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Zhao B, Wei J, Jiang Z, Long Y, Xu Y, Jiang B. Mesenchymal stem cell-derived exosomes: an emerging therapeutic strategy for hepatic ischemia-reperfusion injury. Stem Cell Res Ther 2025; 16:178. [PMID: 40229893 PMCID: PMC11998454 DOI: 10.1186/s13287-025-04302-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Accepted: 04/01/2025] [Indexed: 04/16/2025] Open
Abstract
Hepatic ischemia-reperfusion injury (HIRI) severely threatens the success rates of liver surgery and transplantation. Its complex pathological process involves multiple factors such as oxidative stress, inflammatory responses, and ferroptosis, creating an urgent need for new therapeutic strategies. Exosomes derived from mesenchymal stem cells (MSCs) are emerging as a next-generation acellular therapeutic approach. With their outstanding immune-regulatory capabilities, significant reparative functions, and good biocompatibility, they are leading innovations in the field of HIRI treatment. This article provides a systematic comparison of the therapeutic characteristics of MSC-derived exosomes(MSC-EXOs) from four different sources: adipose tissue, bone marrow, umbilical cord, and induced pluripotent stem cells. Although the clinical translation of MSC-EXOs still faces challenges such as variations in isolation methods, large-scale production, and safety assessments, their remarkable therapeutic effects and vast application potential signal the arrival of a new era of precision treatment for HIRI. This review not only provides a comprehensive theoretical foundation to promote the clinical application of MSC-EXOs but also opens up innovative research directions in the field of regenerative medicine.
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Affiliation(s)
- Bo Zhao
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Jiping Wei
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Zijian Jiang
- Yangtze University, Jingzhou, 434000, Hubei Province, P. R. China
| | - Yiming Long
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China
| | - Yan Xu
- School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, P. R. China
| | - Botao Jiang
- Department of Urology, Xianning Central Hospital, the First Affiliated Hospital of Hubei University of Science and Technology, 228 Jingui Road, Xian an District, Xianning, 437100, Hubei Province, P. R. China.
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Alahmari LA, Ali LS, Fansa HA, Alshaya DS, Al-Salmi FA, El-Hallous EI, Eldesoqui M, Gad Elsaid F, Fayad E, El-Mansy AA, Alsharif G, Khalil DY, Mahmood MB, Khalil RY, Rashwan HM, El-Sawah SG. Antioxidant and Antiapoptotic Effects of Selenium And Nano Selenium-Loaded Exosomes on Hepatic Dysfunction of Type 1 Diabetic Rats. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2025; 343:211-219. [PMID: 39535481 DOI: 10.1002/jez.2881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024]
Abstract
Mesenchymal stem cells-derived exosomes (MSCs-EXs) applications have brought a key breakthrough in treating type 1 diabetes mellitus (T1DM) and its diabetic complications. However, various recent strategies aimed to construct prominent engineered EXs with greater precision and higher efficiency for diabetes syndrome were conducted. In this research, we seek to enhance the medicinal potentialities of MSCs-EXs on type 1 diabetic rats' hepatic complications, via loading with either selenium (Se) or nano selenium (NSe) particles. For consecutive 4-weeks, rats were divided into 8 groups as; control, EXs, EXs + Se, EXs + NSe, STZ-diabetic (D), D + EXs, D + EXs + Se, and D + EXs + NSe groups. The three diabetic-treated groups manifested a significant reduction in hepatic contents of oxidative stress (OS) (MDA, NO, and H2O2) inflammatory (IL-6, TNF-α, and TGF-β), and apoptotic (P53, BAX, caspase-3, and Bcl2) markers, with marked elevation in hepatic antioxidant levels (GSH, GPX, SOD, and CAT). Such results were supported by the marked diminish in serum total proteins, liver function enzymes (AST, ALT, and bilirubin), and both serum and liver lipid profile fractions. In addition, hepatic histological examination showed marked improvement in liver architecture of all treated diabetic rats' groups, compared to diabetic untreated rats. Significantly, diabetic rats with EXs loaded with NSe exhibited the most therapeutic superiority.
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Affiliation(s)
- Layla A Alahmari
- Department of Community Health, College of Applied Medical Sciences, Northern Border University, Arar, Saudi Arabia
| | - Lashin S Ali
- Department of Basic Medical Science, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Physiology Department, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Hoda A Fansa
- Department of Basic Dental Sciences, Faculty of Dentistry, Al-Ahliyya Amman University, Amman, Jordan
- Department of Oral Biology, Faculty of Dentistry, Alexandria University, Egypt
| | - Dalal S Alshaya
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Fawziah A Al-Salmi
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ehab I El-Hallous
- Department of Biology, College of Science, Taif University, Taif, Saudi Arabia
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Mamdouh Eldesoqui
- Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Diriyah, Riyadh, Saudi Arabia
| | - Fahmy Gad Elsaid
- Department of Biology, College of Science, King Khalid University, Asir, Abha, Saudi Arabia
| | - Eman Fayad
- Department of Biotechnology, College of Science, Taif University, Taif, Saudi Arabia
| | - Ahmed A El-Mansy
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa, Jordan
- Department of Medical Histology & Cell Biology, Faculty of Medicine, Mansoura University, Mansours, Egypt
| | - Ghadi Alsharif
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud Bin Abdulaziz University of Health Sciences, Jeddah, Saudi Arabia
- Department of Biomedical Research, King Abdullah International Medical Research Center, Jeddah, Saudi Arabia
| | - Dlovan Y Khalil
- Biology Department, Faculty of Science, Sulaimani University, Sulaimaniyah, Iraq
| | - Maryam Bakir Mahmood
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Rozhan Yassin Khalil
- Obstetrics & Gynecology Department, College of Medicine, Slaimani University, Sulaymaniyah, Iraq
| | - Hanan M Rashwan
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Shady G El-Sawah
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
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Dong J, Luo Y, Gao Y. Therapeutic Potential of Stem Cell-Derived Extracellular Vesicles in Liver Injury. Biomedicines 2024; 12:2489. [PMID: 39595055 PMCID: PMC11591663 DOI: 10.3390/biomedicines12112489] [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: 08/22/2024] [Revised: 09/30/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Liver injury caused by various factors significantly impacts human health. Stem cell transplantation has potential for enhancing liver functionality, but safety concerns such as immune rejection, tumorigenesis, and the formation of emboli in the lungs remain. Recent studies have shown that stem cells primarily exert their effects through the secretion of extracellular vesicles (EVs). EVs have been shown to play crucial roles in reducing inflammation, preventing cell death, and promoting liver cell proliferation. Additionally, they can function as carriers to deliver targeted drugs to the liver, thereby exerting specific physiological effects. EVs possess several advantages, including structural stability, low immunogenicity, minimal tumorigenicity targeting capabilities, and convenient collection. Consequently, EVs have garnered significant attention from researchers and are expected to become alternative therapeutic agents to stem cell therapy. This article provides a comprehensive review of the current research progress in the use of stem cell-derived EVs in the treatment of liver injury.
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Affiliation(s)
- Jingjing Dong
- School of Medicine, Nankai University, Tianjin 300071, China;
| | - Ying Luo
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Institute of Hepatobiliary Disease, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China;
| | - Yingtang Gao
- Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin Institute of Hepatobiliary Disease, Nankai University Affiliated Third Center Hospital, Tianjin 300170, China;
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Wu L, Zhang L, Huang M, Wu Y, Jin S, Zhang Y, Gan X, Yu T, Yu G, Zhang J, Wang X. Mesenchymal Stem Cell-Derived Exosomes: Emerging as a Promising Cell-Free Therapeutic Strategy for Autoimmune Hepatitis. Biomolecules 2024; 14:1353. [PMID: 39595530 PMCID: PMC11592114 DOI: 10.3390/biom14111353] [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: 09/12/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 11/28/2024] Open
Abstract
Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently faces limited treatment options. In its advanced stages, AIH can progress to liver fibrosis and cirrhosis. Recent research has increasingly focused on cell-free therapies, particularly the use of mesenchymal stem cell (MSC)-derived exosomes (Exos), which have shown promise in treating autoimmune diseases, including AIH. MSC-Exos, as microvesicles with low immunogenicity, high safety, and permeability, can deliver RNA, DNA, proteins, lipids, and various drugs for disease treatment, showing promising clinical application prospects. This review provides a comprehensive summary of the current research on MSC-Exos in the treatment of autoimmune hepatitis (AIH) and explores the underlying molecular mechanisms involved. It highlights the significant regulatory effects of MSC-Exos on immune cells and their ability to modify the microenvironment, demonstrating anti-inflammatory and anti-fibrotic properties while promoting liver regeneration. Additionally, this review also discusses potential challenges and future strategies for advancing Exo-based therapies in the treatment of AIH.
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Affiliation(s)
- Liwen Wu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Longze Zhang
- Scientific Research Center, The Third Affiliated Hospital of Zunyi Medical University, Zunyi 563003, China
| | - Minglei Huang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yan Wu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Sikan Jin
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Yaqi Zhang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Xinyun Gan
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Ting Yu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Guang Yu
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Jidong Zhang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
| | - Xianyao Wang
- Department of Immunology, Zunyi Medical University, Zunyi 563003, China
- Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine, Zunyi Medical University, Zunyi 563000, China
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Abid AI, Conzatti G, Toti F, Anton N, Vandamme T. Mesenchymal stem cell-derived exosomes as cell free nanotherapeutics and nanocarriers. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2024; 61:102769. [PMID: 38914247 DOI: 10.1016/j.nano.2024.102769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/18/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Many strategies for regenerating the damaged tissues or degenerating cells are employed in regenerative medicine. Stem cell technology is a modern strategy of the recent approaches, particularly the use of mesenchymal stem cells (MCSs). The ability of MSCs to differentiate as well as their characteristic behaviour as paracrine effector has established them as key elements in tissue repair. Recently, extracellular vesicles (EVs) shed by MSCs have emerged as a promising cell free therapy. This comprehensive review encompasses MSCs-derived exosomes and their therapeutic potential as nanotherapeutics. We also discuss their potency as drug delivery nano-carriers in comparison with liposomes. A better knowledge of EVs behaviour in vivo and of their mechanism of action are key to determine parameters of an optimal formulation in pilot studies and to establish industrial processes.
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Affiliation(s)
- Ali Imran Abid
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France
| | - Guillaume Conzatti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
| | - Florence Toti
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Nicolas Anton
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France
| | - Thierry Vandamme
- UMR 1260, Regenerative Nanomedicine (RNM), INSERM (French National Institute of Health and Medical Research), University of Strasbourg, F-67000 Strasbourg, France; Faculty of Pharmacy, University of Strasbourg, 67400 Illkirch-Graffenstaden, France.
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Akabane M, Imaoka Y, Kawashima J, Endo Y, Schenk A, Sasaki K, Pawlik TM. Innovative Strategies for Liver Transplantation: The Role of Mesenchymal Stem Cells and Their Cell-Free Derivatives. Cells 2024; 13:1604. [PMID: 39404368 PMCID: PMC11475694 DOI: 10.3390/cells13191604] [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: 08/20/2024] [Revised: 09/11/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
Despite being the standard treatment for end-stage liver disease, liver transplantation has limitations like donor scarcity, high surgical costs, and immune rejection risks. Mesenchymal stem cells (MSCs) and their derivatives offer potential for liver regeneration and transplantation. MSCs, known for their multipotency, low immunogenicity, and ease of obtainability, can differentiate into hepatocyte-like cells and secrete bioactive factors that promote liver repair and reduce immune rejection. However, the clinical application of MSCs is limited by risks such as aberrant differentiation and low engraftment rates. As a safer alternative, MSC-derived secretomes and extracellular vesicles (EVs) offer promising therapeutic benefits, including enhanced graft survival, immunomodulation, and reduced ischemia-reperfusion injury. Current research highlights the efficacy of MSC-derived therapies in improving liver transplant outcomes, but further studies are necessary to standardize clinical applications. This review highlights the potential of MSCs and EVs to address key challenges in liver transplantation, paving the way for innovative therapeutic strategies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Yutaka Endo
- Department of Transplant Surgery, University of Rochester Medical Center, Rochester, NY 14642, USA;
| | - Austin Schenk
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
| | - Kazunari Sasaki
- Division of Abdominal Transplant, Department of Surgery, Stanford University, Stanford, CA 94305, USA; (Y.I.); (K.S.)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH 43210, USA; (M.A.); (J.K.); (A.S.)
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [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: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Guo N, Wang Y, Wen Z, Fan X. Promising nanotherapeutics of stem cell extracellular vesicles in liver regeneration. Regen Ther 2024; 26:1037-1047. [PMID: 39569342 PMCID: PMC11576938 DOI: 10.1016/j.reth.2024.09.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Revised: 09/22/2024] [Accepted: 09/26/2024] [Indexed: 11/22/2024] Open
Abstract
Extracellular vesicles (EVs) have gainedsignificant attention due totheir crucialroles invarious biological systems. This review aims to explore the functions of EVs in both in physiological and pathological states of the liver, with a specific focus on the potential mechanisms and concrete evidence of EVs in liver regeneration processes. The review begins by emphasizing the importance of EVs in maintaining liver health and their involvement in different pathological conditions, starting from the liver's own EVs. Reviewing the role of EVs in liver diseases to reveal the impact of EVs in pathological processes (e.g., hepatitis, liver fibrosis, and cirrhosis) and elucidate their signaling functions at the molecular level. Subsequently, the work concentrates on the functions of EVs in liver regeneration, revealing their key role in repair and regeneration following liver injury by carrying growth factors, nucleic acids, and other bioactive molecules. This part not only theoretically clarifies the mechanisms of EVs in liver regeneration but also experimentally demonstrates their role in promoting liver cell proliferation, inhibiting apoptosis, regulating immune responses, and fostering angiogenesis, laying the groundwork for future clinical applications. Moreover, this work provides a comprehensive analysis of the challenges faced by existing EV-based therapies in liver regeneration and offers prospects for future research directions. It highlights that despite the tremendous potential of EVs in treating liver diseases, there are still technical challenges (e.g., EV isolation and purification, dosage control, and targeted delivery). To overcome these challenges, the review suggests improvements to current technologies and the development of new methods to realize the clinical application of EVs in treating liver diseases.
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Affiliation(s)
- Na Guo
- Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Hexi Yuelu District, Changsha, Hunan, 410000, China
| | - Yan Wang
- Department of Basic Medicine, Cangzhou Medical College, No.39, West Jiuhe Road, Cangzhou, 061001, China
| | - Zhaofeng Wen
- Heze Medical College, No.1950, Daxue Road, Heze Shandong, 274000, China
| | - Xiaofei Fan
- Shandong Medical College, No.5460, Second Ring South Road, Jinan, Shandong, 250002, China
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Nojima H, Shimizu H, Murakami T, Shuto K, Koda K. Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy. Cancers (Basel) 2024; 16:850. [PMID: 38473211 DOI: 10.3390/cancers16050850] [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: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.
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Affiliation(s)
- Hiroyuki Nojima
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Hiroaki Shimizu
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Takashi Murakami
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
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10
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Tan F, Li X, Wang Z, Li J, Shahzad K, Zheng J. Clinical applications of stem cell-derived exosomes. Signal Transduct Target Ther 2024; 9:17. [PMID: 38212307 PMCID: PMC10784577 DOI: 10.1038/s41392-023-01704-0] [Citation(s) in RCA: 172] [Impact Index Per Article: 172.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 10/15/2023] [Accepted: 11/12/2023] [Indexed: 01/13/2024] Open
Abstract
Although stem cell-based therapy has demonstrated considerable potential to manage certain diseases more successfully than conventional surgery, it nevertheless comes with inescapable drawbacks that might limit its clinical translation. Compared to stem cells, stem cell-derived exosomes possess numerous advantages, such as non-immunogenicity, non-infusion toxicity, easy access, effortless preservation, and freedom from tumorigenic potential and ethical issues. Exosomes can inherit similar therapeutic effects from their parental cells such as embryonic stem cells and adult stem cells through vertical delivery of their pluripotency or multipotency. After a thorough search and meticulous dissection of relevant literature from the last five years, we present this comprehensive, up-to-date, specialty-specific and disease-oriented review to highlight the surgical application and potential of stem cell-derived exosomes. Exosomes derived from stem cells (e.g., embryonic, induced pluripotent, hematopoietic, mesenchymal, neural, and endothelial stem cells) are capable of treating numerous diseases encountered in orthopedic surgery, neurosurgery, plastic surgery, general surgery, cardiothoracic surgery, urology, head and neck surgery, ophthalmology, and obstetrics and gynecology. The diverse therapeutic effects of stem cells-derived exosomes are a hierarchical translation through tissue-specific responses, and cell-specific molecular signaling pathways. In this review, we highlight stem cell-derived exosomes as a viable and potent alternative to stem cell-based therapy in managing various surgical conditions. We recommend that future research combines wisdoms from surgeons, nanomedicine practitioners, and stem cell researchers in this relevant and intriguing research area.
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Affiliation(s)
- Fei Tan
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China.
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China.
- The Royal College of Surgeons in Ireland, Dublin, Ireland.
- The Royal College of Surgeons of England, London, UK.
| | - Xuran Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Zhao Wang
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
| | - Jiaojiao Li
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Khawar Shahzad
- Department of ORL-HNS, Shanghai Fourth People's Hospital, and School of Medicine, Tongji University, Shanghai, China
- Plasma Medicine and Surgical Implants Center, Tongji University, Shanghai, China
| | - Jialin Zheng
- Center for Translational Neurodegeneration and Regenerative Therapy, Tongji Hospital affiliated to Tongji University School of Medicine, Shanghai, China
- Shanghai Frontiers Science Center of Nanocatalytic Medicine, Tongji University, Shanghai, China
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11
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He S, Su L, Hu H, Liu H, Xiong J, Gong X, Chi H, Wu Q, Yang G. Immunoregulatory functions and therapeutic potential of natural killer cell-derived extracellular vesicles in chronic diseases. Front Immunol 2024; 14:1328094. [PMID: 38239346 PMCID: PMC10795180 DOI: 10.3389/fimmu.2023.1328094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 12/11/2023] [Indexed: 01/22/2024] Open
Abstract
Extracellular vesicles (EVs) have been proven to play a significant immunoregulatory role in many chronic diseases, such as cancer and immune disorders. Among them, EVs derived from NK cells are an essential component of the immune cell functions. These EVs have been demonstrated to carry a variety of toxic proteins and nucleic acids derived from NK cells and play a therapeutic role in diseases like malignancies, liver fibrosis, and lung injury. However, natural NK-derived EVs (NKEVs) have certain limitations in disease treatment, such as low yield and poor targeting. Concurrently, NK cells exhibit characteristics of memory-like NK cells, which have stronger proliferative capacity, increased IFN-γ production, and enhanced cytotoxicity, making them more advantageous for disease treatment. Recent research has shifted its focus towards engineered extracellular vesicles and their potential to improve the efficiency, specificity, and safety of disease treatments. In this review, we will discuss the characteristics of NK-derived EVs and the latest advancements in disease therapy. Specifically, we will compare different cellular sources of NKEVs and explore the current status and prospects of memory-like NK cell-derived EVs and engineered NKEVs.
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Affiliation(s)
- Shuang He
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Haiyang Hu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Haiqi Liu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Jingwen Xiong
- Department of Sports Rehabilitation, Southwest Medical University, Luzhou, China
| | - Xiangjin Gong
- Department of Sports Rehabilitation, Southwest Medical University, Luzhou, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Qibiao Wu
- Faculty of Chinese Medicine, and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, Macao SAR, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
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12
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Zheng L, Gong H, Zhang J, Guo L, Zhai Z, Xia S, Hu Z, Chang J, Jiang Y, Huang X, Ge J, Zhang B, Yan M. Strategies to improve the therapeutic efficacy of mesenchymal stem cell-derived extracellular vesicle (MSC-EV): a promising cell-free therapy for liver disease. Front Bioeng Biotechnol 2023; 11:1322514. [PMID: 38155924 PMCID: PMC10753838 DOI: 10.3389/fbioe.2023.1322514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 11/29/2023] [Indexed: 12/30/2023] Open
Abstract
Liver disease has emerged as a significant worldwide health challenge due to its diverse causative factors and therapeutic complexities. The majority of liver diseases ultimately progress to end-stage liver disease and liver transplantation remains the only effective therapy with the limitations of donor organ shortage, lifelong immunosuppressants and expensive treatment costs. Numerous pre-clinical studies have revealed that extracellular vesicles released by mesenchymal stem cells (MSC-EV) exhibited considerable potential in treating liver diseases. Although natural MSC-EV has many potential advantages, some characteristics of MSC-EV, such as heterogeneity, uneven therapeutic effect, and rapid clearance in vivo constrain its clinical translation. In recent years, researchers have explored plenty of ways to improve the therapeutic efficacy and rotation rate of MSC-EV in the treatment of liver disease. In this review, we summarized current strategies to enhance the therapeutic potency of MSC-EV, mainly including optimization culture conditions in MSC or modifications of MSC-EV, aiming to facilitate the development and clinical application of MSC-EV in treating liver disease.
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Affiliation(s)
- Lijuan Zheng
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Hui Gong
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Zhang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Linna Guo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhuofan Zhai
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Shuang Xia
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Zhiyu Hu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Jing Chang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Yizhu Jiang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Xinran Huang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Jingyi Ge
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
| | - Miao Yan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Changsha, China
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13
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Zhang C, Zhou X, Wang D, Hao L, Zeng Z, Su L. Hydrogel-Loaded Exosomes: A Promising Therapeutic Strategy for Musculoskeletal Disorders. J Clin Pharm Ther 2023; 2023:1-36. [DOI: 10.1155/2023/1105664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2024]
Abstract
Clinical treatment strategies for musculoskeletal disorders have been a hot research topic. Accumulating evidence suggests that hydrogels loaded with MSC-derived EVs show great potential in improving musculoskeletal injuries. The ideal hydrogels should be capable of promoting the development of new tissues and simulating the characteristics of target tissues, with the properties matching the cell-matrix constituents of autologous tissues. Although there have been numerous reports of hydrogels loaded with MSC-derived EVs for the repair of musculoskeletal injuries, such as intervertebral disc injury, tendinopathy, bone fractures, and cartilage injuries, there are still many hurdles to overcome before the clinical application of modified hydrogels. In this review, we focus on the advantages of the isolation technique of EVs in combination with different types of hydrogels. In this context, the efficacy of hydrogels loaded with MSC-derived EVs in different musculoskeletal injuries is discussed in detail to provide a reference for the future application of hydrogels loaded with MSC-derived EVs in the clinical treatment of musculoskeletal injuries.
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Affiliation(s)
- Chunyu Zhang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Xuchang Zhou
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Dongxue Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Li Hao
- Shougang Technician College, Nursing School, Beijing 100043, China
- Department of Rehabilitation, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510000, China
| | - Zhipeng Zeng
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
- Shougang Technician College, Nursing School, Beijing 100043, China
- Department of Rehabilitation, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510000, China
| | - Lei Su
- Department of Rehabilitation, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510000, China
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14
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Li H, Lin W, Zhang G, Liu R, Qu M, Zhang J, Xing X. BMSC-exosomes miR-25-3p Regulates the p53 Signaling Pathway Through PTEN to Inhibit Cell Apoptosis and Ameliorate Liver Ischemia‒reperfusion Injury. Stem Cell Rev Rep 2023; 19:2820-2836. [PMID: 37594613 DOI: 10.1007/s12015-023-10599-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2023] [Indexed: 08/19/2023]
Abstract
BACKGROUND Hepatic ischemia‒reperfusion injury (HIRI) is a pathological phenomenon during liver surgery, and bone marrow-mesenchymal stem cell (BMSC) exosomes (BMSC-Exos) regulate cell apoptosis and reduce ischemia‒reperfusion injury. We aimed to investigate the roles of BMSC-Exos and miR-25b-3p (enriched in BMSC-Exos) in HIRI and elucidate the underlying mechanisms. APPROACHES AND RESULTS An HIRI mouse model was constructed and preinjected with BMSC-Exos, agomir-miR-25, agomir-miR-NC, or PBS via the tail vein. Compared with mice with HIRI, mice with HIRI preinjected with BMSC-Exos had significantly decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and alleviated liver necrosis (P < 0.05). Quantitative hepatic transcriptomics showed that mice with HIRI preinjected with BMSC-Exos exhibited increased cell division, hematopoietic or lymphoid organ development and metabolic processes. miRNA sequencing of BMSC-Exos revealed that miR-25, which is related to I/R injury, was enriched in the exosomes. Compared with HIRI + NC mice, HIRI + miR-25b-3p mice had significantly increased miR-25b-3p expression, decreased ALT/AST levels and apoptosis-related protein expression (P < 0.05), and alleviated liver necrosis. The proliferation of AML-12 cells transfected with miR-25b-3p was significantly higher than that in the mimic NC group (P < 0.01) after hypoxia induction, and the apoptosis rate of cells was significantly lower than that in the NC group (P < 0.01). PTEN was identified as a miR-25b-3p target gene. PTEN expression was significantly diminished in miR-25b-3p-transfected AML12 cells (P < 0.05). HIRI + agomir-miR-25 mice displayed reduced PTEN expression and decreased p53 and cleaved caspase 3 levels compared to HIRI + NC mice. CONCLUSIONS We revealed the roles and underlying mechanisms of BMSC-Exos and miR-25 in HIRI, contributing to the prevention and treatment of HIRI.
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Affiliation(s)
- Hongnan Li
- Department of Public Health, Guilin Medical University, Zhiyuan Rd, Lingui District, Guilin, 541199, Guangxi, China
| | - Weidong Lin
- School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Guangzhi Zhang
- Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing, 100193, China
| | - Runsheng Liu
- Department of Public Health, Guilin Medical University, Zhiyuan Rd, Lingui District, Guilin, 541199, Guangxi, China
| | - Minghai Qu
- Department of Public Health, Guilin Medical University, Zhiyuan Rd, Lingui District, Guilin, 541199, Guangxi, China
| | - Jiayang Zhang
- Department of Public Health, Guilin Medical University, Zhiyuan Rd, Lingui District, Guilin, 541199, Guangxi, China
| | - Xuekun Xing
- Department of Public Health, Guilin Medical University, Zhiyuan Rd, Lingui District, Guilin, 541199, Guangxi, China.
- Guangxi Key Laboratory of Environmental Exposomics and Entire Lifecycle Health Research, Guilin Medical University, Guilin, 541199, Guangxi, China.
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15
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Zhou AK, Jou E, Lu V, Zhang J, Chabra S, Abishek J, Wong E, Zeng X, Guo B. Using Pre-Clinical Studies to Explore the Potential Clinical Uses of Exosomes Secreted from Induced Pluripotent Stem Cell-Derived Mesenchymal Stem cells. Tissue Eng Regen Med 2023; 20:793-809. [PMID: 37651091 PMCID: PMC10519927 DOI: 10.1007/s13770-023-00557-6] [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: 03/19/2023] [Revised: 05/09/2023] [Accepted: 05/16/2023] [Indexed: 09/01/2023] Open
Abstract
Recent studies of exosomes derived from mesenchymal stem cells (MSCs) have indicated high potential clinical applications in many diseases. However, the limited source of MSCs impedes their clinical research and application. Most recently, induced pluripotent stem cells (iPSCs) have become a promising source of MSCs. Exosome therapy based on iPSC-derived MSCs (iMSCs) is a novel technique with much of its therapeutic potential untapped. Compared to MSCs, iMSCs have proved superior in cell proliferation, immunomodulation, generation of exosomes capable of controlling the microenvironment, and bioactive paracrine factor secretion, while also theoretically eliminating the dependence on immunosuppression drugs. The therapeutic effects of iMSC-derived exosomes are explored in many diseases and are best studied in wound healing, cardiovascular disease, and musculoskeletal pathology. It is pertinent clinicians have a strong understanding of stem cell therapy and the latest advances that will eventually translate into clinical practice. In this review, we discuss the various applications of exosomes derived from iMSCs in clinical medicine.
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Affiliation(s)
- Andrew Kailin Zhou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- Watford General Hospital, London, UK
| | - Eric Jou
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Victor Lu
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - James Zhang
- Addenbrookes Major Trauma Unit, Department of Trauma And Orthopaedics, Cambridge University Hospitals, Cambridge, UK
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | - Shirom Chabra
- School Of Clinical Medicine, University Of Cambridge, Cambridge, UK
| | | | | | - Xianwei Zeng
- Beijing Rehabilitation Hospital Affiliated to National Research Centre for Rehabilitation Technical Aids, Ministry of Civil Affairs of China, Beijing, China.
- Weifang People's Hospital, Weifang City, Shandong Province, China.
| | - Baoqiang Guo
- Department of Life Science, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, UK.
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16
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Blondeel J, Gilbo N, De Bondt S, Monbaliu D. Stem cell Derived Extracellular Vesicles to Alleviate ischemia-reperfusion Injury of Transplantable Organs. A Systematic Review. Stem Cell Rev Rep 2023; 19:2225-2250. [PMID: 37548807 DOI: 10.1007/s12015-023-10573-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2023] [Indexed: 08/08/2023]
Abstract
BACKGROUND The possible beneficial effects of stem cell-derived EV on ischemia-reperfusion injury (IRI) in organ transplantation have been frequently investigated; however, the source of EV, as well as the methods of isolation and administration vary widely. We conducted a systematic review to summarize current pre-clinical evidence on stem cell-derived EV therapy for IRI of transplantable organs. METHODS PubMed, Embase and Web of Science were searched from inception until August 19th, 2022, for studies on stem cell-derived EV therapy for IRI after heart, kidney, liver, pancreas, lung and intestine transplantation. The Systematic Review Center for Laboratory animal Experiments (SYRCLE) guidelines were followed to assess potential risk of bias. RESULTS The search yielded 4153 unique articles, of which 96 were retained. We identified 32 studies on cardiac IRI, 38 studies on renal IRI, 21 studies on liver IRI, four studies on lung IRI and one study on intestinal IRI. Most studies used rodent models of transient ischemic injury followed by in situ reperfusion. In all studies, EV therapy was associated with improved outcome albeit to a variable degree. EV-therapy reduced organ injury and improved function while displaying anti-inflammatory-, immunomodulatory- and pro-regenerative properties. CONCLUSION A multitude of animal studies support the potential of stem cell-derived EV-therapy to alleviate IRI after solid organ transplantation but suffer from low reporting quality and wide methodological variability. Future studies should focus on determining optimal stem cell source, dosage, and timing of treatment, as well as long-term efficacy in transplant models.
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Affiliation(s)
- Joris Blondeel
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Transplant Surgery and Coordination, University Hospitals Leuven, Herestraat 49, Leuven, 3000, Belgium
| | - Nicholas Gilbo
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium
- Department of Abdominal Surgery and Transplantation, CHU Liege, Liege, Belgium
| | | | - Diethard Monbaliu
- Department of Microbiology, Immunology and Transplantation, Laboratory of Abdominal Transplantation, KU Leuven, Leuven, Belgium.
- Department of Abdominal Transplant Surgery and Coordination, University Hospitals Leuven, Herestraat 49, Leuven, 3000, Belgium.
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17
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Ma L, Wu Q, Tam PKH. The Current Proceedings of PSC-Based Liver Fibrosis Therapy. Stem Cell Rev Rep 2023; 19:2155-2165. [PMID: 37490204 DOI: 10.1007/s12015-023-10592-4] [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] [Accepted: 07/12/2023] [Indexed: 07/26/2023]
Abstract
Liver fibrosis was initially considered to be an irreversible process which will eventually lead to the occurrence of liver cancer. So far there has been no effective therapeutic approach to treat liver fibrosis although scientists have put tremendous efforts into the underlying mechanisms of this disease. Therefore, in-depth research on novel and safe treatments of liver fibrosis is of great significance to human health. Pluripotent stem cells (PSCs) play important roles in the study of liver fibrosis due to their unique features in self-renewal ability, pluripotency, and paracrine function. This article mainly reviews the applications of PSCs in the study of liver fibrosis in recent years. We discuss the role of PSC-derived liver organoids in the study of liver fibrosis, and the latest research advances on the differentiation of PSCs into hepatocytes or macrophages. We also highlight the importance of exosomes of PSCs for the treatment of liver fibrosis.
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Affiliation(s)
- Li Ma
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, China
| | - Qiang Wu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, China.
| | - Paul Kwong-Hang Tam
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China.
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18
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Dos Santos Bronel BA, Maquigussa E, Boim MA, da Silva Novaes A. Effect of extracellular vesicles derived from induced pluripotent stem cells on mesangial cells underwent a model of fibrosis in vitro. Sci Rep 2023; 13:15749. [PMID: 37735602 PMCID: PMC10514265 DOI: 10.1038/s41598-023-42912-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/15/2023] [Indexed: 09/23/2023] Open
Abstract
The fibrogenic process plays a significant pathophysiological role in the progression of chronic kidney disease. Inhibition of the renin-angiotensin system (RAS) is one strategy to delay disease progression but does not reverse established fibrosis. In this context, induced pluripotent stem cells (iPSCs) have been considered an alternative due to their regenerative potential. iPSCs exert their effects through paracrine signaling, which releases specific biomolecules into the extracellular environment, either directly or within extracellular vesicle (EVs), that can reach target cells. This study aims to evaluate the potential beneficial effects of iPSC-derived EVs (EV-iPSCs) in an in vitro model of fibrosis using mouse mesangial cells (MMCs) stimulated with TGF-β. EV-iPSCs were obtained by differentially ultracentrifuging iPSCs culture medium. MMCs were stimulated with 5 ng/mL of TGF-β and simultaneously treated with or without EV-iPSCs for 24 h. Markers of inflammation, fibrosis, and RAS components were assessed using RT-PCR, western blotting, and immunofluorescence. Under TGF-β stimulus, MMCs exhibited increased expression of inflammation markers, RAS components, and fibrosis. However, these changes were mitigated in the presence of EV-iPSCs. EV-iPSCs effectively reduced inflammation, RAS activation, and fibrogenesis in this fibrosis model involving mesangial cells, suggesting their potential as a strategy to reduce glomerular sclerosis.
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Affiliation(s)
- Bruno Aristides Dos Santos Bronel
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, 781 Pedro de Toledo St, 13° Floor, São Paulo, SP, 04039-032, Brazil
| | - Edgar Maquigussa
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, 781 Pedro de Toledo St, 13° Floor, São Paulo, SP, 04039-032, Brazil
| | - Mirian Aparecida Boim
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, 781 Pedro de Toledo St, 13° Floor, São Paulo, SP, 04039-032, Brazil
| | - Antônio da Silva Novaes
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, 781 Pedro de Toledo St, 13° Floor, São Paulo, SP, 04039-032, Brazil.
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19
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De Stefano N, Calleri A, Faini AC, Navarro-Tableros V, Martini S, Deaglio S, Patrono D, Romagnoli R. Extracellular Vesicles in Liver Transplantation: Current Evidence and Future Challenges. Int J Mol Sci 2023; 24:13547. [PMID: 37686354 PMCID: PMC10488298 DOI: 10.3390/ijms241713547] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/24/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Extracellular vesicles (EVs) are emerging as a promising field of research in liver disease. EVs are small, membrane-bound vesicles that contain various bioactive molecules, such as proteins, lipids, and nucleic acids and are involved in intercellular communication. They have been implicated in numerous physiological and pathological processes, including immune modulation and tissue repair, which make their use appealing in liver transplantation (LT). This review summarizes the current state of knowledge regarding the role of EVs in LT, including their potential use as biomarkers and therapeutic agents and their role in graft rejection. By providing a comprehensive insight into this emerging topic, this research lays the groundwork for the potential application of EVs in LT.
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Affiliation(s)
- Nicola De Stefano
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
| | - Alberto Calleri
- Gastrohepatology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.); (S.M.)
| | - Angelo Corso Faini
- Immunogenetics and Transplant Biology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.F.); (S.D.)
| | - Victor Navarro-Tableros
- 2i3T, Società Per La Gestione Dell’incubatore Di Imprese e Per Il Trasferimento Tecnologico, University of Turin, 10126 Turin, Italy;
| | - Silvia Martini
- Gastrohepatology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.); (S.M.)
| | - Silvia Deaglio
- Immunogenetics and Transplant Biology Unit, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, 10126 Turin, Italy; (A.C.F.); (S.D.)
| | - Damiano Patrono
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
| | - Renato Romagnoli
- General Surgery 2U-Liver Transplant Unit, Department of Surgical Sciences, Azienda Ospedaliero Universitaria Città Della Salute e Della Scienza Di Torino, University of Turin, Corso Bramante 88-90, 10126 Turin, Italy; (N.D.S.); (R.R.)
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20
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Chiou SH, Ong HKA, Chou SJ, Aldoghachi AF, Loh JK, Verusingam ND, Yang YP, Chien Y. Current trends and promising clinical utility of IPSC-derived MSC (iMSC). PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 199:131-154. [PMID: 37678969 DOI: 10.1016/bs.pmbts.2023.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/09/2023]
Abstract
Mesenchymal stem cells (MSCs) differentiated from human induced pluripotent stem cells (iPSC) or induced MSC (iMSCs) are expected to address issues of scalability and safety as well as the difficulty in producing homogenous clinical grade MSCs as demonstrated by the promising outcomes from preclinical and clinical trials, currently ongoing. The assessment of iMSCs based in vitro and in vivo studies have thus far showed more superior performance as compared to that of the primary or native human MSCs, in terms of cell proliferation, expansion capacity, immunomodulation properties as well as the influence of paracrine signaling and exosomal influence in cell-cell interaction. In this chapter, an overview of current well-established methods in generating a sustainable source of iMSCs involving well defined culture media is discussed followed by the properties of iMSC as compared to that of MSC and its promising prospects for continuous development into potential clinical grade applications.
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Affiliation(s)
- Shih-Hwa Chiou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - Han Kiat Alan Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Shih-Jie Chou
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
| | - A F Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Nalini Devi Verusingam
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Yi-Ping Yang
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan.
| | - Yueh Chien
- Department of Medical Research, Taipei Veteran General Hospital, Taipei, Taiwan
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21
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Sitbon A, Delmotte PR, Goumard C, Turco C, Gautheron J, Conti F, Aoudjehane L, Scatton O, Monsel A. Therapeutic potentials of mesenchymal stromal cells-derived extracellular vesicles in liver failure and marginal liver graft rehabilitation: a scoping review. Minerva Anestesiol 2023; 89:690-706. [PMID: 37079286 DOI: 10.23736/s0375-9393.23.17265-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/21/2023]
Abstract
Liver failure includes distinct subgroups of diseases: Acute liver failure (ALF) without preexisting cirrhosis, acute-on-chronic liver failure (ACLF) (severe form of cirrhosis associated with organ failures and excess mortality), and liver fibrosis (LF). Inflammation plays a key role in ALF, LF, and more specifically in ACLF for which we have currently no treatment other than liver transplantation (LT). The increasing incidence of marginal liver grafts and the shortage of liver grafts require us to consider strategies to increase the quantity and quality of available liver grafts. Mesenchymal stromal cells (MSCs) have shown beneficial pleiotropic properties with limited translational potential due to the pitfalls associated with their cellular nature. MSC-derived extracellular vesicles (MSC-EVs) are innovative cell-free therapeutics for immunomodulation and regenerative purposes. MSC-EVs encompass further advantages: pleiotropic effects, low immunogenicity, storage stability, good safety profile, and possibility of bioengineering. Currently, no human studies explored the impact of MSC-EVs on liver disease, but several preclinical studies highlighted their beneficial effects. In ALF and ACLF, data showed that MSC-EVs attenuate hepatic stellate cells activation, exert antioxidant, anti-inflammatory, anti-apoptosis, anti-ferroptosis properties, and promote regeneration of the liver, autophagy, and improve metabolism through mitochondrial function recovery. In LF, MSC-EVs demonstrated anti-fibrotic properties associated with liver tissue regeneration. Normothermic-machine perfusion (NMP) combined with MSC-EVs represents an attractive therapy to improve liver regeneration before LT. Our review suggests a growing interest in MSC-EVs in liver failure and gives an appealing insight into their development to rehabilitate marginal liver grafts through NMP.
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Affiliation(s)
- Alexandre Sitbon
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France -
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France -
| | - Pierre-Romain Delmotte
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Claire Goumard
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Célia Turco
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Liver Transplantation Unit, Department of Digestive and Oncologic Surgery, University Hospital of Besançon, Besançon, France
| | - Jérémie Gautheron
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
| | - Filomena Conti
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Lynda Aoudjehane
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- IHU-Innovation of Cardiometabolism and Nutrition (ICAN), INSERM, Sorbonne University, Paris, France
| | - Olivier Scatton
- UMRS-938, Research Center of Saint-Antoine (CRSA), Sorbonne University, Paris, France
- Department of Digestive, Hepatobiliary Surgery and Liver Transplantation, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Sorbonne University, Paris, France
- INSERM UMRS-959 Immunology-Immunopathology-Immunotherapy (I3), Sorbonne University, Paris, France
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22
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Parthasarathy G, Hirsova P, Kostallari E, Sidhu GS, Ibrahim SH, Malhi H. Extracellular Vesicles in Hepatobiliary Health and Disease. Compr Physiol 2023; 13:4631-4658. [PMID: 37358519 PMCID: PMC10798368 DOI: 10.1002/cphy.c210046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
Extracellular vesicles (EVs) are membrane-bound nanoparticles released by cells and are an important means of intercellular communication in physiological and pathological states. We provide an overview of recent advances in the understanding of EV biogenesis, cargo selection, recipient cell effects, and key considerations in isolation and characterization techniques. Studies on the physiological role of EVs have relied on cell-based model systems due to technical limitations of studying endogenous nanoparticles in vivo . Several recent studies have elucidated the mechanistic role of EVs in liver diseases, including nonalcoholic fatty liver disease, viral hepatitis, cholestatic liver disease, alcohol-associated liver disease, acute liver injury, and liver cancers. Employing disease models and human samples, the biogenesis of lipotoxic EVs downstream of endoplasmic reticulum stress and microvesicles via intracellular activation stress signaling are discussed in detail. The diverse cargoes of EVs including proteins, lipids, and nucleic acids can be enriched in a disease-specific manner. By carrying diverse cargo, EVs can directly confer pathogenic potential, for example, recruitment and activation of monocyte-derived macrophages in NASH and tumorigenicity and chemoresistance in hepatocellular carcinoma. We discuss the pathogenic role of EVs cargoes and the signaling pathways activated by EVs in recipient cells. We review the literature that EVs can serve as biomarkers in hepatobiliary diseases. Further, we describe novel approaches to engineer EVs to deliver regulatory signals to specific cell types, and thus use them as therapeutic shuttles in liver diseases. Lastly, we identify key lacunae and future directions in this promising field of discovery and development. © 2023 American Physiological Society. Compr Physiol 13:4631-4658, 2023.
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Affiliation(s)
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Guneet S. Sidhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Samar H. Ibrahim
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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23
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Lu X, Guo H, Wei X, Lu D, Shu W, Song Y, Qiu N, Xu X. Current Status and Prospect of Delivery Vehicle Based on Mesenchymal Stem Cell-Derived Exosomes in Liver Diseases. Int J Nanomedicine 2023; 18:2873-2890. [PMID: 37283714 PMCID: PMC10239634 DOI: 10.2147/ijn.s404925] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 05/10/2023] [Indexed: 06/08/2023] Open
Abstract
With the improvement of the average life expectancy and increasing incidence of obesity, the burden of liver disease is increasing. Liver disease is a serious threat to human health. Currently, liver transplantation is the only effective treatment for end-stage liver disease. However, liver transplantation still faces unavoidable difficulties. Mesenchymal stem cells (MSCs) can be used as an alternative therapy for liver disease, especially liver cirrhosis, liver failure, and liver transplantation complications. However, MSCs may have potential tumorigenic effects. Exosomes derived from MSCs (MSC-Exos), as the important intercellular communication mode of MSCs, contain various proteins, nucleic acids, and DNA. MSC-Exos can be used as a delivery system to treat liver diseases through immune regulation, apoptosis inhibition, regeneration promotion, drug delivery, and other ways. Good histocompatibility and material exchangeability make MSC-Exos a new treatment for liver diseases. This review summarizes the latest research on MSC-Exos as delivery vehicles in different liver diseases, including liver injury, liver failure, liver fibrosis, hepatocellular carcinoma (HCC), and ischemia and reperfusion injury. In addition, we discuss the advantages, disadvantages, and clinical application prospects of MSC-Exos-based delivery vectors in the treatment of liver diseases.
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Affiliation(s)
- Xinfeng Lu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Haijun Guo
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Xuyong Wei
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Di Lu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
| | - Wenzhi Shu
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Yisu Song
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
| | - Nasha Qiu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
| | - Xiao Xu
- The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310000, People’s Republic of China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, People’s Republic of China
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, People’s Republic of China
- Zhejiang University School of Medicine, Hangzhou, 310058, People’s Republic of China
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24
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Wang DR, Pan J. Extracellular vesicles: Emerged as a promising strategy for regenerative medicine. World J Stem Cells 2023; 15:165-181. [PMID: 37181006 PMCID: PMC10173817 DOI: 10.4252/wjsc.v15.i4.165] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/30/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023] Open
Abstract
Cell transplantation therapy has certain limitations including immune rejection and limited cell viability, which seriously hinder the transformation of stem cell-based tissue regeneration into clinical practice. Extracellular vesicles (EVs) not only possess the advantages of its derived cells, but also can avoid the risks of cell transplantation. EVs are intelligent and controllable biomaterials that can participate in a variety of physiological and pathological activities, tissue repair and regeneration by transmitting a variety of biological signals, showing great potential in cell-free tissue regeneration. In this review, we summarized the origins and characteristics of EVs, introduced the pivotal role of EVs in diverse tissues regeneration, discussed the underlying mechanisms, prospects, and challenges of EVs. We also pointed out the problems that need to be solved, application directions, and prospects of EVs in the future and shed new light on the novel cell-free strategy for using EVs in the field of regenerative medicine.
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Affiliation(s)
- Dian-Ri Wang
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jian Pan
- State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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25
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Aldoghachi AF, Loh JK, Wang ML, Yang YP, Chien CS, Teh HX, Omar AH, Cheong SK, Yeap SK, Ho WY, Ong AHK. Current developments and therapeutic potentials of exosomes from induced pluripotent stem cells-derived mesenchymal stem cells. J Chin Med Assoc 2023; 86:356-365. [PMID: 36762931 DOI: 10.1097/jcma.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent cells derived from adult human tissues that have the ability to proliferate in vitro and maintain their multipotency, making them attractive cell sources for regenerative medicine. However, MSCs reportedly show limited proliferative capacity with inconsistent therapeutic outcomes due to their heterogeneous nature. On the other hand, induced pluripotent stem cells (iPSC) have emerged as an alternative source for the production of various specialized cell types via their ability to differentiate from all three primary germ layers, leading to applications in regenerative medicine, disease modeling, and drug therapy. Notably, iPSCs can differentiate into MSCs in monolayer, commonly referred to as induced mesenchymal stem cells (iMSCs). These cells show superior therapeutic qualities compared with adult MSCs as the applications of the latter are restricted by passage number and autoimmune rejection when applied in tissue regeneration trials. Furthermore, increasing evidence shows that the therapeutic properties of stem cells are a consequence of the paracrine effects mediated by their secretome such as from exosomes, a type of extracellular vesicle secreted by most cell types. Several studies that investigated the potential of exosomes in regenerative medicine and therapy have revealed promising results. Therefore, this review focuses on the recent findings of exosomes secreted from iMSCs as a potential noncell-based therapy.
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Affiliation(s)
- Ahmed Faris Aldoghachi
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Jit-Kai Loh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Mong-Lien Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ping Yang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chian-Shiu Chien
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hui Xin Teh
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
| | - Alfaqih Hussain Omar
- Biomedicine Programme, School of Health Sciences, Universiti Sains Malaysia, Malaysia
| | - Soon-Keng Cheong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
- National Cancer Council (MAKNA), Kuala Lumpur, Malaysia
| | - Swee Keong Yeap
- Marine Biotechnology, China-ASEAN College of Marine Sciences, Xiamen University Malaysia Campus, Jalan Sunsuria, Bandar Sunsuria, Sepang, Selangor, Malaysia
| | - Wan Yong Ho
- Faculty of Sciences and Engineering, University of Nottingham Malaysia, Semenyih, Malaysia
| | - Alan Han-Kiat Ong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Cheras, Malaysia
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26
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Spiers HVM, Stadler LKJ, Smith H, Kosmoliaptsis V. Extracellular Vesicles as Drug Delivery Systems in Organ Transplantation: The Next Frontier. Pharmaceutics 2023; 15:891. [PMID: 36986753 PMCID: PMC10052210 DOI: 10.3390/pharmaceutics15030891] [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: 11/23/2022] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/12/2023] Open
Abstract
Extracellular vesicles are lipid bilayer-delimited nanoparticles excreted into the extracellular space by all cells. They carry a cargo rich in proteins, lipids and DNA, as well as a full complement of RNA species, which they deliver to recipient cells to induce downstream signalling, and they play a key role in many physiological and pathological processes. There is evidence that native and hybrid EVs may be used as effective drug delivery systems, with their intrinsic ability to protect and deliver a functional cargo by utilising endogenous cellular mechanisms making them attractive as therapeutics. Organ transplantation is the gold standard for treatment for suitable patients with end-stage organ failure. However, significant challenges still remain in organ transplantation; prevention of graft rejection requires heavy immunosuppression and the lack of donor organs results in a failure to meet demand, as manifested by growing waiting lists. Pre-clinical studies have demonstrated the ability of EVs to prevent rejection in transplantation and mitigate ischemia reperfusion injury in several disease models. The findings of this work have made clinical translation of EVs possible, with several clinical trials actively recruiting patients. However, there is much to be uncovered, and it is essential to understand the mechanisms behind the therapeutic benefits of EVs. Machine perfusion of isolated organs provides an unparalleled platform for the investigation of EV biology and the testing of the pharmacokinetic and pharmacodynamic properties of EVs. This review classifies EVs and their biogenesis routes, and discusses the isolation and characterisation methods adopted by the international EV research community, before delving into what is known about EVs as drug delivery systems and why organ transplantation represents an ideal platform for their development as drug delivery systems.
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Affiliation(s)
- Harry V M Spiers
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Lukas K J Stadler
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Hugo Smith
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
- NIHR Blood and Transplant Research Unit in Organ Donation and Transplantation, University of Cambridge, Cambridge CB2 0QQ, UK
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27
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Zahmatkesh E, Khoshdel Rad N, Hossein-Khannazer N, Mohamadnejad M, Gramignoli R, Najimi M, Malekzadeh R, Hassan M, Vosough M. Cell and cell-derivative-based therapy for liver diseases: current approaches and future promises. Expert Rev Gastroenterol Hepatol 2023; 17:237-249. [PMID: 36692130 DOI: 10.1080/17474124.2023.2172398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION According to the recent updates from World Health Organization, liver diseases are the 12th most common cause of mortality. Currently, orthotopic liver transplantation (OLT) is the most effective and the only treatment for end-stage liver diseases. Owing to several shortcomings like finite numbers of healthy organ donors, lifelong immunosuppression, and complexity of the procedure, cell and cell-derivatives therapies have emerged as a potential therapeutic alternative for liver diseases. Various cell types and therapies have been proposed and their therapeutic effects evaluated in preclinical or clinical studies, including hepatocytes, hepatocyte-like cells (HLCs) derived from stem cells, human liver stem cells (HLSCs), combination therapies with various types of cells, organoids, and implantable cell-biomaterial constructs with synthetic and natural polymers or even decellularized extracellular matrix (ECM). AREAS COVERED In this review, we highlighted the current status of cell and cell-derivative-based therapies for liver diseases. Furthermore, we discussed future prospects of using HLCs, liver organoids, and their combination therapies. EXPERT OPINION Promising application of stem cell-based techniques including iPSC technology has been integrated into novel techniques such as gene editing, directed differentiation, and organoid technology. iPSCs offer promising prospects to represent novel therapeutic strategies and modeling liver diseases.
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Affiliation(s)
- Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohamadnejad
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roberto Gramignoli
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Reza Malekzadeh
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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28
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Ivosevic Z, Ljujic B, Pavlovic D, Matovic V, Gazdic Jankovic M. Mesenchymal Stem Cell-Derived Extracellular Vesicles: New Soldiers in the War on Immune-Mediated Diseases. Cell Transplant 2023; 32:9636897231207194. [PMID: 37882092 PMCID: PMC10605687 DOI: 10.1177/09636897231207194] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 09/11/2023] [Accepted: 09/27/2023] [Indexed: 10/27/2023] Open
Abstract
Inflammatory diseases are a group of debilitating disorders with varying degrees of long-lasting functional impairment of targeted system. New therapeutic agents that will attenuate on-going inflammation and, at the same time, promote regeneration of injured organ are urgently needed for the treatment of autoimmune and inflammatory disorders. During the last decade numerous studies have demonstrated that crucial therapeutic benefits of mesenchymal stem cells (MSCs) in inflammatory diseases are based on the effects of MSC-produced paracrine mediators and not on the activity of engrafted cells themselves. Thus, to overcome the limitations of stem cell transplantation, MSC-derived extracellular vesicles (MSC-EVs) have been rigorously investigated, as a promising cell-free pharmaceutical component. In this review, we focus on the mechanisms of MSC-EV covering the current knowledge on their potential therapeutic applications for immune-mediated diseases.
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Affiliation(s)
- Zeljko Ivosevic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Biljana Ljujic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Dragica Pavlovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Vesna Matovic
- Cardiology Clinic, University Clinical Center Kragujevac, Kragujevac, Serbia
| | - Marina Gazdic Jankovic
- Department of Genetics, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- Center for Harm Reduction of Biological and Chemical Hazards, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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29
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Lu W, Tang H, Li S, Bai L, Chen Y. Extracellular vesicles as potential biomarkers and treatment options for liver failure: A systematic review up to March 2022. Front Immunol 2023; 14:1116518. [PMID: 36911706 PMCID: PMC9992400 DOI: 10.3389/fimmu.2023.1116518] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 02/09/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction Extracellular vesicles (EVs) carrying functional cargoes are emerging as biomarkers and treatment strategies in multiple liver diseases. Nevertheless, the potential of EVs in liver failure remains indistinct. In this systematic review, we comprehensively analyzed the potential of EVs as biomarkers of liver failure and the therapeutic effects and possible mechanisms of EVs for liver failure. Methods We conducted a systematic review by comprehensively searching the following electronic databases: PubMed, Web of Science, Embase and Cochrane Central Register of Controlled Trials from inception to March 2022. The used text words (synonyms and word variations) and database-specific subject headings included "Extracellular Vesicles", "Exosomes", "Liver Failure", "Liver Injury", etc. Results A total of 1479 studies were identified. After removing 680 duplicate studies and 742 irrelevant studies, 57 studies were finally retained and analyzed. Fourteen studies revealed EVs with functional cargoes could be used to make the diagnosis of liver failure and provide clues for early warning and prognostic assessment of patients with liver failure. Forty-three studies confirmed the administration of EVs from different sources alleviated hepatic damage and improved survival through inhibiting inflammatory response, oxidative stress as well as apoptosis or promoting hepatocyte regeneration and autophagy. Conclusions EVs and their cargoes can be used not only as superior biomarkers of early warning, early diagnosis and prognostic assessments for liver failure, but also as potentially effective treatment options for liver failure. In the future, large-scale studies are urgently needed to verify the diagnostic, predictive and therapeutic value of EVs for liver failure.
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Affiliation(s)
- Wang Lu
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Huixin Tang
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Shanshan Li
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Li Bai
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
| | - Yu Chen
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing, China.,Beijing Municipal Key Laboratory of Liver Failure and Artificial Liver Treatment Research, Beijing, China
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30
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Mesenchymal stem cell-derived exosomes and non-coding RNAs: Regulatory and therapeutic role in liver diseases. Biomed Pharmacother 2023; 157:114040. [PMID: 36423545 DOI: 10.1016/j.biopha.2022.114040] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/16/2022] [Accepted: 11/19/2022] [Indexed: 11/22/2022] Open
Abstract
Liver disease has become a major health problem worldwide due to its high morbidity and mortality. In recent years, a large body of literature has shown that mesenchymal stem cell-derived exosomes (MSC-Exo) are able to play similar physiological roles as mesenchymal stem cells (MSCs). More importantly, there is no immune rejection caused by transplanted cells and the risk of tumor formation, which has become a new strategy for the treatment of various liver diseases. Moreover, accumulating evidence suggests that non-coding RNAs (ncRNAs) are the main effectors by which they exert hepatoprotective effects. Therefore, by searching the databases of Web of Science, PubMed, ScienceDirect, Google Scholar and CNKI, this review comprehensively reviewed the therapeutic effects of MSC-Exo and ncRNAs in liver diseases, including liver injury, liver fibrosis, and hepatocellular carcinoma. According to the data, the therapeutic effects of MSC-Exo and ncRNAs on liver diseases are closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, alleviation of liver oxidative stress, inhibition of apoptosis of hepatocytes and endothelial cells, promotion of angiogenesis, blocking the cell cycle of hepatocellular carcinoma, and inhibition of activation and proliferation of hepatic stellate cells. These important findings will provide a direction and basis for us to explore the potential of MSC-Exo and ncRNAs in the clinical treatment of liver diseases in the future.
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Kim J, Lee SK, Jung M, Jeong SY, You H, Won JY, Han SD, Cho HJ, Park S, Park J, Kim TM, Kim S. Extracellular vesicles from IFN-γ-primed mesenchymal stem cells repress atopic dermatitis in mice. J Nanobiotechnology 2022; 20:526. [PMID: 36496385 PMCID: PMC9741801 DOI: 10.1186/s12951-022-01728-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by immune dysregulation, pruritus, and abnormal epidermal barrier function. Compared with conventional mesenchymal stem cell (MSC), induced pluripotent stem cell (iPSC)-derived mesenchymal stem cell (iMSC) is recognized as a unique source for producing extracellular vesicles (EVs) because it can be obtained in a scalable manner with an enhanced homogeneity. Stimulation of iMSCs with inflammatory cytokines can improve the immune-regulatory, anti-inflammatory, and tissue-repairing potential of iMSC-derived EVs. RESULTS Proteome analysis showed that IFN-γ-iMSC-EVs are enriched with protein sets that are involved in regulating interferon responses and inflammatory pathways. In AD mice, expression of interleukin receptors for Th2 cytokines (IL-4Rα/13Rα1/31Rα) and activation of their corresponding intracellular signaling molecules was reduced. IFN-γ-iMSC-EVs decreased itching, which was supported by reduced inflammatory cell infiltration and mast cells in AD mouse skin; reduced IgE receptor expression and thymic stromal lymphopoietin and NF-kB activation; and recovered impaired skin barrier, as evidenced by upregulation of key genes of epidermal differentiation and lipid synthesis. CONCLUSIONS IFN-γ-iMSC-EVs inhibit Th2-induced immune responses, suppress inflammation, and facilitate skin barrier restoration, contributing to AD improvement.
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Affiliation(s)
- Jimin Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seul Ki Lee
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Minyoung Jung
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Seon-Yeong Jeong
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Haedeun You
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Ji-Yeon Won
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Sang-Deok Han
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Hye Jin Cho
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Somi Park
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
| | - Joonghoon Park
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Tae Min Kim
- grid.31501.360000 0004 0470 5905Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea ,grid.31501.360000 0004 0470 5905Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354 South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul, 05855 South Korea
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Alberti G, Russo E, Corrao S, Anzalone R, Kruzliak P, Miceli V, Conaldi PG, Di Gaudio F, La Rocca G. Current Perspectives on Adult Mesenchymal Stromal Cell-Derived Extracellular Vesicles: Biological Features and Clinical Indications. Biomedicines 2022; 10:2822. [PMID: 36359342 PMCID: PMC9687875 DOI: 10.3390/biomedicines10112822] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/19/2022] [Accepted: 10/28/2022] [Indexed: 08/10/2023] Open
Abstract
Extracellular vesicles (EVs) constitute one of the main mechanisms by which cells communicate with the surrounding tissue or at distance. Vesicle secretion is featured by most cell types, and adult mesenchymal stromal cells (MSCs) of different tissue origins have shown the ability to produce them. In recent years, several reports disclosed the molecular composition and suggested clinical indications for EVs derived from adult MSCs. The parental cells were already known for their roles in different disease settings in regulating inflammation, immune modulation, or transdifferentiation to promote cell repopulation. Interestingly, most reports also suggested that part of the properties of parental cells were maintained by isolated EV populations. This review analyzes the recent development in the field of cell-free therapies, focusing on several adult tissues as a source of MSC-derived EVs and the available clinical data from in vivo models.
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Affiliation(s)
- Giusi Alberti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Eleonora Russo
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Simona Corrao
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
| | - Rita Anzalone
- Department of Surgical, Oncological and Stomatological Sciences (DICHIRONS), University of Palermo, 90127 Palermo, Italy
| | - Peter Kruzliak
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03601 Martin, Slovakia
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | - Giampiero La Rocca
- Department of Biomedicine, Neurosciences and Advanced Diagnostics (BiND), University of Palermo, 90127 Palermo, Italy
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Xie D, Qian B, Li X. Nucleic acids and proteins carried by exosomes from various sources: Potential role in liver diseases. Front Physiol 2022; 13:957036. [PMID: 36213232 PMCID: PMC9538374 DOI: 10.3389/fphys.2022.957036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 08/17/2022] [Indexed: 12/24/2022] Open
Abstract
Exosomes are extracellular membrane-encapsulated vesicles that are released into the extracellular space or biological fluids by many cell types through exocytosis. As a newly identified form of intercellular signal communication, exosomes mediate various pathological and physiological processes by exchanging various active substances between cells. The incidence and mortality of liver diseases is increasing worldwide. Therefore, we reviewed recent studies evaluating the role of exosomes from various sources in the diagnosis and treatment of liver diseases.
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Affiliation(s)
- Danna Xie
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
| | - Baolin Qian
- Department of Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xun Li
- The First Clinical Medical College of Lanzhou University, Lanzhou, China
- Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou, China
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
- Center for Cancer Prevention and Treatment, School of Medicine, Lanzhou University, Lanzhou, China
- Gansu Provincial Institute of Hepatobiliary and Pancreatic Surgery, Lanzhou, China
- *Correspondence: Xun Li,
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Ding Y, Luo Q, Que H, Wang N, Gong P, Gu J. Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Agent for the Treatment of Liver Diseases. Int J Mol Sci 2022; 23:ijms231810972. [PMID: 36142881 PMCID: PMC9502508 DOI: 10.3390/ijms231810972] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/16/2022] Open
Abstract
Liver disease has become a major global health and economic burden due to its broad spectrum of diseases, multiple causes and difficult treatment. Most liver diseases progress to end-stage liver disease, which has a large amount of matrix deposition that makes it difficult for the liver and hepatocytes to regenerate. Liver transplantation is the only treatment for end-stage liver disease, but the shortage of suitable organs, expensive treatment costs and surgical complications greatly reduce patient survival rates. Therefore, there is an urgent need for an effective treatment modality. Cell-free therapy has become a research hotspot in the field of regenerative medicine. Mesenchymal stem cell (MSC)-derived exosomes have regulatory properties and transport functional "cargo" through physiological barriers to target cells to exert communication and regulatory activities. These exosomes also have little tumorigenic risk. MSC-derived exosomes promote hepatocyte proliferation and repair damaged liver tissue by participating in intercellular communication and regulating signal transduction, which supports their promise as a new strategy for the treatment of liver diseases. This paper reviews the physiological functions of exosomes and highlights the physiological changes and alterations in signaling pathways related to MSC-derived exosomes for the treatment of liver diseases in some relevant clinical studies. We also summarize the advantages of exosomes as drug delivery vehicles and discuss the challenges of exosome treatment of liver diseases in the future.
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Affiliation(s)
| | | | | | | | - Puyang Gong
- Correspondence: (P.G.); (J.G.); Tel.: +86-28-85656463 (J.G.)
| | - Jian Gu
- Correspondence: (P.G.); (J.G.); Tel.: +86-28-85656463 (J.G.)
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Recent Advances in Extracellular Vesicle-Based Therapies Using Induced Pluripotent Stem Cell-Derived Mesenchymal Stromal Cells. Biomedicines 2022; 10:biomedicines10092281. [PMID: 36140386 PMCID: PMC9496279 DOI: 10.3390/biomedicines10092281] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/09/2022] [Accepted: 09/11/2022] [Indexed: 11/26/2022] Open
Abstract
Extracellular vesicles (EVs) are being widely investigated as acellular therapeutics in regenerative medicine applications. EVs isolated from mesenchymal stromal cells (MSCs) are by far the most frequently used in preclinical models for diverse therapeutic applications, including inflammatory, degenerative, or acute diseases. Although they represent promising tools as cell-free therapeutic agents, one limitation to their use is related to the batch-to-batch unreliability that may arise from the heterogeneity between MSC donors. Isolating EVs from MSCs derived from induced pluripotent stem cells (iMSCs) might allow unlimited access to cells with a more stable phenotype and function. In the present review, we first present the latest findings regarding the functional aspects of EVs isolated from iMSCs and their interest in regenerative medicine for the treatment of various diseases. We will then discuss future directions for their translation to clinics with good manufacturing practice implementation.
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36
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Boyd-Gibbins N, Karagiannis P, Hwang DW, Kim SI. iPSCs in NK Cell Manufacturing and NKEV Development. Front Immunol 2022; 13:890894. [PMID: 35874677 PMCID: PMC9305199 DOI: 10.3389/fimmu.2022.890894] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 06/03/2022] [Indexed: 11/27/2022] Open
Abstract
Natural killer (NK) cell immunotherapies for cancer can complement existing T cell therapies while benefiting from advancements already made in the immunotherapy field. For NK cell manufacturing, induced pluripotent stem cells (iPSCs) offer advantages including eliminating donor variation and providing an ideal platform for genome engineering. At the same time, extracellular vesicles (EVs) have become a major research interest, and purified NK cell extracellular vesicles (NKEVs) have been shown to reproduce the key functions of their parent NK cells. NKEVs have the potential to be developed into a standalone therapeutic with reduced complexity and immunogenicity compared to cell therapies. This review explores the role iPSC technology can play in both NK cell manufacturing and NKEV development.
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Affiliation(s)
| | - Peter Karagiannis
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
| | - Do Won Hwang
- Research and Development Center, THERABEST Co., Ltd., Seoul, South Korea
| | - Shin-Il Kim
- THERABEST Japan, Inc., Kobe, Japan
- Research and Development Center, THERABEST Co., Ltd., Seoul, South Korea
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37
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miR-29a-3p in Exosomes from Heme Oxygenase-1 Modified Bone Marrow Mesenchymal Stem Cells Alleviates Steatotic Liver Ischemia-Reperfusion Injury in Rats by Suppressing Ferroptosis via Iron Responsive Element Binding Protein 2. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6520789. [PMID: 35720183 PMCID: PMC9203237 DOI: 10.1155/2022/6520789] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 05/03/2022] [Accepted: 05/20/2022] [Indexed: 12/28/2022]
Abstract
Hepatic ischemia-reperfusion injury (IRI) is an inevitable result of liver surgery. Steatotic livers are extremely sensitive to IRI and have worse tolerance. Ferroptosis is considered to be one of the main factors of organ IRI. This study is aimed at exploring the role of ferroptosis in the effect of heme oxygenase-1-modified bone marrow mesenchymal stem cells (HO-1/BMMSCs) on steatotic liver IRI and its mechanism. An IRI model of a steatotic liver and a hypoxia reoxygenation (HR) model of steatotic hepatocytes (SHPs) were established. Rat BMMSCs were extracted and transfected with the Ho1 gene to establish HO-1/BMMSCs, and their exosomes were extracted by ultracentrifugation. Ireb2 was knocked down to verify its role in ferroptosis and cell injury in SHP-HR. Public database screening combined with quantitative real-time reverse transcription PCR identified microRNAs (miRNAs) targeting Ireb2 in HO-1/BMMSCs exosomes. miR-29a-3p mimic and inhibitor were used for functional verification experiments. Liver function, histopathology, terminal deoxynulceotidyl transferase nick-end-labeling staining, cell viability, mitochondrial membrane potential, and cell death were measured to evaluate liver tissue and hepatocyte injury. Ferroptosis was assessed by detecting the levels of IREB2, Fe2+, malondialdehyde, glutathione, lipid reactive oxygen species, glutathione peroxidase 4, prostaglandin-endoperoxide synthase 2 mRNA, and mitochondrial morphology. The results revealed that HO-1/BMMSCs improved liver tissue and hepatocyte injury and suppressed ferroptosis in vivo and in vitro. The expression of IREB2 was increased in steatotic liver IRI and SHP-HR. Knocking down Ireb2 reduced the level of Fe2+ and inhibited ferroptosis. HO-1/BMMSC exosomes reduced the expression of IREB2 and inhibited ferroptosis and cell damage. Furthermore, we confirmed high levels of miR-29a-3p in HO-1/BMMSCs exosomes. Overexpression of miR-29a-3p downregulated the expression of Ireb2 and inhibited ferroptosis. Downregulation of miR-29a-3p blocked the protective effect of HO-1/BMMSC exosomes on SHP-HR cell injury. In conclusion, ferroptosis plays an important role in HO-1/BMMSC-mediated alleviation of steatotic liver IRI. HO-1/BMMSCs could suppress ferroptosis by targeting Ireb2 via the exosomal transfer of miR-29a-3p.
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38
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Psaraki A, Ntari L, Karakostas C, Korrou-Karava D, Roubelakis MG. Extracellular vesicles derived from mesenchymal stem/stromal cells: The regenerative impact in liver diseases. Hepatology 2022; 75:1590-1603. [PMID: 34449901 DOI: 10.1002/hep.32129] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 08/04/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023]
Abstract
Liver dysfunctions are classified into acute and chronic diseases, which comprise a heterogeneous group of pathological features and a high mortality rate. Liver transplantation remains the gold-standard therapy for most liver diseases, with concomitant limitations related to donor organ shortage and lifelong immunosuppressive therapy. A concept in liver therapy intends to overcome these limitations based on the secreted extracellular vesicles (EVs; microvesicles and exosomes) by mesenchymal stem/stromal cells (MSCs). A significant number of studies have shown that factors released by MSCs could induce liver repair and ameliorate systemic inflammation through paracrine effects. It is well known that this paracrine action is based not only on the secretion of cytokines and growth factors but also on EVs, which regulate pathways associated with inflammation, hepatic fibrosis, integrin-linked protein kinase signaling, and apoptosis. Herein, we extensively discuss the differential effects of MSC-EVs on different liver diseases and on cellular and animal models and address the complex molecular mechanisms involved in the therapeutic potential of EVs. In addition, we cover the crucial information regarding the type of molecules contained in MSC-EVs that can be effective in the context of liver diseases. In conclusion, outcomes on MSC-EV-mediated therapy are expected to lead to an innovative, cell-free, noninvasive, less immunogenic, and nontoxic alternative strategy for liver treatment and to provide important mechanistic information on the reparative function of liver cells.
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Affiliation(s)
- Adriana Psaraki
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Lydia Ntari
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Christos Karakostas
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Despoina Korrou-Karava
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Maria G Roubelakis
- Laboratory of BiologyMedical SchoolNational and Kapodistrian University of AthensAthensGreece
- Centre of Basic ResearchBiomedical Research Foundation of the Academy of AthensAthensGreece
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39
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Assis JLD, Fernandes AM, Aniceto BS, Fernandes da Costa PP, Banchio C, Girardini J, Vieyra A, Valverde RRHF, Einicker‐Lamas M. Sphingosine 1‐Phosphate Prevents Human Embryonic Stem Cell Death Following Ischemic Injury. EUR J LIPID SCI TECH 2022. [DOI: 10.1002/ejlt.202200019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Juliane L. de Assis
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Aline M. Fernandes
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Bárbara S. Aniceto
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Pedro P. Fernandes da Costa
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Claudia Banchio
- Instituto de Biologia Molecular y Celular de Rosário Rosário Argentina
| | - Javier Girardini
- Instituto de Biologia Molecular y Celular de Rosário Rosário Argentina
| | - Adalberto Vieyra
- Laboratório de Físico‐Química Biológica Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Rafael R. H. F. Valverde
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Marcelo Einicker‐Lamas
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
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Wang C, Liu J, Yan Y, Tan Y. Role of Exosomes in Chronic Liver Disease Development and Their Potential Clinical Applications. J Immunol Res 2022; 2022:1695802. [PMID: 35571570 PMCID: PMC9106457 DOI: 10.1155/2022/1695802] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/02/2022] [Accepted: 04/18/2022] [Indexed: 12/11/2022] Open
Abstract
Extracellular vesicles (EVs) are vesicular bodies (40-1000 nm) with double-layer membrane structures released by different cell types into extracellular environments, including apoptosis bodies, microvesicles, and exosomes. Exosomes (30-100 nm) are vesicles enclosed by extracellular membrane and contain effective molecules of secretory cells. They are derived from intracellular multivesicular bodies (MVBs) that fuse with the plasma membrane and release their intracellular vesicles by exocytosis. Research has shown that almost all human cells could secrete exosomes, which have a certain relationship with corresponding diseases. In chronic liver diseases, exosomes release a variety of bioactive components into extracellular spaces, mediating intercellular signal transduction and materials transport. Moreover, exosomes play a role in the diagnosis, treatment, and prognosis of various chronic liver diseases as potential biomarkers and therapeutic targets. Previous studies have found that mesenchymal stem cell-derived exosomes (MSC-ex) could alleviate acute and chronic liver injury and have the advantages of high biocompatibility and low immunogenicity. In this paper, we briefly summarize the role of exosomes in the pathogenesis of different chronic liver diseases and the latest research progresses of MSC-ex as the clinical therapeutic targets.
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Affiliation(s)
- Chen Wang
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Jiangsu University, Zhenjiang, 212005 Jiangsu, China
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Jinwen Liu
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Yongmin Yan
- School of Medicine, Jiangsu University, Zhenjiang, 212013 Jiangsu, China
| | - Youwen Tan
- The Third Hospital of Zhenjiang Affiliated Jiangsu University, Jiangsu University, Zhenjiang, 212005 Jiangsu, China
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41
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Pan Y, Tan WF, Yang MQ, Li JY, Geller DA. The therapeutic potential of exosomes derived from different cell sources in liver diseases. Am J Physiol Gastrointest Liver Physiol 2022; 322:G397-G404. [PMID: 35107032 PMCID: PMC8917924 DOI: 10.1152/ajpgi.00054.2021] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Exosomes are small nanovesicles with a size of approximately 40-120 nm that are secreted from cells. They are involved in the regulation of cell homeostasis and mediate intercellular communication. In addition, they carry proteins, nucleic acids, and lipids that regulate the biological activity of receptor cells. Recent studies have shown that exosomes perform important functions in liver diseases. This review will focus on liver diseases (drug-induced liver injury, hepatic ischemia-reperfusion injury, liver fibrosis, acute liver failure, and hepatocellular carcinoma) and summarize the therapeutic potential of exosomes from different cell sources in liver disease.
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Affiliation(s)
- Yun Pan
- 1Colorectal Cancer Center, Tenth People’s Hospital of Tongji University, Tongji University School of Medicine, Shanghai, People’s Republic of China
| | - Wei-Feng Tan
- 2Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China
| | - Mu-Qing Yang
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - Ji-Yu Li
- 3Department of General Surgery, Tenth People’s Hospital of Tongji University, Tongji University, Shanghai, People’s Republic of China
| | - David A. Geller
- 4Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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Zhuang Y, Song S, Xiao D, Liu X, Han X, Du S, Li Y, He Y, Zhang S. Exosomes Secreted by Nucleus Pulposus Stem Cells Derived From Degenerative Intervertebral Disc Exacerbate Annulus Fibrosus Cell Degradation via Let-7b-5p. Front Mol Biosci 2022; 8:766115. [PMID: 35111808 PMCID: PMC8802296 DOI: 10.3389/fmolb.2021.766115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 11/30/2021] [Indexed: 12/21/2022] Open
Abstract
The pathogenesis of intervertebral disc degeneration (IDD) is complex and remains unclear. Nucleus pulposus stem cells (NPSCs) and annulus fibrosus cells (AFCs) play a critical role in the maintenance of intervertebral disc structure and function. Exosome-mediated miRNAs regulate cell proliferation, differentiation, apoptosis, and degradation. However, it is not clear whether the degenerative intervertebral disc-derived nucleus pulposus stem cells (D-NPSCs) can regulate the function of AFCs by delivering exosomes. Here, we show that exosomes secreted by nucleus pulposus stem cells derived from degenerative intervertebral disc (D-DPSC-exo) can exacerbate AFC degeneration via inhibiting cell proliferation, migration, matrix synthesis, and promoting apoptosis. Specifically, let-7b-5p was highly expressed in D-DPSC-exo. Transfection of let-7b-5p mimic was found to promote apoptosis and inhibit proliferation migration and matrix synthesis of AFCs. In addition, transfection with let-7b-5p inhibitor caused the effect of D-DPSC-exo on AFCs to be reversed. Furthermore, we found that D-DPSC-exo and let-7b-5p inhibited IGF1R expression and blocked the activation of the PI3K–Akt pathway. Results suggested that NPSC-exo exacerbated cell degeneration of AFCs via let-7b-5p, accompanied by inhibition of IGF1R expression, and PI3K–Akt pathway activation. Therefore, insights from this work may provide a clue for targeted molecular therapy of intervertebral disc degeneration.
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Affiliation(s)
- Yin Zhuang
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Sheng Song
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Dan Xiao
- Department of Spine Surgery, Orthopedics Center, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Xueguang Liu
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Xiaofei Han
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Shihao Du
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Yuan Li
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Yanming He
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
| | - Shujun Zhang
- Department of Spine Surgery, Wuxi 9th Affiliated Hospital of Soochow University, Wuxi, China
- *Correspondence: Shujun Zhang,
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Ruan HG, Gu WC, Xia W, Gong Y, Zhou XL, Chen WY, Xiong J. METTL3 Is Suppressed by Circular RNA circMETTL3/miR-34c-3p Signaling and Limits the Tumor Growth and Metastasis in Triple Negative Breast Cancer. Front Oncol 2022; 11:778132. [PMID: 35004298 PMCID: PMC8727604 DOI: 10.3389/fonc.2021.778132] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 12/03/2021] [Indexed: 12/27/2022] Open
Abstract
Despite N6-methyladenosine (m6A) is functionally important in various biological processes, its role in the underlying regulatory mechanism in TNBC are lacking. In this study, we investigate the pathological role and the underlying mechanism of the m6A methylated RNA level and its major methyltransferase METTL3 in the TNBC progression. We found that the m6A methylated RNA was dramatically decreased in TNBC tissues and cell lines. Functionally, we demonstrated that METTL3 inhibits the proliferation, migration, and invasion ability of TNBC cells. Moreover, we found METTL3 is repressed by miR-34c-3p in TNBC cells. On the mechanism, we found that circMETTL3 could act as a sponge for miR-34c-3p and inhibits cell proliferation, invasion, tumor growth and metastasis by up-regulating the expression of miR-34c-3p target gene METTL3. In conclusion, our study demonstrates the functional importance and regulatory mechanism of METTL3 in suppressing the tumor growth of TNBC.
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Affiliation(s)
- Han-Guang Ruan
- Department of Breast Oncology, The Third Hospital of Nanchang, Nanchang, China
| | - Wen-Chao Gu
- Department of Diagnostic of Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Wen Xia
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yan Gong
- Department of Breast Oncology, The Third Hospital of Nanchang, Nanchang, China
| | - Xue-Liang Zhou
- Department of Cardiac Surgery, The First Affiliated Hospital, Nanchang University, Nanchang, China
| | - Wen-Yan Chen
- Department of Breast Oncology, The Third Hospital of Nanchang, Nanchang, China
| | - Juan Xiong
- Department of Radiation Oncology, Jiangxi Cancer Hospital, Nanchang, China
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Aguiar Koga BA, Fernandes LA, Fratini P, Sogayar MC, Carreira ACO. Role of MSC-derived small extracellular vesicles in tissue repair and regeneration. Front Cell Dev Biol 2022; 10:1047094. [PMID: 36935901 PMCID: PMC10014555 DOI: 10.3389/fcell.2022.1047094] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 12/07/2022] [Indexed: 03/05/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and repair, secreting vesicles to the extracellular environment. Isolated exosomes were shown to affect angiogenesis, immunomodulation and tissue regeneration. Numerous efforts have been dedicated to describe the mechanism of action of these extracellular vesicles (EVs) and guarantee their safety, since the final aim is their therapeutic application in the clinic. The major advantage of applying MSC-derived EVs is their low or inexistent immunogenicity, prompting their use as drug delivery or therapeutic agents, as well as wound healing, different cancer types, and inflammatory processes in the neurological and cardiovascular systems. MSC-derived EVs display no vascular obstruction effects or apparent adverse effects. Their nano-size ensures their passage through the blood-brain barrier, demonstrating no cytotoxic or immunogenic effects. Several in vitro tests have been conducted with EVs obtained from different sources to understand their biology, molecular content, signaling pathways, and mechanisms of action. Application of EVs to human therapies has recently become a reality, with clinical trials being conducted to treat Alzheimer's disease, retina degeneration, and COVID-19 patients. Herein, we describe and compare the different extracellular vesicles isolation methods and therapeutic applications regarding the tissue repair and regeneration process, presenting the latest clinical trial reports.
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Affiliation(s)
- Bruna Andrade Aguiar Koga
- Cell and Molecular Therapy Group (NUCEL), School of Medicine, University of São Paulo, São Paulo, Brazil
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Letícia Alves Fernandes
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Paula Fratini
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
| | - Mari Cleide Sogayar
- Cell and Molecular Therapy Group (NUCEL), School of Medicine, University of São Paulo, São Paulo, Brazil
- Biochemistry Department, Chemistry Institute, University of São Paulo, São Paulo, Brazil
| | - Ana Claudia Oliveira Carreira
- Cell and Molecular Therapy Group (NUCEL), School of Medicine, University of São Paulo, São Paulo, Brazil
- Department of Surgery, Faculty of Veterinary Medicine and Animal Science, University of São Paulo, São Paulo, Brazil
- Center for Natural and Human Sciences, Federal University of ABC, São Paulo, Brazil
- *Correspondence: Ana Claudia Oliveira Carreira, ,
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Yao J, Yu Y, Nyberg SL. Induced Pluripotent Stem Cells for the Treatment of Liver Diseases: Novel Concepts. Cells Tissues Organs 2022; 211:368-384. [PMID: 32615573 PMCID: PMC7775900 DOI: 10.1159/000508182] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/24/2020] [Indexed: 01/03/2023] Open
Abstract
Millions of people worldwide with incurable liver disease die because of inadequate treatment options and limited availability of donor organs for liver transplantation. Regenerative medicine as an innovative approach to repairing and replacing cells, tissues, and organs is undergoing a major revolution due to the unprecedented need for organs for patients around the world. Induced pluripotent stem cells (iPSCs) have been widely studied in the field of liver regeneration and are considered to be the most promising candidate therapies. This review will conclude the current state of efforts to derive human iPSCs for potential use in the modeling and treatment of liver disease.
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Affiliation(s)
- Jia Yao
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Clinical Research and Project Management Office, The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yue Yu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key Laboratory of Living Donor Liver Transplantation; Nanjing, China
| | - Scott L. Nyberg
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, USA.,Corresponding Author: Scott L. Nyberg, William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN 55905, USA, Tel: Rochester, MN 55905, USA, Fax: (507) 284-2511,
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46
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Fei Y, Shao J, Huang G, Wang L, Zou S, Sun H, Zheng C, Yang J. Effect of Edaravone on MicroRNA Expression in Exosomes after Hepatic Ischemia-reperfusion Injury. Curr Mol Pharmacol 2021; 15:870-882. [PMID: 34847855 DOI: 10.2174/1874467214666211130162152] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/05/2021] [Accepted: 09/23/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND AND OBJECTIVE Hepatic ischemia-reperfusion injury (HIRI) results in serious complications after liver resection and transplantation. Edaravone (ED) has a protective effect on IRI. This study was designed to evaluate whether ED could protect the liver of rats from HIRI injury and explored its exosomal miRNA-related mechanism. METHODS The sham group, hepatic ischemia/reperfusion (IR group), and hepatic ischemia/reperfusion + edaravone (ED group) models were established. We determined the protective effect of ED by measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), superoxide dismutase (SOD); enzyme-linked immunosorbent assay for tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β); hematoxylin-eosin staining and immunohistochemistry for histopathological changes. Exosomal miRNAs were subjected to second-generation sequencing to identify their differential expression. The results were analyzed using bioinformatics methods and validated using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS HIRI rats showed higher levels of ALT, AST, oxidative stress, and inflammatory markers; ED attenuated these effects. The sequencing results showed 6 upregulated and 13 downregulated miRNAs in the IR vs. sham groups, 10 upregulated and 10 downregulated miRNAs in the ED vs. IR groups. PC-3p-190-42101 was screened as an overlapping differentially expressed miRNA, and RT-qPCR validation showed that its expression in HIRI rats was significantly decreased; ED prevented this downregulation. Moreover, the expression of PC-3P-190-42101 was significantly correlated with the level of inflammatory factors. CONCLUSION These findings indicate that ED can regulate the level of inflammatory factors by affecting the expression of miRNA PC-3p-190-42101 in plasma exosomes to protect the liver from IRI.
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Affiliation(s)
- Yanxia Fei
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Jiali Shao
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Ge Huang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Lijuan Wang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Shuangfa Zou
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Huiping Sun
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Chumei Zheng
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
| | - Jinfeng Yang
- Department of Anesthesiology, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan. China
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Driscoll J, Wehrkamp C, Ota Y, Thomas JN, Yan IK, Patel T. Biological Nanotherapeutics for Liver Disease. Hepatology 2021; 74:2863-2875. [PMID: 33825210 DOI: 10.1002/hep.31847] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 03/19/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022]
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of biological nano-sized vesicles that are released from cells and contribute to intercellular communication. Emerging knowledge about their biogenesis, composition, release, and uptake has resulted in broad interest in elucidating their potential roles in disease pathophysiology. The distinct biological properties of these biological nanoparticles emphasize several appealing advantages for potential therapeutic applications compared with the use of synthetic nanoparticles. When administered systemically, EVs are taken up and sequestered within the liver, further emphasizing opportunities for therapeutic use. Consequently, there is growing interest in their use for liver diseases. EVs can be used directly as therapeutics, and several studies have highlighted the intrinsic therapeutic properties of mesenchymal stem cell-derived EVs for chronic and acute liver diseases. Alternatively, EVs can be modified to facilitate their use for the delivery of therapeutic cargo. In this review, we discuss the cellular sources of EV, provide a concise overview of their potential use in diverse processes, and outline several promising applications for the use of EV-based therapeutics for liver diseases. The use of EV-based therapeutics provides a viable approach to target hepatic pathophysiology.
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Affiliation(s)
- Julia Driscoll
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Cody Wehrkamp
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Yu Ota
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | | | - Irene K Yan
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, FL
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Kostallari E, Valainathan S, Biquard L, Shah VH, Rautou PE. Role of extracellular vesicles in liver diseases and their therapeutic potential. Adv Drug Deliv Rev 2021; 175:113816. [PMID: 34087329 PMCID: PMC10798367 DOI: 10.1016/j.addr.2021.05.026] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/29/2021] [Indexed: 02/07/2023]
Abstract
More than eight hundred million people worldwide have chronic liver disease, with two million deaths per year. Recurring liver injury results in fibrogenesis, progressing towards cirrhosis, for which there doesn't exists any cure except liver transplantation. Better understanding of the mechanisms leading to cirrhosis and its complications is needed to develop effective therapies. Extracellular vesicles (EVs) are released by cells and are important for cell-to-cell communication. EVs have been reported to be involved in homeostasis maintenance, as well as in liver diseases. In this review, we present current knowledge on the role of EVs in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, alcohol-associated liver disease, chronic viral hepatitis, primary liver cancers, acute liver injury and liver regeneration. Moreover, therapeutic strategies involving EVs as targets or as tools to treat liver diseases are summarized.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Shantha Valainathan
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France
| | - Louise Biquard
- Université de Paris, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.
| | - Pierre-Emmanuel Rautou
- Université de Paris, AP-HP, Hôpital Beaujon, Service d'Hépatologie, DMU DIGEST, Centre de Référence des Maladies Vasculaires du Foie, FILFOIE, ERN RARE-LIVER, Centre de recherche sur l'inflammation, Inserm, UMR 1149, Paris, France.
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Zha S, Tay JCK, Zhu S, Li Z, Du Z, Wang S. Generation of Mesenchymal Stromal Cells with Low Immunogenicity from Human PBMC-Derived β2 Microglobulin Knockout Induced Pluripotent Stem Cells. Cell Transplant 2021; 29:963689720965529. [PMID: 33172291 PMCID: PMC7784598 DOI: 10.1177/0963689720965529] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are viewed as immune-privileged cells and have been broadly applied in allogeneic adoptive cell transfer for regenerative medicine or immune-suppressing purpose. However, the surface expression of human leukocyte antigen (HLA) class I molecules on MSCs could still possibly induce the rejection of allogeneic MSCs from the recipients. Here, we disrupted the β2 microglobulin (B2M) gene in human peripheral blood mononuclear cell-derived induced pluripotent stem cells (iPSCs) with two clustered regulatory interspaced short palindromic repeat (CRISPR)-associated Cas9 endonuclease-based methods. The B2M knockout iPSCs did not express HLA class I molecules but maintained their pluripotency and genome stability. Subsequently, MSCs were derived from the HLA-negative iPSCs (iMSCs). We demonstrated that B2M knockout did not affect iMSC phenotype, multipotency, and immune suppressive characteristics and, most importantly, reduced iMSC immunogenicity to allogeneic peripheral blood mononuclear cells. Thus, B2M knockout iPSCs could serve as unlimited off-the-shelf cell resources in adoptive cell transfer, while the derived iMSCs hold great potential as universal grafts in allogeneic MSC transplantation.
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Affiliation(s)
- Shijun Zha
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Johan Chin-Kang Tay
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Sumin Zhu
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhendong Li
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Zhicheng Du
- Department of Biological Sciences, National University of Singapore, Singapore
| | - Shu Wang
- Department of Biological Sciences, National University of Singapore, Singapore
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50
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Chinnici CM, Russelli G, Bulati M, Miceli V, Gallo A, Busà R, Tinnirello R, Conaldi PG, Iannolo G. Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment. World J Gastroenterol 2021; 27:1905-1919. [PMID: 34007129 PMCID: PMC8108038 DOI: 10.3748/wjg.v27.i17.1905] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 04/05/2021] [Indexed: 02/06/2023] Open
Abstract
Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.
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Affiliation(s)
- Cinzia Maria Chinnici
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
- Department of Regenerative Medicine, Fondazione Ri.MED, Palermo 90127, Italy
| | - Giovanna Russelli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Matteo Bulati
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Vitale Miceli
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Alessia Gallo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Rosalia Busà
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Rosaria Tinnirello
- Neuroscience Unit, CNR Institute of Biomedicine and Molecular Immunology, Palermo 90146, Italy
| | - Pier Giulio Conaldi
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
| | - Gioacchin Iannolo
- Department of Research, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IRCCS-ISMETT), Palermo 90127, Italy
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