |
Collapse
|
|
44
|
Burgos-Ravanal R, Campos A, Díaz-Vesga MC, González MF, León D, Lobos-González L, Leyton L, Kogan MJ, Quest AFG. Extracellular Vesicles as Mediators of Cancer Disease and as Nanosystems in Theranostic Applications. Cancers (Basel) 2021; 13:3324. [PMID: 34283059 PMCID: PMC8268753 DOI: 10.3390/cancers13133324] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/16/2021] [Accepted: 06/20/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer remains a leading cause of death worldwide despite decades of intense efforts to understand the molecular underpinnings of the disease. To date, much of the focus in research has been on the cancer cells themselves and how they acquire specific traits during disease development and progression. However, these cells are known to secrete large numbers of extracellular vesicles (EVs), which are now becoming recognized as key players in cancer. EVs contain a large number of different molecules, including but not limited to proteins, mRNAs, and miRNAs, and they are actively secreted by many different cell types. In the last two decades, a considerable body of evidence has become available indicating that EVs play a very active role in cell communication. Cancer cells are heterogeneous, and recent evidence reveals that cancer cell-derived EV cargos can change the behavior of target cells. For instance, more aggressive cancer cells can transfer their "traits" to less aggressive cancer cells and convert them into more malignant tumor cells or, alternatively, eliminate those cells in a process referred to as "cell competition". This review discusses how EVs participate in the multistep acquisition of specific traits developed by tumor cells, which are referred to as "the hallmarks of cancer" defined by Hanahan and Weinberg. Moreover, as will be discussed, EVs play an important role in drug resistance, and these more recent advances may explain, at least in part, why pharmacological therapies are often ineffective. Finally, we discuss literature proposing the use of EVs for therapeutic and prognostic purposes in cancer.
Collapse
Affiliation(s)
- Renato Burgos-Ravanal
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
| | - América Campos
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
- Exosome Biology Laboratory, Centre for Clinical Diagnostics, UQ Centre for Clinical Research, Royal Brisbane and Women’s Hospital, The University of Queensland, Brisbane 4029, Australia
| | - Magda C. Díaz-Vesga
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
- Grupo de Investigación en Ciencias Básicas y Clínicas de la Salud, Pontificia Universidad Javeriana de Cali, Cali 760008, Colombia
| | - María Fernanda González
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
| | - Daniela León
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile
| | - Lorena Lobos-González
- Centro de Medicina Regenerativa, Facultad de Medicina, Universidad del Desarrollo-Clínica Alemana, Santiago 7590943, Chile;
| | - Lisette Leyton
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
| | - Marcelo J. Kogan
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
- Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santos Dumont 964, Independencia, Santiago 8380494, Chile
| | - Andrew F. G. Quest
- Laboratorio de Comunicaciones Celulares, Centro de Estudios en Ejercicio, Metabolismo y Cáncer (CEMC), Programa de Biología Celular y Molecular, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (R.B.-R.); (A.C.); (M.C.D.-V.); (M.F.G.); (L.L.)
- Centro Avanzado para Estudios en Enfermedades Crónicas (ACCDIS), Santiago 8380453, Chile;
| |
Collapse
|
|
45
|
Verdi J, Ketabchi N, Noorbakhsh N, Saleh M, Ebrahimi-Barough S, Seyhoun I, Kavianpour M. Development and Clinical Application of Tumor-derived Exosomes in Patients with Cancer. Curr Stem Cell Res Ther 2021; 17:91-102. [PMID: 34161212 DOI: 10.2174/1574888x16666210622123942] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/16/2020] [Accepted: 03/11/2021] [Indexed: 11/22/2022]
Abstract
A tumor is an abnormal growth of cells within a tissue that can lead to death due to late diagnosis, poor prognosis, drug resistance, and finally enhanced metastasis formation. Exosomes are nanovesicles that have been derived from all the different cell types. These vesicles can transfer various molecules, including the distinct form of nucleic acids (mRNA, miRNA, and circRNA) and proteins. Tumor-derived exosomes (TEXs) have exceptionally important roles through multiple molecular and cellular pathways like progression, tumorigenesis, drug resistance, and as well as metastasis. TEXs are detectable in all body fluids, such as serum and urine, a convenient and non-invasive way to access these nano-sized vesicles. TEXs lead to the symptom expression of genetic aberrations in the tumor cell population, making them an accurate and sensitive biomarker for the diagnosis and prognosis of tumors. On the other hand, TEXs contain major histocompatibility complexes (MHCs) and play important dual roles in regulating tumor immune responses; they can mediate both immune activation and suppression through tumor-associated immunity. Despite numerous scientific studies, there are still many technical barriers to distinguish TEXs from non-tumor-derived exosomes. Removing exosomes lead to a wide difference in outcomes inside a patient's body. Hence, controversial pieces of evidence have demonstrated the vital role of TEXs as hopeful biomarkers for the early detection of cancers, evaluation of therapeutic effects, and monitoring of the patient.
Collapse
Affiliation(s)
- Javad Verdi
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Neda Ketabchi
- Department of Medical Laboratory Sciences, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Negar Noorbakhsh
- Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Mahshid Saleh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Iman Seyhoun
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Kavianpour
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
46
|
Li A, Zhao Y, Li Y, Jiang L, Gu Y, Liu J. Cell-derived biomimetic nanocarriers for targeted cancer therapy: cell membranes and extracellular vesicles. Drug Deliv 2021; 28:1237-1255. [PMID: 34142930 PMCID: PMC8216268 DOI: 10.1080/10717544.2021.1938757] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nanotechnology provides synthetic carriers for cancer drug delivery that protect cargos from degradation, control drug release and increase local accumulation at tumors. However, these non-natural vehicles display poor tumor targeting and potential toxicity and are eliminated by the immune system. Recently, biomimetic nanocarriers have been widely developed based on the concept of ‘mimicking nature.’ Among them, cell-derived biomimetic vehicles have become the focus of bionics research because of their multiple natural functions, such as low immunogenicity, long circulation time and targeting ability. Cell membrane-coated carriers and extracellular vesicles are two widely used cell-based biomimetic materials. Here, this review summarizes the latest progress in the application of these two biomimetic carriers in targeted cancer therapy. Their properties and performance are compared, and their future challenges and development prospects are discussed.
Collapse
Affiliation(s)
- Aixue Li
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.,Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yunan Zhao
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yixiu Li
- Department of Pharmacy, Shanghai Integrated Traditional Chinese and Western Medicine Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Liangdi Jiang
- College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China.,Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yongwei Gu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jiyong Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| |
Collapse
|
|
47
|
Lin B, Xie W, Zeng C, Wu X, Chen A, Li H, Jiang R, Li P. Transfer of exosomal microRNA-203-3p from dendritic cells to bone marrow-derived macrophages reduces development of atherosclerosis by downregulating Ctss in mice. Aging (Albany NY) 2021; 13:15638-15658. [PMID: 34077394 PMCID: PMC8221304 DOI: 10.18632/aging.103842] [Citation(s) in RCA: 17] [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: 12/17/2019] [Accepted: 07/14/2020] [Indexed: 01/05/2023]
Abstract
Dendritic cell-derived exosomes have been proven to be efficient adjuvant options for anti-tumor vaccines in cancer immunotherapy. However, their potency in atherosclerosis remains unclear. Here we summarize the association of microRNA-203-3p (miR-203-3p) with dendritic cell-derived exosomes and atherosclerosis. Firstly, dendritic cell-derived exosomes and bone marrow-derived macrophages were isolated, after which expression of miR-203-3p and cathepsin S was determined. After the establishment of atherosclerosis mouse models, gain- and loss-of-function experiments were conducted for the analysis of effects of miR-203-3p and cathepsin S on foam-cell formation, lipid accumulation, collagen deposition and serum total cholesterol. The results found high expression of cathepsin S in atherosclerosis mice and downregulation of miR-203-3p in the serum of atherosclerosis patients and ox-LDL-simulated bone marrow-derived macrophages. Cathepsin S was the target gene of miR-203-3p. miR-203-3p transporting from exosomes to bone marrow-derived macrophages resulted in inhibition of cathepsin S expression and atherosclerosis-related phenotypes in bone marrow-derived macrophages, thus alleviating atherosclerosis in mice, and this process was found to involve the p38/MAPK signaling pathway. These findings provided evidence that the transfer of miR-203-3p by dendritic cell-derived exosomes targeted cathepsin S in bone marrow-derived macrophages to attenuate atherosclerosis progression in mice, serving as a promising clinical target for atherosclerosis.
Collapse
Affiliation(s)
- Beiyou Lin
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| | - Wenchao Xie
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| | - Chunmei Zeng
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| | - Xiaodan Wu
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University and Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention and Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning 530021, P.R. China
| | - Ang Chen
- Department of Cardiology, The First Affiliated Hospital of Guangxi Medical University and Guangxi Key Laboratory Base of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention and Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning 530021, P.R. China
| | - Hao Li
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| | - Rina Jiang
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| | - Ping Li
- Department of Cardiology, Yulin First People’s Hospital and The Sixth Affiliated Hospital of Guangxi Medical University, Yulin 537000, P.R. China
| |
Collapse
|
|
48
|
A Confocal Microscopic Study of Gene Transfer into the Mesencephalic Tegmentum of Juvenile Chum Salmon, Oncorhynchus keta, Using Mouse Adeno-Associated Viral Vectors. Int J Mol Sci 2021; 22:ijms22115661. [PMID: 34073457 PMCID: PMC8199053 DOI: 10.3390/ijms22115661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 05/21/2021] [Accepted: 05/23/2021] [Indexed: 11/17/2022] Open
Abstract
To date, data on the presence of adenoviral receptors in fish are very limited. In the present work, we used mouse recombinant adeno-associated viral vectors (rAAV) with a calcium indicator of the latest generation GCaMP6m that are usually applied for the dorsal hippocampus of mice but were not previously used for gene delivery into fish brain. The aim of our work was to study the feasibility of transduction of rAAV in the mouse hippocampus into brain cells of juvenile chum salmon and subsequent determination of the phenotype of rAAV-labeled cells by confocal laser scanning microscopy (CLSM). Delivery of the gene in vivo was carried out by intracranial injection of a GCaMP6m-GFP-containing vector directly into the mesencephalic tegmentum region of juvenile (one-year-old) chum salmon, Oncorhynchus keta. AAV incorporation into brain cells of the juvenile chum salmon was assessed at 1 week after a single injection of the vector. AAV expression in various areas of the thalamus, pretectum, posterior-tuberal region, postcommissural region, medial and lateral regions of the tegmentum, and mesencephalic reticular formation of juvenile O. keta was evaluated using CLSM followed by immunohistochemical analysis of the localization of the neuron-specific calcium binding protein HuCD in combination with nuclear staining with DAPI. The results of the analysis showed partial colocalization of cells expressing GCaMP6m-GFP with red fluorescent HuCD protein. Thus, cells of the thalamus, posterior tuberal region, mesencephalic tegmentum, cells of the accessory visual system, mesencephalic reticular formation, hypothalamus, and postcommissural region of the mesencephalon of juvenile chum salmon expressing GCaMP6m-GFP were attributed to the neuron-specific line of chum salmon brain cells, which indicates the ability of hippocampal mammal rAAV to integrate into neurons of the central nervous system of fish with subsequent expression of viral proteins, which obviously indicates the neuronal expression of a mammalian adenoviral receptor homolog by juvenile chum salmon neurons.
Collapse
|
|
49
|
Mazzariol M, Camussi G, Brizzi MF. Extracellular Vesicles Tune the Immune System in Renal Disease: A Focus on Systemic Lupus Erythematosus, Antiphospholipid Syndrome, Thrombotic Microangiopathy and ANCA-Vasculitis. Int J Mol Sci 2021; 22:ijms22084194. [PMID: 33919576 PMCID: PMC8073859 DOI: 10.3390/ijms22084194] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 01/02/2023] Open
Abstract
Extracellular vesicles (EV) are microparticles released in biological fluids by different cell types, both in physiological and pathological conditions. Owing to their ability to carry and transfer biomolecules, EV are mediators of cell-to-cell communication and are involved in the pathogenesis of several diseases. The ability of EV to modulate the immune system, the coagulation cascade, the angiogenetic process, and to drive endothelial dysfunction plays a crucial role in the pathophysiology of both autoimmune and renal diseases. Recent studies have demonstrated the involvement of EV in the control of renal homeostasis by acting as intercellular signaling molecules, mediators of inflammation and tissue regeneration. Moreover, circulating EV and urinary EV secreted by renal cells have been investigated as potential early biomarkers of renal injury. In the present review, we discuss the recent findings on the involvement of EV in autoimmunity and in renal intercellular communication. We focused on EV-mediated interaction between the immune system and the kidney in autoimmune diseases displaying common renal damage, such as antiphospholipid syndrome, systemic lupus erythematosus, thrombotic microangiopathy, and vasculitis. Although further studies are needed to extend our knowledge on EV in renal pathology, a deeper investigation of the impact of EV in kidney autoimmune diseases may also provide insight into renal biological processes. Furthermore, EV may represent promising biomarkers of renal diseases with potential future applications as diagnostic and therapeutic tools.
Collapse
|
|
50
|
Shi Y, Du L, Lv D, Li Y, Zhang Z, Huang X, Tang H. Emerging role and therapeutic application of exosome in hepatitis virus infection and associated diseases. J Gastroenterol 2021; 56:336-349. [PMID: 33665710 PMCID: PMC8005397 DOI: 10.1007/s00535-021-01765-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 01/23/2021] [Indexed: 02/05/2023]
Abstract
Hepatitis viruses are chief pathogens of hepatitis and end-stage liver diseases. Their replication and related pathogenic process highly rely on the host micro-environment and multiple cellular elements, including exosomes. Representing with a sort of cell-derived vesicle structure, exosomes were considered to be dispensable cellular components, even wastes. Along with advancing investigation, a specific profile of exosome in driving hepatitis viruses' infection and hepatic disease progression is revealed. Exosomes greatly affect the pathogenesis of hepatitis viruses by mediating their replication and modulating the host immune responses. The characteristics of host exosomes are markedly changed after infection with hepatitis viruses. Exosomes released from hepatitis virus-infected cells can carry viral nucleic or protein components, thereby acting as an effective subterfuge for hepatitis viruses by participating in viral transportation and immune escape. On the contrary, immune cell-derived exosomes contribute toward the innate antiviral immune defense and virus eradication. There is growing evidence supporting the application of exosomal biomarkers for predicting disease progress or therapeutic outcome, while exosomal nanoshuttles are regarded as promising therapeutic options based on their delivery properties and immune compatibility. In this review, we summarize the biogenesis and secretion mechanism of exosomes, review the recent findings pertaining to the role of exosomes in the interplay between hepatitis viruses and innate immune responses, and conclude their potential in further therapeutic application.
Collapse
Affiliation(s)
- Ying Shi
- Center of Infectious Diseases, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
- School of Medicine, University of Electronic Science and Technology of China, No. 4 Section 2, North Jianshe Road, Chengdu, 610054, Sichuan, China
- Department of Hepatobiliary Surgery and Cell Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, No. 32 Western Section 2, 1st Ring Rd., Chengdu, 610072, Sichuan, China
| | - Lingyao Du
- Center of Infectious Diseases, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, No. 17 People's South Road, Chengdu, 610041, Sichuan, China
| | - Duoduo Lv
- Center of Infectious Diseases, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, No. 17 People's South Road, Chengdu, 610041, Sichuan, China
| | - Yan Li
- School of Medicine, University of Electronic Science and Technology of China, No. 4 Section 2, North Jianshe Road, Chengdu, 610054, Sichuan, China
- Department of Hepatobiliary Surgery and Cell Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, No. 32 Western Section 2, 1st Ring Rd., Chengdu, 610072, Sichuan, China
| | - Zilong Zhang
- School of Medicine, University of Electronic Science and Technology of China, No. 4 Section 2, North Jianshe Road, Chengdu, 610054, Sichuan, China
- Department of Hepatobiliary Surgery and Cell Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, No. 32 Western Section 2, 1st Ring Rd., Chengdu, 610072, Sichuan, China
| | - Xiaolun Huang
- School of Medicine, University of Electronic Science and Technology of China, No. 4 Section 2, North Jianshe Road, Chengdu, 610054, Sichuan, China
- Department of Hepatobiliary Surgery and Cell Transplantation Center, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, No. 32 Western Section 2, 1st Ring Rd., Chengdu, 610072, Sichuan, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, 610041, Sichuan, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, No. 17 People's South Road, Chengdu, 610041, Sichuan, China.
| |
Collapse
|