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Qin D, Huang P, Chen J, Wu C, Liang Y. The therapeutic potential of different mesenchymal stem cells and their derived exosomes in metabolic dysfunction-associated steatotic liver disease. Front Endocrinol (Lausanne) 2025; 16:1558194. [PMID: 40248144 PMCID: PMC12003127 DOI: 10.3389/fendo.2025.1558194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/14/2025] [Indexed: 04/19/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease is a metabolic disease with an increasing incidence. Its pathogenesis involves the interaction of multiple factors. There is currently no specific treatment, so early prevention and treatment are crucial. Mesenchymal stem cells are a type of cell with the ability to self-renew and differentiate in multiple directions. They have a wide range of sources, including umbilical cords, bone marrow, and fat, and have various biological functions such as anti-inflammation, immune regulation, anti-oxidation, and inhibition of fibrosis. They have shown significant potential in the treatment of non-alcoholic fatty liver disease. In recent years, mesenchymal stem cells derived exosomes have been shown to be rich in bioactive substances, and to be involved in intercellular communication, regulating metabolism, reducing inflammatory responses, improving lipid metabolism, inhibiting fibrosis, and other processes that contribute to the treatment of metabolic dysfunction-associated steatotic liver disease. Mesenchymal stem cells and mesenchymal stem cell-derived exosomes play an important role in the pathogenesis and treatment of metabolic dysfunction-associated steatotic liver disease and provide new potential and direction for the treatment of Metabolic dysfunction-associated steatotic liver disease. This article reviews the role and effects of mesenchymal stem cells and mesenchymal stem cell-derived exosomes from different sources in Metabolic dysfunction-associated steatotic liver disease and discusses their prospects as potential therapeutic strategies.
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Affiliation(s)
- Dan Qin
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Pingping Huang
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jialing Chen
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Changjun Wu
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yuzhen Liang
- Department of Endocrinology, The Second Affiliated Hospital of Guangxi Medical University, Nanning, China
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Wang J, Bao S, An Q, Li C, Feng J. Roles of extracellular vesicles from different origins in metabolic-associated fatty liver disease: progress and perspectives. Front Immunol 2025; 16:1544012. [PMID: 40129979 PMCID: PMC11930831 DOI: 10.3389/fimmu.2025.1544012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/19/2025] [Indexed: 03/26/2025] Open
Abstract
Metabolic-Associated Fatty Liver Disease (MAFLD) is the most common chronic liver disease worldwide, associated with systemic metabolic dysregulation. It can progress from simple hepatic steatosis (MAFL) to more severe conditions like Metabolic-Associated Steatohepatitis (MASH), fibrosis, cirrhosis, and Hepatocellular Carcinoma (HCC). There is a critical lack of reliable non-invasive diagnostic methods and effective pharmaceutical treatments for MAFLD/MASH, emphasizing the need for further research. Extracellular vesicles (EVs) are nanoscale structures that play important roles in cell signaling by delivering bioactive molecules. However, there is a significant gap in literature regarding the roles of EVs from hosts, plants, and microbiota in MAFLD. This review explores the potential of EVs from various sources-host, plants, and microbiota-as biomarkers, therapeutic agents, drug carriers, and treatment targets for MAFLD. Firstly, the roles of host-derived extracellular vesicles (EVs) in MAFLD, with a focus on cell-type specific EVs and their components-proteins, miRNAs, and lipids-for disease diagnosis and monitoring were discussed. Moreover, it highlighted the therapeutic potential of mesenchymal stem cell (MSC)-derived EVs in reducing lipid accumulation and liver injury, and immune cell-derived EVs in mitigating inflammation and fibrosis. The review also discussed the use of host-derived EVs as drug carriers and therapeutic targets due to their ability to deliver bioactive molecules that impact disease mechanisms. Additionally, it summarized research on plant-derived EVs, which help reduce liver lipid accumulation, inflammation, and enhance gut barrier function in MAFLD. Also, the review explored microbial-derived EVs as novel therapeutic targets, particularly in relation to insulin resistance, liver inflammation, and dysfunction in MAFLD. Overall, by exploring the diverse roles of EVs from host, plant, and microbiota sources in MAFLD, this review offers valuable insights into their potential as non-invasive biomarkers and novel therapeutic strategies, which could pave the way for more effective diagnostic and treatment options for this increasingly prevalent liver disease. Notably, the challenges of translating EVs into clinical practice were also thoroughly discussed, aiming to provide possible directions and strategies for future research.
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Affiliation(s)
- Jing Wang
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Shuoqiang Bao
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Qi An
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Caihong Li
- School of Public Health, Gansu University of Chinese Medicine, Lanzhou, China
| | - Juan Feng
- College of Health Science and Environmental Engineering, Shenzhen Technology University, Shenzhen, China
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Wang Q, Tang X, Wang Y, Zhang D, Li X, Liu S. The role of extracellular vesicles in non-alcoholic steatohepatitis: Emerging mechanisms, potential therapeutics and biomarkers. J Adv Res 2025; 69:157-168. [PMID: 38494073 PMCID: PMC11954800 DOI: 10.1016/j.jare.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 03/19/2024] Open
Abstract
Non-alcoholic steatohepatitis (NASH), an emerging global healthcare problem, has become the leading cause of liver transplantation in recent decades. No effective therapies in the clinic have been proven due to the incomplete understanding of the pathogenesis of NASH, and further studies are expected to continue to delve into the mechanisms of NASH. Extracellular vesicles (EVs), which are small lipid membrane vesicles carrying proteins, microRNAs and other molecules, have been identified to play a vital role in cell-to-cell communication and are involved in the development and progression of various diseases. In recent years, there has been increasing interest in the role of EVs in NASH. Many studies have revealed that EVs mediate important pathological processes in NASH, and the role of EVs in NASH is distinct and variable depending on their origin cells and target cells. This review outlines the emerging mechanisms of EVs in the development of NASH and the preclinical evidence related to stem cell-derived EVs as a potential therapeutic strategy for NASH. Moreover, possible strategies involving EVs as clinical diagnostic, staging and prognostic biomarkers for NASH are summarized.
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Affiliation(s)
- Qianrong Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xiangning Tang
- Department of endocrinology, the Second Affiliated Hospital of University of South China, 421001 Hunan Province, China
| | - Yu Wang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Danyi Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
| | - Shanshan Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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Ma X, Peng L, Zhu X, Chu T, Yang C, Zhou B, Sun X, Gao T, Zhang M, Chen P, Chen H. Isolation, identification, and challenges of extracellular vesicles: emerging players in clinical applications. Apoptosis 2025; 30:422-445. [PMID: 39522104 DOI: 10.1007/s10495-024-02036-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Extracellular vesicles (EVs) serve as critical mediators of intercellular communication, encompassing exosomes, microvesicles, and apoptotic vesicles that play significant roles in diverse physiological and pathological contexts. Numerous studies have demonstrated that EVs derived from mesenchymal stem cells (MSC-EVs) play a pivotal role in facilitating tissue and organ repair, alleviating inflammation and apoptosis, enhancing the proliferation of endogenous stem cells within tissues and organs, and modulating immune function-these functions have been extensively utilized in clinical applications. The precise classification, isolation, and identification of MSC-EVs are essential for their clinical applications. This article provides a comprehensive overview of the biological properties of EVs, emphasizing both their advantages and limitations in isolation and identification methodologies. Additionally, we summarize the protein markers associated with MSC-EVs, emphasizing their significance in the treatment of various diseases. Finally, this article addresses the current challenges and dilemmas in developing clinical applications for MSC-EVs, aiming to offer valuable insights for future research.
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Affiliation(s)
- Xiaoxiao Ma
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Lanwei Peng
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiaohui Zhu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianqi Chu
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Changcheng Yang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Bohao Zhou
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Xiangwei Sun
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Tianya Gao
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Mengqi Zhang
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China
| | - Ping Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
| | - Haiyan Chen
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha, 410081, People's Republic of China.
- East China Institute of Digital Medical Engineering, Shangrao, 334000, People's Republic of China.
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Zhu WY, Li X, Xie JL, Lu Q, Ma YJ, Zhu ZJ, Liu J. Hotspots and trends in stem cell therapy for liver fibrosis and cirrhosis: A bibliometric analysis. World J Hepatol 2025; 17:96105. [PMID: 39871895 PMCID: PMC11736489 DOI: 10.4254/wjh.v17.i1.96105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 10/29/2024] [Accepted: 11/19/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND Liver fibrosis and cirrhosis are global medical challenges that require safe and effective treatments. In the past two decades, there has been a surge in research on stem cell therapy for liver fibrosis and cirrhosis. This study aimed to conduct a comprehensive analysis of the research hotspots and trends in this field through bibliometrics. AIM To conduct a bibliometric analysis on hotspots and trends in stem cell therapy for treatment of liver fibrosis and cirrhosis. METHODS Publications on stem cell therapy for liver fibrosis and cirrhosis were retrieved from the Web of Science Core Collection database. The distribution and collaboration among literature, authors, countries, and institutions were analyzed visually using Excel, CiteSpace, Bibliometrix R-package, VOSviewer and Pajek software. Additionally, an investigation of keywords, burst keywords, and clusters was conducted. RESULTS As of September 20, 2024, a total of 1935 documents were retrieved dating from 2004 to 2024, with 1186 strongly relevant publications obtained after screening. China, the United States, and Japan were the major contributors in this field. Cairo University, Zhejiang University and Yamaguchi University were the major institution in this field. The journal Stem Cell Research & Therapy published the most papers. There were 686 authors, with Shuji Terai, Isao Sakaida, Soon Koo Baik, and Lanjuan Li publishing the most papers. The research focused on alcoholic cirrhosis and nonalcoholic fatty liver disease. The emerging areas of interest were extracellular vesicles, exosomes, and their enriched microRNAs. The field is experiencing rapid growth due to the changing research trends and increasing literature. CONCLUSION These findings provide a thorough overview of stem cell therapy in the field of liver fibrosis and cirrhosis.
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Affiliation(s)
- Wen-Yan Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
- College of Pharmacy, Chongqing Medical University, Chongqing 400016, China
| | - Xiang Li
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jia-Ling Xie
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Qin Lu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China
| | - Ying-Jie Ma
- Office of Scientific Research of Army Medical Center, Army Medical University, Chongqing 400042, China
| | - Zhao-Jing Zhu
- Chongqing Engineering Research Center of Pharmaceutical Sciences, Chongqing Medical and Pharmaceutical College, Chongqing 401331, China
| | - Juan Liu
- Immunology Research Center of Medical Research Institute, Southwest University, Chongqing 402460, China.
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Li X, Chen R, Kemper S, Xu Z, Brigstock DR. Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis. Biomedicines 2025; 13:274. [PMID: 40002688 PMCID: PMC11852249 DOI: 10.3390/biomedicines13020274] [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: 12/12/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
INTRODUCTION Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver failure globally and is characterized by hepatic steatosis and inflammation, which may progress to fibrosis, the severity of which is highly predictive of patient demise and death. In view of the lack of treatment options for MASH, we investigated the therapeutic properties of extracellular vesicles (EVs) from normal human hepatocytes, which we have previously been shown to alleviate toxin-mediated hepatic fibrosis in mice. METHODS C57BI/6J mice were fed a choline-deficient amino acid-defined high (60%) fat (CDAA-HF) diet for up to 12 weeks while receiving i.p. administration of EVs purified from cultured human HepG2 hepatocytes. RESULTS CDAA-HF diet consumption resulted in severe hepatic steatosis, increased frequency of CD45+ lymphocytes and F4/80+ macrophages, robust production of aortic smooth muscle actin (ACTA2), and deposition of interstitial collagen, as well as altered serum levels of ALT, AST, cholesterol, triglycerides, alkaline phosphatase, unconjugated bilirubin, and total protein, thus recapitulating typical MASH phenotypes. EVs administered preventively or therapeutically resulted in the restoration of serum marker levels, reduced hepatic inflammation and attenuation of collagen deposition, ACTA2 production, and expression of fibrosis-associated genes. HepG2 EVs contained 205 miRs and, among the 30 most abundant miRs, seven (miRs-423-5p, -483-5p, -191-5p, -148a-3p, -423-3p, -92a-3p, -122-5p) are predicted to directly target fibrosis-related genes (collagens, ACTA2, MMPs, and TIMPs). CONCLUSIONS Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death.
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Affiliation(s)
- Xinlei Li
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - Ruju Chen
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - Sherri Kemper
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
| | - Zhaohui Xu
- Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA;
| | - David R. Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA; (X.L.); (R.C.); (S.K.)
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
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Krishnan I, Ling MTM, Ng MH, Law JX, Yusof MRM, Thangarajah T, Mahmood Z, Uda Zahli NI, Rajamanickam S, Subramani B, Lokanathan Y. Efficacy of Fetal Wharton's Jelly Mesenchymal Stem Cells-Derived Small Extracellular Vesicles in Metabolic Syndrome. Biomolecules 2025; 15:44. [PMID: 39858439 PMCID: PMC11763124 DOI: 10.3390/biom15010044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/17/2024] [Accepted: 12/23/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVE Metabolic syndrome (MetS) is characterized by abdominal obesity, increased blood pressure (BP), fasting blood glucose (FBG) and triglyceride levels, and reduced high-density lipoprotein (HDL) levels. This study aims to investigate the efficacy of the Wharton's jelly mesenchymal stem cells (WJMSCs)-derived small extracellular vesicles' (sEVs) preparations in managing MetS. METHOD Twenty-four rats were fed with a high-fat and high-fructose diet to induce MetS for 16 weeks and randomized into three groups (n = 8/group): a MetS Control group treated with normal saline, MetS Low Dose (LD) group treated with a LD of sEVs preparations (3 × 109 particle/rat), and MetS High Dose (HD) group treated with a HD of sEVs preparations (9 × 109 particles/rat). The Control Non-Disease (ND) group was given a standard rat diet and autoclaved tap water with normal saline as treatment. Treatments were given via intravenous injection every three weeks for twelve weeks. Rats were assessed every six weeks for physical measurements, FBG, lipid profiles, CRP, leptin, adiponectin, and BP. Necropsy evaluation was performed on the lungs, liver, spleen, and kidney. RESULTS Significant reductions in FBG, triglycerides, BP, and increased HDL levels were observed in the treated groups compared to the control group. However, significant abdominal circumference (AC) improvement was not observed in the treated groups. Non-significant associations were found between fasting CRP, leptin, and adiponectin levels with MetS rats after treatment. In addition, sEVs preparations improved inflammation and hemorrhage in the lung and mineralisation in the renal of the treated group. CONCLUSIONS Human fetal WJMSCs-derived sEVs preparations improve all the clusters of MetS in rats except AC and could be further explored as a treatment for MetS.
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Affiliation(s)
- Illayaraja Krishnan
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (M.T.M.L.); (M.H.N.); (J.X.L.)
| | - Magdalene Tan Mei Ling
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (M.T.M.L.); (M.H.N.); (J.X.L.)
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya (UM), Kuala Lumpur 50603, Malaysia
| | - Min Hwei Ng
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (M.T.M.L.); (M.H.N.); (J.X.L.)
| | - Jia Xian Law
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (M.T.M.L.); (M.H.N.); (J.X.L.)
| | - Mohd Rafizul Mohd Yusof
- Department of Parasitology and Medical Entomology, Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia;
| | - Thavachelvi Thangarajah
- Department of Obstetrics and Gynaecology, Hospital Angkatan Tentera (HAT) Tuanku Mizan, Wangsa Maju, Kuala Lumpur 53300, Malaysia;
| | - Zalina Mahmood
- Production and Blood Supply Management Division, National Blood Centre, Jalan Tun Razak, Kuala Lumpur 50400, Malaysia;
| | - Nurul Izzati Uda Zahli
- Department of Veterinary Pathology and Microbiology, Faculty of Veterinary Medicine, Universiti Putra Malaysia (UPM), Serdang 43400, Malaysia;
| | - Shathiya Rajamanickam
- Medixcell Sdn. Bhd., Level 5, Equatorial Plaza, Lot 5-5 & 5-6, Jalan Sultan Ismail, Kuala Lumpur 50250, Malaysia; (S.R.); (B.S.)
| | - Baskar Subramani
- Medixcell Sdn. Bhd., Level 5, Equatorial Plaza, Lot 5-5 & 5-6, Jalan Sultan Ismail, Kuala Lumpur 50250, Malaysia; (S.R.); (B.S.)
| | - Yogeswaran Lokanathan
- Department of Tissue Engineering and Regenerative Medicine (DTERM), Faculty of Medicine, Universiti Kebangsaan Malaysia (UKM), Cheras, Kuala Lumpur 56000, Malaysia; (I.K.); (M.T.M.L.); (M.H.N.); (J.X.L.)
- Advance Bioactive Materials-Cells UKM Research Group, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
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Zou X, Brigstock D. Extracellular Vesicles from Mesenchymal Stem Cells: Potential as Therapeutics in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Biomedicines 2024; 12:2848. [PMID: 39767754 PMCID: PMC11673942 DOI: 10.3390/biomedicines12122848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 12/06/2024] [Accepted: 12/12/2024] [Indexed: 01/03/2025] Open
Abstract
Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by the accumulation of triglycerides within hepatocytes, which can progress to more severe conditions, such as metabolic dysfunction-associated steatohepatitis (MASH), which may include progressive fibrosis, leading to cirrhosis, cancer, and death. This goal of this review is to highlight recent research showing the potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in reducing the key pathogenic pathways of MASLD or MASH. Methods: Relevant published studies were identified using PubMed with one or more of the following search terms: MASLD, MASH, NAFLD, NASH, exosome, extracellular vesicle (EV), therapy, and/or mesenchymal stem cells (MSC). The primary literature were subsequently downloaded and summarized. Results: Using in vitro or in vivo models, MSC-EVs have been found to counteract oxidative stress, a significant contributor to liver injury in MASH, and to suppress disease progression, including steatosis, inflammation, and, in a few instances, fibrosis. Some of these outcomes have been attributed to specific EV cargo components including microRNAs and proteins. Thus, MSC-EVs enriched with these types of molecules may have improved the therapeutic efficacy for MASLD/MASH and represent a novel approach to potentially halt or reverse the disease process. Conclusions: MSC-EVs are attractive therapeutic agents for treating MASLD/MASH. Further studies are necessary to validate the clinical applicability and efficacy of MSC-EVs in human MASH patients, focusing on optimizing delivery strategies and identifying the pathogenic pathways that are targeted by specific EV components.
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Affiliation(s)
- Xue Zou
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
| | - David Brigstock
- Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH 43212, USA
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Li W, Yu L. Role and therapeutic perspectives of extracellular vesicles derived from liver and adipose tissue in metabolic dysfunction-associated steatotic liver disease. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2024; 52:355-369. [PMID: 38833340 DOI: 10.1080/21691401.2024.2360008] [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: 10/13/2023] [Accepted: 05/22/2024] [Indexed: 06/06/2024]
Abstract
The global epidemic of metabolic diseases has led to the emergence of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), which pose a significant threat to human health. Despite recent advances in research on the pathogenesis and treatment of MASLD/MASH, there is still a lack of more effective and targeted therapies. Extracellular vesicles (EVs) discovered in a wide range of tissues and body fluids encapsulate different activated biomolecules and mediate intercellular communication. Recent studies have shown that EVs derived from the liver and adipose tissue (AT) play vital roles in MASLD/MASH pathogenesis and therapeutics, depending on their sources and intervention types. Besides, adipose-derived stem cell (ADSC)-derived EVs appear to be more effective in mitigating MASLD/MASH. This review presents an overview of the definition, extraction strategies, and characterisation of EVs, with a particular focus on the biogenesis and release of exosomes. It also reviews the effects and potential molecular mechanisms of liver- and AT-derived EVs on MASLD/MASH, and emphasises the contribution and clinical therapeutic potential of ADSC-derived EVs. Furthermore, the future perspective of EV therapy in a clinical setting is discussed.
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Affiliation(s)
- Wandi Li
- Senior Department of Burns and Plastic Surgery, the Fourth Medical Center of PLA General Hospital, Haidian District, Beijing, P.R. China
| | - Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, P.R. China
- Endocrine Department, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Henan, P.R. China
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Gao FQ, Zhu JQ, Feng XD. Innovative mesenchymal stem cell treatments for fatty liver disease. World J Stem Cells 2024; 16:846-853. [PMID: 39351260 PMCID: PMC11438732 DOI: 10.4252/wjsc.v16.i9.846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/26/2024] [Accepted: 09/09/2024] [Indexed: 09/24/2024] Open
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.
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Affiliation(s)
- Fei-Qiong Gao
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou 310003, Zhejiang Province, China
| | - Jia-Qi Zhu
- Laboratory Medicine Center, Department of Clinical Laboratory, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Xu-Dong Feng
- Department of Clinical Laboratory, Ningbo Medical Center Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo 315000, Zhejiang Province, China.
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11
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Chávez-López LM, Carballo-López GI, Lugo-Ibarra KDC, Castro-Ceseña AB. A comprehensive framework for managing metabolic dysfunction-associated steatotic liver disease: analyzing novel risk factors and advances in nanotechnology-based treatments and diagnosis. RSC Med Chem 2024; 15:2622-2642. [PMID: 39149095 PMCID: PMC11324041 DOI: 10.1039/d4md00420e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 08/17/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) presents a growing global health challenge requiring innovative approaches for effective management. This comprehensive review examines novel risk factors, including environmental pollutants like heavy metals, and underscores the complexity of personalized medicine tailored to individual patient profiles, influenced by gender and sex differences. Traditional treatments for MASLD, such as glucose- and lipid-lowering agents, show mixed results, highlighting the necessity for larger, long-term studies to establish safety and efficacy. Alternative therapies, including antioxidants, stem cells, and antiplatelets, although promising, demand extensive clinical trials for validation. This review highlights the importance of personalized medicine, considering individual variations and specific factors such as gender and sex, to optimize treatment responses. The shift from metabolic-associated fatty liver disease (MAFLD) to MASLD terminology underscores the metabolic components of the disease, aligning with the multiple-hit theory and highlighting the necessity for comprehensive risk factor management. Our vision advocates for an integrated approach to MASLD, encompassing extensive risk factor analysis and the development of safer, more effective treatments. Primary prevention and awareness initiatives are crucial in addressing the rising prevalence of MASLD. Future research must prioritize larger, long-term studies and personalized medicine principles to ensure the effective use of emerging therapies and technologies. The review underscores the need for continuous exploration and innovation, balancing the benefits and challenges of nanotechnology, to combat MASLD and improve patient outcomes comprehensively.
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Affiliation(s)
- Lucia M Chávez-López
- Facultad de Medicina, Centro de Estudios Universitarios Xochicalco Campus Ensenada San Francisco 1139, Fraccionamiento Misión C.P. 22830 Ensenada Baja California Mexico
- Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE) Carretera Ensenada-Tijuana No. 3918, Zona Playitas C.P. 22860 Ensenada Baja California Mexico
| | - Gabriela I Carballo-López
- Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE) Carretera Ensenada-Tijuana No. 3918, Zona Playitas C.P. 22860 Ensenada Baja California Mexico
| | | | - Ana B Castro-Ceseña
- Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE) Carretera Ensenada-Tijuana No. 3918, Zona Playitas C.P. 22860 Ensenada Baja California Mexico
- CONAHCYT - Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada, Baja California (CICESE) Carretera Ensenada-Tijuana No. 3918, Zona Playitas C.P. 22860 Ensenada Baja California Mexico
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12
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Masuda A, Nakamura T, Iwamoto H, Suzuki H, Sakaue T, Tanaka T, Imamura Y, Mori N, Koga H, Kawaguchi T. Ex-vivo expanded CD34 + cell transplantation alleviates fibrotic liver injury via innate immune modulation in metabolic dysfunction-associated steatohepatitis mice. Cytotherapy 2024; 26:899-909. [PMID: 38678462 DOI: 10.1016/j.jcyt.2024.03.488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Revised: 03/11/2024] [Accepted: 03/18/2024] [Indexed: 05/01/2024]
Abstract
BACKGROUND In drug-induced liver injury, vascular endothelial progenitor cells, specifically the CD34+ cell fractions, have been found to decrease liver fibrosis and promote regeneration. However, it is unclear whether CD34+ cell transplantation has anti-fibrogenic effects on MASH, which has previously been treated effectively with anti-angiogenic therapy. We investigated the efficacy of ex vivo-expanded CD34+ cells in treating MASH livers. MATERIALS AND METHODS Diet-induced MASH mice were fed a choline-deficient, L-amino acid-defined, high-fat diet for 12 or 20 weeks, and were designated as a mild and a severe fibrosis model, respectively. Mouse bone marrow CD34+ cells were expanded for 7 days, transplanted into each mouse once or twice 2 weeks later, and sacrificed at 4 weeks after the first transplantation. RESULTS Expanded CD34+ cell transplantation ameliorated liver fibrosis, regardless of fibrosis degree, as indicated by the decrease in α-smooth muscle actin-positive cells, hydroxyproline concentration, and fibrogenic gene expression of Col1a1 and Timp1. Furthermore, engrafted CD34+ cells reduced alanine transaminase levels, the number of TUNEL+ hepatocytes, and 8-OHdG concentration. RNA-sequencing data showed that "defense response to virus" was the most down-regulated category in the Gene Ontology analysis and subsequent analysis revealed the suppression of RIG-I-like receptors/Irf7/Stat1/Cxcl10 axis in expanded CD34+ cell-transplanted livers. Finally, the downregulation of CXCL10 expression inhibits the mobilization of inflammatory immune cells, macrophages, T cells, and natural killer cells to the MASH liver. CONCLUSIONS These findings suggest that transplanted expanded CD34+ cells alleviate fibrotic liver injury in MASH mouse models through possible modulation of the innate immune response, which is abnormally activated by hepatocyte lipotoxicity.
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Affiliation(s)
- Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan.
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Yasuko Imamura
- Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Nobuyuki Mori
- Department of Social Welfare, Kyushu University of Nursing and Social Welfare, Tamana, Kumamoto, 8650061, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan; Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University, Kurume, Fukuoka, 8300011, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka, 8300011, Japan
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13
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Jiang Y, Yusoff NM, Du J, Moses EJ, Lin JT. Current perspectives on mesenchymal stem cells as a potential therapeutic strategy for non-alcoholic fatty liver disease. World J Stem Cells 2024; 16:760-772. [PMID: 39086561 PMCID: PMC11287429 DOI: 10.4252/wjsc.v16.i7.760] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/18/2024] [Accepted: 06/14/2024] [Indexed: 07/25/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as a significant health challenge, characterized by its widespread prevalence, intricate natural progression and multifaceted pathogenesis. Although NAFLD initially presents as benign fat accumulation, it may progress to steatosis, non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Mesenchymal stem cells (MSCs) are recognized for their intrinsic self-renewal, superior biocompatibility, and minimal immunogenicity, positioning them as a therapeutic innovation for liver diseases. Therefore, this review aims to elucidate the potential roles of MSCs in alleviating the progression of NAFLD by alteration of underlying molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. The insights are expected to provide further understanding of the potential of MSCs in NAFLD therapeutics, and support the development of MSC-based therapy in the treatment of NAFLD.
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Affiliation(s)
- Yan Jiang
- School of Nursing, Xinxiang Medical University, Xinxiang 453000, Henan Province, China
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Narazah Mohd Yusoff
- Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Jiang Du
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
| | - Emmanuel Jairaj Moses
- Department of Biomedical Sciences, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas 13200, Pulau Pinang, Malaysia
| | - Jun-Tang Lin
- Stem Cells and Biotherapy Engineering Research Center of Henan, National Joint Engineering Laboratory of Stem Cells and Biotherapy, School of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, Henan Province, China
- Henan Joint International Research Laboratory of Stem Cell Medicine, School of Medical Engineering, Xinxiang Medical University, Xinxiang 453000, Henan Province, China.
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14
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Mladenović D, Vesković M, Šutulović N, Hrnčić D, Stanojlović O, Radić L, Macut JB, Macut D. Adipose-derived extracellular vesicles - a novel cross-talk mechanism in insulin resistance, non-alcoholic fatty liver disease, and polycystic ovary syndrome. Endocrine 2024; 85:18-34. [PMID: 38285412 DOI: 10.1007/s12020-024-03702-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/14/2024] [Indexed: 01/30/2024]
Abstract
Obesity is the best described risk factor for the development of non-alcoholic fatty liver disease (NAFLD)/metabolic dysfunction associated steatotic liver disease (MASLD) and polycystic ovary syndrome (PCOS) while the major pathogenic mechanism linking these entities is insulin resistance (IR). IR is primarily caused by increased secretion of proinflammatory cytokines, adipokines, and lipids from visceral adipose tissue. Increased fatty acid mobilization results in ectopic fat deposition in the liver which causes endoplasmic reticulum stress, mitochondrial dysfunction, and oxidative stress resulting in increased cytokine production and subsequent inflammation. Similarly, IR with hyperinsulinemia cause hyperandrogenism, the hallmark of PCOS, and inflammation in the ovaries. Proinflammatory cytokines from both liver and ovaries aggravate IR thus providing a complex interaction between adipose tissue, liver, and ovaries in inducing metabolic abnormalities in obese subjects. Although many pathogenic mechanisms of IR, NAFLD/MASLD, and PCOS are known, there is still no effective therapy for these entities suggesting the need for further evaluation of their pathogenesis. Extracellular vesicles (EVs) represent a novel cross-talk mechanism between organs and include membrane-bound vesicles containing proteins, lipids, and nucleic acids that may change the phenotype and function of target cells. Adipose tissue releases EVs that promote IR, the development of all stages of NAFLD/MASLD and PCOS, while mesenchymal stem cell-derived AVs may alleviate metabolic abnormalities and may represent a novel therapeutic device in NAFLD/MASLD, and PCOS. The purpose of this review is to summarize the current knowledge on the role of adipose tissue-derived EVs in the pathogenesis of IR, NAFLD/MASLD, and PCOS.
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Affiliation(s)
- Dušan Mladenović
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
| | - Milena Vesković
- Institute of Pathophysiology "Ljubodrag Buba Mihailovic", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Nikola Šutulović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Dragan Hrnčić
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Olivera Stanojlović
- Laboratory for Neurophysiology, Institute of Medical Physiology "Richard Burian", Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Lena Radić
- Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
| | - Jelica Bjekić Macut
- University of Belgrade Faculty of Medicine, Department of Endocrinology, UMC Bežanijska kosa, Belgrade, Serbia
| | - Djuro Macut
- University of Belgrade Faculty of Medicine, Clinic for Endocrinology, Diabetes and Metabolic Diseases, University Clinical Centre of Serbia, Belgrade, Serbia
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15
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Lou K, Luo H, Jiang X, Feng S. Applications of emerging extracellular vesicles technologies in the treatment of inflammatory diseases. Front Immunol 2024; 15:1364401. [PMID: 38545101 PMCID: PMC10965547 DOI: 10.3389/fimmu.2024.1364401] [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: 01/02/2024] [Accepted: 03/04/2024] [Indexed: 04/17/2024] Open
Abstract
The emerging extracellular vesicles technologies is an advanced therapeutic approach showing promising potential for addressing inflammatory diseases. These techniques have been proven to have positive effects on immune modulation and anti-inflammatory responses. With these advancements, a comprehensive review and update on the role of extracellular vesicles in inflammatory diseases have become timely. This review aims to summarize the research progress of extracellular vesicle technologies such as plant-derived extracellular vesicles, milk-derived extracellular vesicles, mesenchymal stem cell-derived extracellular vesicles, macrophage-derived extracellular vesicles, etc., in the treatment of inflammatory diseases. It elucidates their potential significance in regulating inflammation, promoting tissue repair, and treating diseases. The goal is to provide insights for future research in this field, fostering the application and development of extracellular vesicle technology in the treatment of inflammatory diseases.
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Affiliation(s)
- Kecheng Lou
- Department of Urology, Lanxi People’s Hospital, Jinhua, Zhejiang, China
| | - Hui Luo
- The First Clinical College, Gannan Medical University, Ganzhou, Jiangxi, China
| | - Xinghua Jiang
- Department of Urology, Jingdezhen Second People’s Hospital, Jingdezhen, Jiangxi, China
| | - Shangzhi Feng
- Department of Urology, Jiujiang University Clinic College/Hospital, Jiujiang, Jiangxi, China
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16
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Zhu L, Wang Q, Guo M, Fang H, Li T, Zhu Y, Jiang H, Xiao P, Hu M. Mesenchymal Stem Cell-Derived Exosomes in Various Chronic Liver Diseases: Hype or Hope? J Inflamm Res 2024; 17:171-189. [PMID: 38223423 PMCID: PMC10788055 DOI: 10.2147/jir.s439974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 12/27/2023] [Indexed: 01/16/2024] Open
Abstract
Chronic liver conditions are associated with high mortality rates and have a large adverse effect on human well-being as well as a significant financial burden. Currently, the only effective treatment available for the effects of liver failure and cirrhosis resulting from the progression of several chronic liver diseases is liver transplantation carried out at the original location. This implies that developing novel and effective treatments is imperative. Regenerative medicine has long been associated with stem cell therapy. Mesenchymal stem cells (MSCs), a type of cell with great differentiation potential, have become the preferred source for stem cell therapy. According to recent studies, MSCs' paracrine products-rather than their capacity for differentiation-play a significant therapeutic effect. MSC exosomes, a type of extracellular vesicle (MSC-EV), came into view as the paracrine substances of MSCs. According to research, MSC exosomes can maintain tissue homeostasis, which is necessary for healthy tissue function. All tissues contain them, and they take part in a variety of biological activities that support cellular activity and tissue regeneration in order to preserve tissue homeostasis. The outcomes support the use of MSCs and the exosomes they produce as a therapeutic option for a range of diseases. This review provides a brief overview of the source of MSC-EVs and outlines their physiological roles and biochemical capabilities. The elucidation of the role of MSC-EVs in the recovery and repair of hepatic tissues, as well as their contribution to maintaining tissue homeostasis, is discussed in relation to different chronic liver diseases. This review aims to provide new insights into the unique roles that MSC-EVs play in the treatment of chronic liver diseases.
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Affiliation(s)
- Lujian Zhu
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Qin Wang
- Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Maodong Guo
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Hao Fang
- Department of Traumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Ting Li
- Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China
| | - Yin Zhu
- Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China
| | - Huimian Jiang
- Department of Infectious Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China
| | - Peiguang Xiao
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
| | - Minli Hu
- Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China
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17
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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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18
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Ling MTM, Govindaraju K, Lokanathan Y, Abidin AZ, Ibrahim B. Mesenchymal stem cell-derived extracellular vesicles for metabolic syndrome therapy: Assessing efficacy with nuclear magnetic resonance spectroscopy. Cell Biochem Funct 2023; 41:1044-1059. [PMID: 37933415 DOI: 10.1002/cbf.3881] [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: 05/27/2023] [Revised: 09/27/2023] [Accepted: 10/21/2023] [Indexed: 11/08/2023]
Abstract
Metabolic syndrome (MetS) represents a cluster of metabolic abnormalities. The prevalence of MetS has surged, transforming it into a pressing public health concern that could potentially affect around 20%-25% of the global population. As MetS continues its ascent, diverse interventions, pharmacological, nonpharmacological and combined have been deployed. Yet, a comprehensive remedy that fully eradicates MetS symptoms remains elusive, compounded by the risks of polypharmacy's emergence. Acknowledging the imperative to grasp MetS's intricate pathologies, deeper insights for future research and therapy optimisation become paramount. Conventional treatments often target specific syndrome elements. However, a novel approach emerges in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) therapy, promising a holistic shift. MSC-EVs, tiny membranous vesicles secreted by mesenchymal stem cells, have garnered immense attention for their multifaceted bioactivity and regenerative potential. Their ability to modulate inflammation, enhance tissue repair and regulate metabolic pathways has prompted researchers to explore their therapeutic application in MetS. This review primarily aims to provide an overview of how MSC-EVs therapy can improve metabolic parameters in subjects with MetS disease and also introduce the usefulness of NMR spectroscopy in assessing the efficacy of MSC-EVs therapy for treating MetS.
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Affiliation(s)
- Magdalene Tan Mei Ling
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Kayatri Govindaraju
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
| | - Yogeswaran Lokanathan
- Centre for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Asmaa' Zainal Abidin
- Department of Chemistry and Biology, Centre for Defense Foundation Studies, Universiti Pertahanan Nasional Malaysia, Kuala Lumpur, Malaysia
| | - Baharudin Ibrahim
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Universiti Malaya, Kuala Lumpur, Malaysia
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19
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Kholodenko IV, Yarygin KN. Hepatic Macrophages as Targets for the MSC-Based Cell Therapy in Non-Alcoholic Steatohepatitis. Biomedicines 2023; 11:3056. [PMID: 38002056 PMCID: PMC10669188 DOI: 10.3390/biomedicines11113056] [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: 10/15/2023] [Revised: 11/02/2023] [Accepted: 11/03/2023] [Indexed: 11/26/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a serious public health issue associated with the obesity pandemic. Obesity is the main risk factor for the non-alcoholic fatty liver disease (NAFLD), which progresses to NASH and then to end-stage liver disease. Currently, there are no specific pharmacotherapies of NAFLD/NASH approved by the FDA or other national regulatory bodies and the treatment includes lifestyle adjustment and medicines for improving lipid metabolism, enhancing sensitivity to insulin, balancing oxidation, and counteracting fibrosis. Accordingly, further basic research and development of new therapeutic approaches are greatly needed. Mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles prevent induced hepatocyte death in vitro and attenuate NASH symptoms in animal models of the disease. They interact with hepatocytes directly, but also target other liver cells, including Kupffer cells and macrophages recruited from the blood flow. This review provides an update on the pathogenesis of NAFLD/NASH and the key role of macrophages in the development of the disease. We examine in detail the mechanisms of the cross-talk between the MSCs and the macrophages, which are likely to be among the key targets of MSCs and their derivatives in the course of NAFLD/NASH cell therapy.
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Affiliation(s)
- Irina V. Kholodenko
- Laboratory of Cell Biology, Orekhovich Institute of Biomedical Chemistry, 119121 Moscow, Russia;
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20
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Kim J, Lee SK, Jeong SY, You H, Han SD, Park S, Kim S, Kim TM. Multifaceted action of stem cell-derived extracellular vesicles for nonalcoholic steatohepatitis. J Control Release 2023; 364:S0168-3659(23)00706-X. [PMID: 39491172 DOI: 10.1016/j.jconrel.2023.10.045] [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: 06/22/2023] [Revised: 10/24/2023] [Accepted: 10/27/2023] [Indexed: 11/05/2024]
Abstract
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with metabolic syndrome. Extracellular vesicles (EVs) are essential signaling mediators containing functional biomolecules. EVs are secreted from various cell types, and recent studies have shown that mesenchymal stem cell-derived EVs have therapeutic potential against immune and metabolic diseases. In this study, we investigated whether EVs from induced mesenchymal stem cells (iMSC-EVs) regulate AMPK signaling and lipid metabolism using cell-based studies and two different mouse models of NASH (methionine/choline-deficient diet-induced and ob/ob mice). Protein analysis revealed that iMSC-EVs carry cargo proteins with the potential to regulate lipid metabolism. iMSC-EVs inhibited free fatty acid release from adipose tissues by downregulating the activity of lipolytic genes in NASH. In addition, iMSC-EVs improved hepatic steatosis by modulating AMPK signaling, which plays essential role in metabolic homeostasis in the liver. Moreover, iMSC-EVs reduced CD36 expression, contributing to the blockade of free fatty acid transport to the liver of NASH mice. Finally, iMSC-EVs reduced inflammation, endoplasmic reticulum stress, and apoptosis while promoting hepatic regeneration of the NASH liver. In conclusion, iMSC-EVs can potentially serve as cell-free therapeutics for NASH owing to their multifaceted modality.
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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
| | - 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
| | - Sang-Deok Han
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Somi Park
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Soo Kim
- Brexogen Research Center, Brexogen Inc., Songpa-Gu, Seoul 05855, South Korea
| | - Tae Min Kim
- Graduate School of International Agricultural Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea; Institutes of Green-Bio Science and Technology, Seoul National University, Pyeongchang, Gangwon-do 25354, South Korea.
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21
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Takeda N, Tsuchiya A, Mito M, Natsui K, Natusi Y, Koseki Y, Tomiyoshi K, Yamazaki F, Yoshida Y, Abe H, Sano M, Kido T, Yoshioka Y, Kikuta J, Itoh T, Nishimura K, Ishii M, Ochiya T, Miyajima A, Terai S. Analysis of distribution, collection, and confirmation of capacity dependency of small extracellular vesicles toward a therapy for liver cirrhosis. Inflamm Regen 2023; 43:48. [PMID: 37814342 PMCID: PMC10561446 DOI: 10.1186/s41232-023-00299-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/24/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND The progression of liver fibrosis leads to portal hypertension and liver dysfunction. However, no antifibrotic agents have been approved for cirrhosis to date, making them an unmet medical need. Small extracellular vesicles (sEVs) of mesenchymal stem cells (MSCs) are among these candidate agents. In this study, we investigated the effects of sEVs of MSCs, analyzed their distribution in the liver post-administration, whether their effect was dose-dependent, and whether it was possible to collect a large number of sEVs. METHODS sEVs expressing tdTomato were generated, and their uptake into constituent liver cells was observed in vitro, as well as their sites of uptake and cells in the liver using a mouse model of liver cirrhosis. The efficiency of sEV collection using tangential flow filtration (TFF) and changes in the therapeutic effects of sEVs in a volume-dependent manner were examined. RESULTS The sEVs of MSCs accumulated mostly in macrophages in damaged areas of the liver. In addition, the therapeutic effect of sEVs was not necessarily dose-dependent, and it reached a plateau when the dosage exceeded a certain level. Furthermore, although ultracentrifugation was commonly used to collect sEVs for research purposes, we verified that TFF could be used for efficient sEV collection and that their effectiveness is not reduced. CONCLUSION In this study, we identified some unknown aspects regarding the dynamics, collection, and capacity dependence of sEVs. Our results provide important fundamentals for the development of therapies using sEVs and hold potential implications for the therapeutic applications of sEV-based therapies for liver cirrhosis.
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Affiliation(s)
- Nobutaka Takeda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan.
- Future Medical Research Center for Exosome and Designer Cell (F-EDC), Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan.
| | - Masaki Mito
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Yui Natusi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Yohei Koseki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Kei Tomiyoshi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Fusako Yamazaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Yuki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan
| | - Masayuki Sano
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Central 5, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8565, Japan
| | - Taketomo Kido
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, University of Tokyo, Tokyo, 113-0032, Japan
| | - Yusuke Yoshioka
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Junichi Kikuta
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Tohru Itoh
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, University of Tokyo, Tokyo, 113-0032, Japan
| | - Ken Nishimura
- Laboratory of Gene Regulation, Institute of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan
| | - Masaru Ishii
- Department of Immunology and Cell Biology, Graduate School of Medicine and Frontier Biosciences, Osaka University, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan
| | - Atsushi Miyajima
- Laboratory of Stem Cell Therapy, Institute for Quantitative Biosciences, University of Tokyo, Tokyo, 113-0032, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan.
- Future Medical Research Center for Exosome and Designer Cell (F-EDC), Niigata University, 1-757 Asahimachi-Dori, Chuo-Ku, Niigata, 951-8510, Japan.
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22
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Jiang W, Xu Y, Chen JC, Lee YH, Hu Y, Liu CH, Chen E, Tang H, Zhang H, Wu D. Role of extracellular vesicles in nonalcoholic fatty liver disease. Front Endocrinol (Lausanne) 2023; 14:1196831. [PMID: 37534206 PMCID: PMC10392952 DOI: 10.3389/fendo.2023.1196831] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 06/21/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that affects approximately one-quarter of the global population and is becoming increasingly prevalent worldwide. The lack of current noninvasive tools and efficient treatment is recognized as a significant barrier to the clinical management of these conditions. Extracellular vesicles (EVs) are nanoscale vesicles released by various cells and deliver bioactive molecules to target cells, thereby mediating various processes, including the development of NAFLD. SCOPE OF REVIEW There is still a long way to actualize the application of EVs in NAFLD diagnosis and treatment. Herein, we summarize the roles of EVs in NAFLD and highlight their prospects for clinical application as a novel noninvasive diagnostic tool as well as a promising therapy for NAFLD, owing to their unique physiochemical characteristics. We summarize the literatures on the mechanisms by which EVs act as mediators of intercellular communication by regulating metabolism, insulin resistance, inflammation, immune response, intestinal microecology, and fibrosis in NAFLD. We also discuss future challenges that must be resolved to improve the therapeutic potential of EVs. MAJOR CONCLUSIONS The levels and contents of EVs change dynamically at different stages of diseases and this phenomenon may be exploited for establishing sensitive stage-specific markers. EVs also have high application potential as drug delivery systems with low immunogenicity and high biocompatibility and can be easily engineered. Research on the mechanisms and clinical applications of EVs in NAFLD is in its initial phase and the applicability of EVs in NAFLD diagnosis and treatment is expected to grow with technological progress.
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Affiliation(s)
- Wei Jiang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Youhui Xu
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Jou-Chen Chen
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yi-Hung Lee
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Yushin Hu
- West China College of Stomatology, Sichuan University, Chengdu, China
| | - Chang-Hai Liu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Enqiang Chen
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Hua Zhang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China
- NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, China
- Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Dongbo Wu
- Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, China
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Yang F, Wu Y, Chen Y, Xi J, Chu Y, Jin J, Yan Y. Human umbilical cord mesenchymal stem cell-derived exosomes ameliorate liver steatosis by promoting fatty acid oxidation and reducing fatty acid synthesis. JHEP Rep 2023; 5:100746. [PMID: 37274776 PMCID: PMC10232730 DOI: 10.1016/j.jhepr.2023.100746] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 03/06/2023] [Accepted: 03/14/2023] [Indexed: 06/07/2023] Open
Abstract
Background & Aims Non-alcoholic fatty liver disease (NAFLD) affects nearly a quarter of the population with no approved pharmacological therapy. Liver steatosis is a primary characteristic of NAFLD. Recent studies suggest that human umbilical cord mesenchymal stem cell-derived exosomes (MSC-ex) may provide a promising strategy for treating liver injury; however, the role and underlying mechanisms of MSC-ex in steatosis are not fully understood. Methods Oleic-palmitic acid-treated hepatic cells and high-fat diet (HFD)-induced NAFLD mice were established to observe the effect of MSC-ex. Using non-targeted lipidomics and transcriptome analyses, we analysed the gene pathways positively correlated with MSC-ex. Mass spectrometry and gene knockdown/overexpression analyses were performed to evaluate the effect of calcium/calmodulin-dependent protein kinase 1 (CAMKK1) transferred by MSC-ex on lipid homoeostasis regulation. Results Here, we demonstrate that MSC-ex promote fatty acid oxidation and reduce lipogenesis in oleic-palmitic acid-treated hepatic cells and HFD-induced NAFLD mice. Non-targeted lipidomics and transcriptome analyses suggested that the effect of MSC-ex on lipid accumulation positively correlated with the phosphorylation of AMP-activated protein kinase. Furthermore, mass spectrometry and gene knockdown/overexpression analyses revealed that MSC-ex-transferred CAMKK1 is responsible for ameliorating lipid accumulation in an AMP-activated protein kinase-dependent manner, which subsequently inhibits SREBP-1C-mediated fatty acid synthesis and enhances peroxisome proliferator-activated receptor alpha (PPARα)-mediated fatty acid oxidation. Conclusions MSC-ex may prevent HFD-induced NAFLD via CAMKK1-mediated lipid homoeostasis regulation. Impact and Implications NAFLD includes many conditions, from simple steatosis to non-alcoholic steatohepatitis, which can lead to fibrosis, cirrhosis, and even hepatocellular carcinoma. So far, there is no approved drug for treating liver steatosis of NAFLD. Thus, better therapies are needed to regulate lipid metabolism and prevent the progression from liver steatosis to chronic liver disease. By using a combination of non-targeted lipidomic and transcriptome analyses, we revealed that human umbilical cord mesenchymal stem cell-derived exosomes (MSC-ex) effectively reduced lipid deposition and improved liver function from HFD-induced liver steatosis. Our study highlights the importance of exosomal CAMKK1 from MSC-ex in mediating lipid metabolism regulation via AMPK-mediated PPARα/CPT-1A and SREBP-1C/fatty acid synthase signalling in hepatocytes. These findings are significant in elucidating novel mechanisms related to MSC-ex-based therapies for preventing NAFLD.
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Affiliation(s)
- Fuji Yang
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanshuang Wu
- School of Medicine, Jiangsu University, Zhenjiang, China
- Department of Laboratory Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yifei Chen
- School of Medicine, Jiangsu University, Zhenjiang, China
| | - Jianbo Xi
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, China
| | - Ying Chu
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, China
| | - Jianhua Jin
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, China
| | - Yongmin Yan
- Department of Laboratory Medicine, Wujin Hospital Affiliated with Jiangsu University, Jiangsu University, Changzhou, China
- Changzhou Key Laboratory of Molecular Diagnostics and Precision Cancer Medicine, Wujin Hospital Affiliated with Jiangsu University (Wujin Clinical College of Xuzhou Medical University), Changzhou, China
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Vp V, Kannan A, Perumal MK. Role of adipocyte-derived extracellular vesicles during the progression of liver inflammation to hepatocellular carcinoma. J Cell Physiol 2023; 238:1125-1140. [PMID: 36960683 DOI: 10.1002/jcp.31008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/03/2023] [Accepted: 03/11/2023] [Indexed: 03/25/2023]
Abstract
Extracellular vesicles are membrane-bound cargos that vary in size and are stably transported through various bodily fluids. Extracellular vesicles communicate information between the cells and organs. Extracellular vesicles from the diseased cells alter cellular responses of the recipient cells contributing to disease progression. In obesity, adipocytes become hypertrophic and the extracellular vesicles from these dysfunctional adipocytes showed altered cargo contents instigating pathophysiological response leading to chronic liver diseases. In this review, the role of adipocyte-derived extracellular vesicles on the progression of liver inflammation, fibrosis, cirrhosis, and hepatocellular carcinoma are extensively discussed. Newer approaches are crucial to take advantage of extracellular vesicles and their content as biomarkers to diagnose initial liver inflammation before reaching to an irreversible liver failure stage.
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Affiliation(s)
- Venkateish Vp
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Anbarasu Kannan
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Madan Kumar Perumal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore, Karnataka, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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25
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Watanabe Y, Abe H, Kimura N, Arao Y, Ishikawa N, Yuichiro M, Setsu T, Sakamaki A, Kamimura H, Yokoo T, Kamimura K, Tsuchiya A, Terai S. Navitoclax improves acute-on-chronic liver failure by eliminating senescent cells in mice. Hepatol Res 2023; 53:460-472. [PMID: 36628578 DOI: 10.1111/hepr.13879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 12/21/2022] [Accepted: 12/25/2022] [Indexed: 01/12/2023]
Abstract
AIM Acute-on-chronic liver failure (ACLF), a disease with poor prognosis, is reportedly caused by cellular senescence due to mitochondrial dysfunction. In this study, we described and analyzed the underlying mechanism of a novel approach for ACLF using ABT263/navitoclax (Navi) that selectively eliminates senescent cells. METHODS Irradiation-induced senescent hepatocytes were used for in vitro evaluation of the effects of Navi on ACLF (n = 6 for each group). Lipopolysaccharide- and carbon tetrachloride-induced ACLF mouse model was used for in vivo evaluation of the effects of Navi administration compared with the control using one-way or two-way analysis of variance, followed by Student's t-test or Kruskal-Wallis test. The effects on the senescence-associated secretory phenotype (n = 8 for each group) and mitochondrial functions, including adenosine triphosphate concentration and membrane potential (n = 8 for each group), were investigated using real-time polymerase chain reaction, immunohistochemistry, and enzyme analysis. RESULTS Navi eliminated irradiation-induced senescent hepatocytes in vitro, leading to non-senescent hepatocyte proliferation. Navi eliminated senescent cells in the liver in vivo, resulting in downregulation of mRNA expression of senescence-associated secretory phenotype factors, a decrease of liver enzymes, and upregulated proliferation of non-senescent cells in the liver. Regarding mitochondrial functional assessment in the liver, adenosine triphosphate concentration and membrane potential were upregulated after Navi administration in vitro and in vivo. CONCLUSIONS Navi may ameliorate ACLF damage by eliminating senescent cells in the liver, downregulating senescence-associated secretory phenotype factors, and upregulating mitochondrial functions. We believe that this novel approach using Navi will pave the way for ACLF treatment.
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Affiliation(s)
- Yusuke Watanabe
- Division of Preemptive Medicine for Digestive Disease and Healthy Active Life, School of Medicine, Niigata University, Niigata, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroyuki Abe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yoshihisa Arao
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Natsuki Ishikawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Maeda Yuichiro
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Toru Setsu
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Akira Sakamaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takeshi Yokoo
- Division of Preemptive Medicine for Digestive Disease and Healthy Active Life, School of Medicine, Niigata University, Niigata, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kenya Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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Zhang B, Zhang B, Lai RC, Sim WK, Lam KP, Lim SK. MSC-sEV Treatment Polarizes Pro-Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH. Int J Mol Sci 2023; 24:ijms24098092. [PMID: 37175803 PMCID: PMC10179074 DOI: 10.3390/ijms24098092] [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: 03/03/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Mesenchymal stem/stromal cell small extracellular vesicles (MSC-sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC-sEV use is an important consideration. One concern is that MSC-sEVs have been shown to induce M2 macrophage polarization, which is known to be pro-fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC-sEVs alleviate high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH). To assess whether the pro-fibrotic M2 macrophage polarization induced by MSC-sEVs could worsen liver fibrosis, we first verified that our MSC-sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC-sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle- and Telmisartan-treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL-6 levels were reduced in MSC-sEV treated animals, our data suggests that MSC-sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro-fibrotic M2 macrophage polarization.
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Affiliation(s)
- Bin Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Biyan Zhang
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
| | - Ruenn Chai Lai
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Wei Kian Sim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
| | - Kong Peng Lam
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Singapore 117545, Singapore
- School of Biological Sciences, College of Science, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - Sai Kiang Lim
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Singapore
- Department of Surgery, YLL School of Medicine, NUS, 5 Lower Kent Ridge Road, Singapore 119074, Singapore
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27
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Lopez-Yus M, García-Sobreviela MP, del Moral-Bergos R, Arbones-Mainar JM. Gene Therapy Based on Mesenchymal Stem Cells Derived from Adipose Tissue for the Treatment of Obesity and Its Metabolic Complications. Int J Mol Sci 2023; 24:7468. [PMID: 37108631 PMCID: PMC10138576 DOI: 10.3390/ijms24087468] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/12/2023] [Accepted: 04/16/2023] [Indexed: 04/29/2023] Open
Abstract
Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs.
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Affiliation(s)
- Marta Lopez-Yus
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
| | - Maria Pilar García-Sobreviela
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
| | - Raquel del Moral-Bergos
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
| | - Jose M. Arbones-Mainar
- Adipocyte and Fat Biology Laboratory (AdipoFat), Translational Research Unit, University Hospital Miguel Servet, 50009 Zaragoza, Spain
- Instituto Aragones de Ciencias de la Salud (IACS), 50009 Zaragoza, Spain
- Instituto de Investigación Sanitaria (IIS) Aragon, 50009 Zaragoza, Spain
- CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, 28029 Madrid, Spain
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Fang X, Gao F, Yao Q, Xu H, Yu J, Cao H, Li S. Pooled Analysis of Mesenchymal Stromal Cell-Derived Extracellular Vesicle Therapy for Liver Disease in Preclinical Models. J Pers Med 2023; 13:441. [PMID: 36983624 PMCID: PMC10056150 DOI: 10.3390/jpm13030441] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 02/25/2023] [Accepted: 02/26/2023] [Indexed: 03/05/2023] Open
Abstract
BACKGROUND Although increasing preclinical studies have emphasized the benefits of exosome-related therapies, the efficacy of mesenchymal stromal cell (MSC)-derived extracellular vesicles (EV) for liver injury is unclear. In this work, a pooled analysis was conducted to explore the overall effect of MSC-EV in animal models. METHODS A systematic search of the PubMed, EMBASE, Web of Science, and Cochrane Library databases was performed, from initiation to February 2022, for preclinical studies with liver disease models. The treatment outcomes were evaluated based on liver function, histological analysis, and inflammatory cytokines. RESULTS After screening, 39 studies were included. Pooled analyses demonstrated that MSC-EV therapy significantly improved liver functions (ALB, ALT, AST, ALP, and γ-GT), promoted the repair of injured liver tissue (damaged area, Ishak's score), reduced inflammatory factors (TNF-α, IL-1β, IL-6, and IFN-γ), and increased an anti-inflammatory cytokine (IL-10) compared to the placebo control group. Subgroup analyses indicated that MSC-EV had therapeutic effects on liver fibrosis (n = 16), acute liver injury (n = 11), non-alcoholic fatty liver disease (n = 3), autoimmune hepatitis (n = 4), and hepatic ischemia-reperfusion injury (n = 6). Additionally, the therapeutic effect of EV was comparable to that of MSCs. CONCLUSION MSC-EV have therapeutic potential for acute and chronic liver diseases.
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Affiliation(s)
- Xinru Fang
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 310003, China
| | - Feiqiong Gao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qigu Yao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Haoying Xu
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Laboratory Medicine, The Fourth Affiliated Hospital, International Institutes of Medicine, Zhejiang University School of Medicine, Yiwu 310003, China
| | - Jiong Yu
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongcui Cao
- State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
- Key Laboratory of Diagnosis and Treatment of Aging and Physic-Chemical Injury Diseases of Zhejiang Province, 79 Qingchun Rd, Hangzhou 310003, China
| | - Shibo Li
- Department of Infectious Disease, Zhoushan Hospital, Zhejiang University School of Medicine, Zhoushan 316021, China
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Natsui K, Tsuchiya A, Imamiya R, Osada-Oka M, Ishii Y, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Ohashi R, Ling Y, Ueda K, Moritoki N, Sato K, Nakajima T, Hasegawa Y, Okuda S, Shibata S, Terai S. Escherichia coli-derived outer-membrane vesicles induce immune activation and progression of cirrhosis in mice and humans. Liver Int 2023; 43:1126-1140. [PMID: 36751961 DOI: 10.1111/liv.15539] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/14/2023] [Accepted: 02/05/2023] [Indexed: 02/09/2023]
Abstract
BACKGROUND AND AIMS Decompensated cirrhosis with fibrosis progression causes portal hypertension followed by an oedematous intestinal tract. These conditions weaken the barrier function against bacteria in the intestinal tract, a condition called leaky gut, resulting in invasion by bacteria and bacterial components. Here, we investigated the role of outer-membrane vesicles (OMVs) of Escherichia coli, which is the representative pathogenic gut-derived bacteria in patients with cirrhosis in the pathogenesis of cirrhosis. METHODS We investigated the involvement of OMVs in humans using human serum and ascites samples and also investigated the involvement of OMVs from E. coli in mice using mouse liver-derived cells and a mouse cirrhosis model. RESULTS In vitro, OMVs induced inflammatory responses to macrophages and neutrophils, including the upregulation of C-type lectin domain family 4 member E (Clec4e), and induced the suppression of albumin production in hepatocytes but had a relatively little direct effect on hepatic stellate cells. In a mouse cirrhosis model, administration of OMVs led to increased liver inflammation, especially affecting the activation of macrophages, worsening fibrosis and decreasing albumin production. Albumin administration weakened these inflammatory changes. In addition, multiple antibodies against bacterial components were increased with a progressing Child-Pugh grade, and OMVs were detected in ascites of patients with decompensated cirrhosis. CONCLUSIONS In conclusion, OMVs induce inflammation, fibrosis and suppression of albumin production, affecting the pathogenesis of cirrhosis. We believe that our study paves the way for the future prevention and treatment of cirrhosis.
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Affiliation(s)
- Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.,Future Medical Research Center for Exosome and Designer Cell (F-DEC), Niigata University, Niigata, Japan
| | - Risa Imamiya
- Food Hygiene and Environmental Health, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Mayuko Osada-Oka
- Food Hygiene and Environmental Health, Division of Applied Life Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto, Japan
| | - Yui Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yohei Koseki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Nobutaka Takeda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kei Tomiyoshi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Fusako Yamazaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Riuko Ohashi
- Histopathology Core Facility, Niigata University Faculty of Medicine, Niigata, Japan
| | - Yiwei Ling
- Medical AI Center, Niigata University School of Medicine, Niigata, Japan
| | - Koji Ueda
- Project for Realization of Personalized Cancer Medicine, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Nobuko Moritoki
- Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan
| | - Kazuhiro Sato
- Laboratory of Clinical Omics Research, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
| | - Takahiro Nakajima
- Laboratory of Medical Omics Research, KAZUSA DNA Research Institute, Chiba, Japan
| | - Yoshinori Hasegawa
- Laboratory of Clinical Omics Research, Department of Applied Genomics, Kazusa DNA Research Institute, Chiba, Japan
| | - Shujiro Okuda
- Medical AI Center, Niigata University School of Medicine, Niigata, Japan
| | - Shinsuke Shibata
- Future Medical Research Center for Exosome and Designer Cell (F-DEC), Niigata University, Niigata, Japan.,Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.,Division of Microscopic Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan.,Future Medical Research Center for Exosome and Designer Cell (F-DEC), Niigata University, Niigata, Japan
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Eguchi A, Iwasa M, Nakagawa H. Extracellular vesicles in fatty liver disease and steatohepatitis: Role as biomarkers and therapeutic targets. Liver Int 2023; 43:292-298. [PMID: 36462157 DOI: 10.1111/liv.15490] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 01/01/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) are characterized by lipid deposition in hepatocytes in the absence or presence of excessive alcohol consumption, respectively, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) or alcoholic hepatitis (AH) and from mild fibrosis to cirrhosis. Fatty liver disease and steatohepatitis similarly occur in individuals who have both metabolic syndrome and excessive alcohol intake; therefore, the single overarching term metabolic associated fatty liver disease (MAFLD) has been proposed to better reflect these risk factors and the continuity of disease progression. Extracellular vesicles (EVs) are membrane-bound endogenous nanoparticles released into the extracellular space by a majority of cell types. Liver disease-related EVs contain a variety of cellular cargo and are internalized into target cells resulting in the transfer of bioinformation reflecting the state of the donor cell to the recipient. Furthermore, EV composition can be used to identify the degree and type of liver disease, suggesting that EV composition may be a useful biomarker. With regard to MAFLD, the presence of metabolic risk factors, such as insulin resistance, will be indicated by adipose tissue-derived EVs and with that comes the potential to use as a clinical monitor of overall metabolic status. However, the inhibition of specific EV composition may be difficult to implement as a real-world therapeutic approach. Current global evidence shows that mesenchymal stem cell (MSCs)-derived EVs (MSC-EVs) play an important role in regulating the immune response, which has spawned a clinical trial to treat liver disease.
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Affiliation(s)
- Akiko Eguchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Motoh Iwasa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
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Mechanisms of Action of Mesenchymal Stem Cells in Metabolic-Associated Fatty Liver Disease. Stem Cells Int 2023; 2023:3919002. [PMID: 36644008 PMCID: PMC9839417 DOI: 10.1155/2023/3919002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 11/15/2022] [Accepted: 12/09/2022] [Indexed: 01/09/2023] Open
Abstract
Metabolic-associated fatty liver disease (MAFLD) is currently the most common chronic liver disease worldwide. However, its pathophysiological mechanism is complicated, and currently, it has no FDA-approved pharmacological therapies. In recent years, mesenchymal stem cell (MSC) therapy has attracted increasing attention in the treatment of hepatic diseases. MSCs are multipotent stromal cells that originated from mesoderm mesenchyme, which have self-renewal and multipotent differentiation capability. Recent experiments and studies have found that MSCs have the latent capacity to be used for MAFLD treatment. MSCs have the potential to differentiate into hepatocytes, which could be induced into hepatocyte-like cells (HLCs) with liver-specific morphology and function under appropriate conditions to promote liver tissue regeneration. They can also reduce liver tissue injury and reverse the development of MAFLD by regulating immune response, antifibrotic activities, and lipid metabolism. Moreover, several advantages are attributed to MSC-derived exosomes (MSC-exosomes), such as targeted delivery, reliable reparability, and poor immunogenicity. After entering the target cells, MSC-exosomes help regulate cell function and signal transduction; thus, it is expected to become an emerging treatment for MAFLD. In this review, we comprehensively discussed the roles of MSCs in MAFLD, main signaling pathways of MSCs that affect MAFLD, and mechanisms of MSC-exosomes on MAFLD.
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Flessa CM, Nasiri-Ansari N, Kyrou I, Leca BM, Lianou M, Chatzigeorgiou A, Kaltsas G, Kassi E, Randeva HS. Genetic and Diet-Induced Animal Models for Non-Alcoholic Fatty Liver Disease (NAFLD) Research. Int J Mol Sci 2022; 23:15791. [PMID: 36555433 PMCID: PMC9780957 DOI: 10.3390/ijms232415791] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/05/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022] Open
Abstract
A rapidly increasing incidence of non-alcoholic fatty liver disease (NAFLD) is noted worldwide due to the adoption of western-type lifestyles and eating habits. This makes the understanding of the molecular mechanisms that drive the pathogenesis of this chronic disease and the development of newly approved treatments of utmost necessity. Animal models are indispensable tools for achieving these ends. Although the ideal mouse model for human NAFLD does not exist yet, several models have arisen with the combination of dietary interventions, genetic manipulations and/or administration of chemical substances. Herein, we present the most common mouse models used in the research of NAFLD, either for the whole disease spectrum or for a particular disease stage (e.g., non-alcoholic steatohepatitis). We also discuss the advantages and disadvantages of each model, along with the challenges facing the researchers who aim to develop and use animal models for translational research in NAFLD. Based on these characteristics and the specific study aims/needs, researchers should select the most appropriate model with caution when translating results from animal to human.
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Affiliation(s)
- Christina-Maria Flessa
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Narjes Nasiri-Ansari
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Ioannis Kyrou
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- Research Institute for Health and Wellbeing, Coventry University, Coventry CV1 5FB, UK
- Aston Medical School, College of Health and Life Sciences, Aston University, Birmingham B4 7ET, UK
- Laboratory of Dietetics and Quality of Life, Department of Food Science and Human Nutrition, School of Food and Nutritional Sciences, Agricultural University of Athens, 11855 Athens, Greece
| | - Bianca M. Leca
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
| | - Maria Lianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Gregory Kaltsas
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Endocrine Unit, 1st Department of Propaedeutic Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Harpal S. Randeva
- Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry CV2 2DX, UK
- Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
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Tsuchiya A, Terai S, Horiguchi I, Homma Y, Saito A, Nakamura N, Sato Y, Ochiya T, Kino-oka M, Working Group of Attitudes for Preparation and Treatment of Exosomes of Japanese Society of Regenerative Medicine. Basic points to consider regarding the preparation of extracellular vesicles and their clinical applications in Japan. Regen Ther 2022; 21:19-24. [PMID: 35619946 PMCID: PMC9127121 DOI: 10.1016/j.reth.2022.05.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Revised: 05/02/2022] [Accepted: 05/04/2022] [Indexed: 12/23/2022] Open
Abstract
In recent years, extracellular vesicles (EVs)1 have attracted attention as a new therapeutic tool. In Europe, the United States, and Asia, there is an accelerating trend of moving beyond basic research on clinical trials. However, treatment using EVs is still in the research and development stage, and the general public has insufficient awareness and understanding of the risks involved in ensuring safety and efficacy, the status of laws and regulations, and global research and development trends regarding their use. The Japanese Society for Regenerative Medicine, which has promoted the research and development of regenerative medicine, an innovative medical technology based on the principle of delivering it safely, effectively, and promptly, including the establishment of laws and regulations, would like to express two positions in light of the rapid development of therapies using EVs: 1) concern about treatments that are based solely on the discretion of medical practitioners, and 2) active promotion of treatments based on sound scientific evidence. Because EVs are released from cells, there are many similarities between EVs and processed cells2 in terms of manufacturing processes and safety hazards. As for efficacy, the mechanism of action of EVs is still unclear, as is the case with specified processed cellsb; in such cases, it is difficult to measure potency, identify efficacy-related quality attributes, and evaluate the comparability of quality before and after a change in the manufacturing process. In other words, the number of quality attributes that can be obtained for EVs is limited because of their complex characteristics, and it is difficult to grasp their quality through specifications and characterization. Therefore, while designing a quality control strategy for EVs, it is important to ensure the quality of the final product (EVs) by controlling the raw materials and manufacturing process. On the contrary, since EVs do not contain living cell components and are not classified into specified processed cells, non-commercial clinical research on treatments using EVs and individual medical treatments with EVs at the discretion of medical practitioners are out of the scope of the Act on the Safety of Regenerative Medicine of Japan3. At present, there are no relevant laws or regulations for the use of EVs other than the Medical Practitioners’ Act and the Medical Care Act in Japan. Therefore, there is a concern that treatment will be performed without sufficient objective evaluation of the scientific basis for safety and efficacy. Despite these concerns, the development of therapies using EVs is underway worldwide. This could potentially lead to a wide variety of new therapeutic areas if the methods needed to stably secure and mass cultivate cells as raw materials and the technologies needed for the mass production of EVs can be developed, in addition to understanding the risks involved and developing relevant laws and regulations. As part of the Japanese Society for Regenerative Medicine, we will continue to work on the development of these methods and technologies and hope that such a promising field will be promoted with a high level of safety before reaching the public.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
- Corresponding author. Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Ikki Horiguchi
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Yasuhiro Homma
- Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Atsuhiro Saito
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan
| | - Norimasa Nakamura
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
- Institute for Medical Science in Sports, Osaka Health Science University, Osaka, Japan
- Global Center for Medical Engineering and Informatics, Osaka University, Osaka, Japan
| | - Yoji Sato
- Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Kawasaki, Japan
| | - Takahiro Ochiya
- Department of Molecular and Cellular Medicine, Tokyo Medical University, Tokyo, Japan
| | - Masahiro Kino-oka
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka, Japan
- Corresponding author. Department of Biotechnology, Graduate School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Ishii Y, Tsuchiya A, Natsui K, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Shimbo T, Tamai K, Terai S. Synthesized HMGB1 peptide prevents the progression of inflammation, steatosis, fibrosis, and tumor occurrence in a non-alcoholic steatohepatitis mouse model. Hepatol Res 2022; 52:985-997. [PMID: 35932481 DOI: 10.1111/hepr.13825] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/12/2022]
Abstract
AIM Non-alcoholic steatohepatitis (NASH) with fibrosis eventually leads to cirrhosis and hepatocellular carcinoma. Thus, the development of therapies other than dietary restriction and exercise, particularly those that suppress steatosis and fibrosis of the liver and have a long-term beneficial effect, is necessary. We aimed to evaluate the therapeutic effects of the HMGB1 peptide synthesized from box A using the melanocortin-4 receptor-deficient (Mc4r-KO) NASH model mouse. METHODS We performed short- and long-term administration of this peptide and evaluated the effects on steatosis, fibrosis, and carcinogenesis using Mc4r-KO mice. We also analyzed the direct effect of this peptide on macrophages and hepatic stellate cells in vitro and performed lipidomics and metabolomics techniques to evaluate the effect. RESULTS Although this peptide did not show direct effects on macrophages and hepatic stellate cells in vitro, in the short-term administration model, we could confirm the reduction of liver damage, steatosis, and fibrosis progression. The results of lipidomics and metabolomics suggested that the peptide might ameliorate NASH by promoting lipolysis via the activation of fatty acid β-oxidation and improving insulin resistance. In the long-term administration model, this peptide prevented progression to cirrhosis but retained the steatosis state, that is, the peptide prevents the progression to "burnt-out NASH." This peptide inhibited carcinogenesis by about one-third. CONCLUSION This HMGB1 peptide can reduce liver damage, improve fibrosis and steatosis, and inhibit carcinogenesis, suggesting that the peptide would be a new treatment candidate for NASH and can contribute to the long-term prognosis for patients with NASH.
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Affiliation(s)
- Yui Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Youhei Koseki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Nobutaka Takeda
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Kei Tomiyoshi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Fusako Yamazaki
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Yuki Yoshida
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, Suita, Osaka, Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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Shi Y, Yang X, Wang S, Wu Y, Zheng L, Tang Y, Gao Y, Niu J. Human umbilical cord mesenchymal stromal cell-derived exosomes protect against MCD-induced NASH in a mouse model. Stem Cell Res Ther 2022; 13:517. [DOI: 10.1186/s13287-022-03201-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 03/28/2022] [Indexed: 11/15/2022] Open
Abstract
Abstract
Background and aims
Human umbilical cord mesenchymal stem cells (hUC-MSCs) are increasingly being studied in clinical trials of end-stage liver disease because of their good tissue repair and anti-inflammatory effects. hUC-MSC exosomes are vesicles with spherical structures secreted by cells that produce them. The diameter of exosomes is much smaller than that of hUC-MSCs, suggesting that exosomes might be a novel and safer therapeutic product of mesenchymal stem cells. As exosomes have been suggested to have biochemical functions similar to those of hUC-MSCs, this study investigated the efficiency of hUC-MSC-derived exosomes in protecting against nonalcoholic steatohepatitis using an MCD-induced mouse model.
Methods
Human umbilical cord mesenchymal stem cell-derived exosomes were extracted and purified. The effect of these exosomes on disease progression in an MCD-induced nonalcoholic steatohepatitis mouse model was investigated.
Results
The results showed that UC-MSC exosomes intravenously transplanted into mice with MCD-induced NASH improved MCD-induced body weight loss and liver damage in a mouse model. Additionally, the inflammatory cytokines in liver tissue were reduced, which may be caused by exosome-induced macrophage anti-inflammatory phenotypes both in vitro and in vivo. In addition, UC-MSC exosomes reversed PPARα level in ox-LDL-treated hepatocytes in vitro and in NASH mouse liver, which had been downregulated.
Conclusions
UC-MSC exosomes alleviate MCD-induced NASH in mice by regulating the anti-inflammatory phenotype of macrophages and by reversing PPARα protein expression in liver cells, which holds great potential in NASH therapy.
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Xu X, Poulsen KL, Wu L, Liu S, Miyata T, Song Q, Wei Q, Zhao C, Lin C, Yang J. Targeted therapeutics and novel signaling pathways in non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH). Signal Transduct Target Ther 2022; 7:287. [PMID: 35963848 PMCID: PMC9376100 DOI: 10.1038/s41392-022-01119-3] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut-liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.
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Affiliation(s)
- Xiaohan Xu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
| | - Kyle L Poulsen
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA
| | - Lijuan Wu
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Shan Liu
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Tatsunori Miyata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Qiaoling Song
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Qingda Wei
- School of Medicine, Zhengzhou University, Zhengzhou, China
| | - Chenyang Zhao
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China
| | - Chunhua Lin
- Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, China
| | - Jinbo Yang
- School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
- Innovation Center of Marine Drug Screening & Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China.
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Tsuchiya A, Natsui K, Ishii Y, Koseki Y, Takeda N, Tomiyoshi K, Yamazaki F, Yoshida Y, Terai S. Small extracellular vesicles and liver diseases: From diagnosis to therapy. World J Hepatol 2022; 14:1307-1318. [PMID: 36158910 PMCID: PMC9376785 DOI: 10.4254/wjh.v14.i7.1307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/20/2022] [Accepted: 07/06/2022] [Indexed: 02/06/2023] Open
Abstract
Extracellular vesicles (EVs), especially small EVs (sEVs) derived from liver cells, have been the focus of much attention in the normal physiology and pathogenesis of various diseases affecting the liver. sEVs are approximately 100 nm in size, enclosed within lipid bilayers, and are very stable. The lipids, proteins, and nucleic acids, including miRNAs, contained within these vesicles are known to play important roles in intercellular communication. This mini-review summarizes the application of sEVs. First, liver diseases and the related diagnostic markers are described, and the current active status of miRNA research in diagnosis of hepatocellular carcinoma (HCC) is reported. Second, the biodistribution and pharmacokinetics of sEVs are described, and the liver is highlighted as the organ with the highest accumulation of sEVs. Third, the relationship between sEVs and the pathogenesis of liver disorders is described with emphesis on the current active status of miRNA research in HCC recurrence and survival. Finally, the possibility of future therapy using sEVs from mesenchymal stem (stromal) cells for cirrhosis and other diseases is described.
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Affiliation(s)
- Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, Niigata 951-8510, Japan
| | - Kazuki Natsui
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yui Ishii
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yohei Koseki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Nobutaka Takeda
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Kei Tomiyoshi
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Fusako Yamazaki
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Yuki Yoshida
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
| | - Shuji Terai
- Department of Gastroenterology and Hepatology, Niigata University, Niigata 951-8510, Japan
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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Sun J, Zhang D, Li Y. Extracellular Vesicles in Pathogenesis and Treatment of Metabolic Associated Fatty Liver Disease. Front Physiol 2022; 13:909518. [PMID: 35770186 PMCID: PMC9234305 DOI: 10.3389/fphys.2022.909518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 05/23/2022] [Indexed: 11/13/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is the most common chronic liver disease worldwide due to the sedentary and overeating lifestyle. Yet, the pathophysiology of MAFLD is still unclear and no drug has been approved for MAFLD treatment. Extracellular vesicles (EVs) are heterogenous membrane-bound particles released from almost all types of cells. These nano-sized particles mediate intercellular communication through their bioactive cargos including nucleic acids, proteins, and lipids. The EVs modulate metabolic homeostasis via communication between adipose tissue and liver. The dysregulation of lipid metabolism leads to inflammation in liver and the number and compounds of EVs are changed during MAFLD. The injured hepatocytes secrete EVs to induce the migration of bone marrow-derived monocytes and the activation of macrophages in liver. The EVs secreted by different cells regulate the alteration of hepatic stellate cell (HSC) phenotypes and HSC activation gives rise to liver fibrosis. Based on the participation of EVs in MAFLD progression, we discuss the prospects of EVs as a therapeutic target and their application in drug delivery.
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Affiliation(s)
- Ji Sun
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Dianbao Zhang
- Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, and Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, China
- *Correspondence: Yiling Li, ; Dianbao Zhang,
| | - Yiling Li
- Department of Gastroenterology, The First Affiliated Hospital of China Medical University, Shenyang, China
- *Correspondence: Yiling Li, ; Dianbao Zhang,
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Moayedfard Z, Sani F, Alizadeh A, Bagheri Lankarani K, Zarei M, Azarpira N. The role of the immune system in the pathogenesis of NAFLD and potential therapeutic impacts of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther 2022; 13:242. [PMID: 35672797 PMCID: PMC9175371 DOI: 10.1186/s13287-022-02929-6] [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: 11/21/2021] [Accepted: 05/23/2022] [Indexed: 12/15/2022] Open
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) is characterized by intra-hepatocyte triglyceride accumulation and concomitant involvement of the immune system with subsequent histological changes, tissue damage, and clinical findings. There are various molecular pathways involved in the progression of NAFLD including lipotoxicity, endoplasmic reticulum stress, and the immune response. Both innate and adaptive immune systems are involved in the NAFLD pathogenesis, and crosstalk between the immune cells and liver cells participates in its initiation and progression. Among the various treatments for this disease, new cell based therapies have been proposed. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC) (MSC-EVs) are new cell-free vehicles with low immunogenicity, which can suppress detrimental immune responses in inflamed tissues. This review aimed to express the immune system's molecular pathways associated with the initiation and progression of NAFLD. Then, the possible role of MSC-EVs in the treatment of this entity through immune response modulation was discussed. Finally, engineered EVs enhanced by specific therapeutic miRNA were suggested for alleviating the pathological cellular events in liver disease.
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Affiliation(s)
- Zahra Moayedfard
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farnaz Sani
- Hematology and Cell Therapy Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Aliakbar Alizadeh
- Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mohammad Zarei
- Renal Division, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA, USA
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Khalili Street, P.O. Box: 7193711351, Shiraz, Iran.
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Tang Y, Wu P, Li L, Xu W, Jiang J. Mesenchymal Stem Cells and Their Small Extracellular Vesicles as Crucial Immunological Efficacy for Hepatic Diseases. Front Immunol 2022; 13:880523. [PMID: 35603168 PMCID: PMC9121380 DOI: 10.3389/fimmu.2022.880523] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cell small extracellular vesicles (MSC-sEVs) are a priority for researchers because of their role in tissue regeneration. sEVs act as paracrine factors and carry various cargos, revealing the state of the parent cells and contributing to cell–cell communication during both physiological and pathological circumstances. Hepatic diseases are mainly characterized by inflammatory cell infiltration and hepatocyte necrosis and fibrosis, bringing the focus onto immune regulation and other regulatory mechanisms of MSCs/MSC-sEVs. Increasing evidence suggests that MSCs and their sEVs protect against acute and chronic liver injury by inducing macrophages (MΦ) to transform into the M2 subtype, accelerating regulatory T/B (Treg/Breg) cell activation and promoting immunosuppression. MSCs/MSC-sEVs also prevent the proliferation and differentiation of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. This review summarizes the potential roles for MSCs/MSC-sEVs, including immunomodulation and tissue regeneration, in various liver diseases. There is also a specific focus on the use of MSC-sEVs for targeted drug delivery to treat hepatitis.
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Affiliation(s)
- Yuting Tang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Peipei Wu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Linli Li
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Wenrong Xu
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Wenrong Xu, ; Jiajia Jiang,
| | - Jiajia Jiang
- Aoyang Institute of Cancer, Affiliated Aoyang Hospital of Jiangsu University, Suzhou, China
- Zhenjiang Key Laboratory of High Technology Research on Exosome Foundation and Transformation Application, School of Medicine, Jiangsu University, Zhenjiang, China
- *Correspondence: Wenrong Xu, ; Jiajia Jiang,
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Mikłosz A, Nikitiuk BE, Chabowski A. Using adipose-derived mesenchymal stem cells to fight the metabolic complications of obesity: Where do we stand? Obes Rev 2022; 23:e13413. [PMID: 34985174 PMCID: PMC9285813 DOI: 10.1111/obr.13413] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/07/2021] [Accepted: 12/07/2021] [Indexed: 12/15/2022]
Abstract
Obesity is a critical risk factor for the development of metabolic diseases, and its prevalence is increasing worldwide. Stem cell-based therapies have become a promising tool for therapeutic intervention. Among them are adipose-derived mesenchymal stem cells (ADMSCs), secreting numerous bioactive molecules, like growth factors, cytokines, and chemokines. Their unique features, including immunosuppressive and immunomodulatory properties, make them an ideal candidates for clinical applications. Numerous experimental studies have shown that ADMSCs can improve pancreatic islet cell viability and function, ameliorate hyperglycemia, improve insulin sensitivity, restore liver function, counteract dyslipidemia, lower pro-inflammatory cytokines, and reduce oxidative stress in the animal models. These results prompted scientists to use ADMSCs clinically. However, up to date, there have been few clinical studies or ongoing trails using ADMSCs to treat metabolic disorders such as type 2 diabetes mellitus (T2DM) or liver cirrhosis. Most human studies have implemented autologous ADMSCs with minimal risk of cellular rejection. Because the functionality of ADMSCs is significantly reduced in subjects with obesity and/or metabolic syndrome, their efficacy is questioned. ADMSCs transplantation may offer a potential therapeutic approach for the treatment of metabolic complications of obesity, but randomized controlled trials are required to establish their safety and efficacy in humans prior to routine clinical use.
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Affiliation(s)
- Agnieszka Mikłosz
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
| | | | - Adrian Chabowski
- Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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Yan Q, Sun YS, An R, Liu F, Fang Q, Wang Z, Xu T, Chen L, Du J. Application and progress of the detection technologies in hepatocellular carcinoma. Genes Dis 2022. [PMID: 37492708 PMCID: PMC10363596 DOI: 10.1016/j.gendis.2022.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a very high incidence and fatality rate, and in most cases, it is already at an advanced stage when diagnosed. Therefore, early prevention and detection of HCC are two of the most effective strategies. However, the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy, which is known as the "gold standard". In this review, we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring, and found that in addition to the traditional imaging detection and liver biopsy, alpha fetoprotein (AFP), lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), protein induced by vitamin K absence or antagonist-II (PIVKA-II) and other biomarkers are excellent biomarkers for HCC, especially when they are combined together. Most notably, the emerging liquid biopsy shows great promise in detecting HCC. In addition, lactic dehydrogenase (LDH), suppressor of cytokine signaling (SOCS) and other relevant biomarkers may become promising biomarkers for HCC post-treatment monitoring. Through the detailed introduction of the diagnostic technology of HCC, we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis, to improve the diagnostic rate of HCC and reduce its mortality.
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Wu R, Fan X, Wang Y, Shen M, Zheng Y, Zhao S, Yang L. Mesenchymal Stem Cell-Derived Extracellular Vesicles in Liver Immunity and Therapy. Front Immunol 2022; 13:833878. [PMID: 35309311 PMCID: PMC8930843 DOI: 10.3389/fimmu.2022.833878] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/15/2022] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs), as the most common cell source for stem cell therapy, play an important role in the modulation of innate and adaptive immune responses and have been widely used in clinical trials to treat autoimmune and inflammatory diseases. Recent experimental and clinical studies have shown that MSC-derived extracellular vesicles (MSC-EVs) can inhibit the activation and proliferation of a variety of proinflammatory cells, such as Th1, Th17 and M1 macrophages, reducing the secretion of proinflammatory cytokines, while promoting the proliferation of anti-inflammatory cells, such as M2 macrophages and Tregs, and increasing the secretion of anti-inflammatory cytokines, thus playing a role in immune regulation and exhibiting immunomodulatory functions. Besides MSC-EVs are more convenient and less immunogenic than MSCs. There is growing interest in the role of MSC-EVs in liver diseases owing to the intrinsic liver tropism of MSC-EVs. In this review, we focus on the immunomodulatory effects of MSC-EVs and summarize the pivotal roles of MSC-EVs as a cell-free therapy in liver diseases, including NAFLD, AIH, acute liver failure, liver fibrosis and hepatic ischemia–reperfusion injury. Moreover, we provide a concise overview of the potential use and limits of MSC-EVs in clinical application.
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Motegi S, Tsuchiya A, Iwasawa T, Sato T, Kumagai M, Natsui K, Nojiri S, Ogawa M, Takeuchi S, Sakai Y, Miyagawa S, Sawa Y, Terai S. A novel prostaglandin I 2 agonist, ONO-1301, attenuates liver inflammation and suppresses fibrosis in non-alcoholic steatohepatitis model mice. Inflamm Regen 2022; 42:3. [PMID: 35101153 PMCID: PMC8805395 DOI: 10.1186/s41232-021-00191-6] [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: 08/23/2021] [Accepted: 12/20/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND ONO-1301 is a novel long-lasting prostaglandin (PG) I2 mimetic with inhibitory activity on thromboxane (TX) A2 synthase. This drug can also induce endogenous prostaglandin (PG)I2 and PGE2 levels. Furthermore, ONO-1301 acts as a cytokine inducer and can initiate tissue repair in a variety of diseases, such as pulmonary hypertension, pulmonary fibrosis, cardiac infarction, and obstructive nephropathy. In this study, our aim was to evaluate the effect of ONO-1301 on liver inflammation and fibrosis in a mouse model of non-alcoholic steatohepatitis (NASH). METHODS The therapeutic effects of ONO-1301 against liver damage, fibrosis, and occurrence of liver tumors were evaluated using melanocortin 4 receptor-deficient (Mc4r-KO) NASH model mice. The effects of ONO-1301 against macrophages, hepatic stellate cells, and endothelial cells were also evaluated in vitro. RESULTS ONO-1301 ameliorated liver damage and fibrosis progression, was effective regardless of NASH status, and suppressed the occurrence of liver tumors in Mc4r-KO NASH model mice. In the in vitro study, ONO-1301 suppressed LPS-induced inflammatory responses in cultured macrophages, suppressed hepatic stellate cell (HSC) activation, upregulated vascular endothelial growth factor (VEGF) expression in HSCs, and upregulated hepatocyte growth factor (HGF) and VEGF expression in endothelial cells. CONCLUSIONS The results of our study highlight the potential of ONO-1301 to reverse the progression and prevent the occurrence of liver tumors in NASH using in vivo and in vitro models. ONO-1301 is a multidirectional drug that can play a key role in various pathways and can be further analyzed for use as a new drug candidate against NASH.
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Affiliation(s)
- Satoko Motegi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
| | - Takahiro Iwasawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Takeki Sato
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masaru Kumagai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Shunsuke Nojiri
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan
| | - Yosiki Sakai
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Yoshiki Sawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka Suita, Osaka, 565-0871, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan.
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Hosseini NF, Dalirfardouei R, Aliramaei MR, Najafi R. Stem cells or their exosomes: which is preferred in COVID-19 treatment? Biotechnol Lett 2022; 44:159-177. [PMID: 35043287 PMCID: PMC8765836 DOI: 10.1007/s10529-021-03209-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 11/04/2021] [Indexed: 02/06/2023]
Abstract
It only took 8 months for the pneumonia caused by a previously unknown coronavirus to turn into a global pandemic of unprecedentedly far-reaching implications. Failure of the already discovered treatment measures opened up a new opportunity to evaluate the potentials of mesenchymal stem cells and their extracellular vesicles (EVs), exosomes in particular. Eventually, the initial success experienced after the use of MSCs in treating the new pneumonia by Lnge and his team backed up the idea of MSC-based therapies and pushed them closer to becoming a reality. However, MSC-related concerns regarding safety such as abnormal differentiation, spontaneous malignant and the formation of ectopic tissues have triggered the replacement of MSCs by their secreted exosomes. The issue has been further strengthened by the fact that the exosomes leave similar treatment impacts when compared to their parental cells. In recent years, much attention has been paid to the use of MSC-derived exosomes in the treatment of a variety of diseases. With a primary focus on COVID-19 and its current treatment methods, the present review looks into the potentials of MSCs and MSC-derived exosomes in battling the ongoing pandemic. Finally, the research will draw an analogy between exosomes and their parental cells, when it comes to the progresses and challenges in using exosomes as a large-scale treatment method.
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Affiliation(s)
- Nashmin Fayazi Hosseini
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Razieh Dalirfardouei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Endometrium and Endometriosis Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | | | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran.
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Li ZJ, Wang LQ, Li YZ, Wang CY, Huang JZ, Yu NZ, Long X. Application of adipose-derived stem cells in treating fibrosis. World J Stem Cells 2021; 13:1747-1761. [PMID: 34909121 PMCID: PMC8641015 DOI: 10.4252/wjsc.v13.i11.1747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/18/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is the hyperactivation of fibroblasts that results in excessive accumulation of extracellular matrix, which is involved in numerous pathological changes and diseases. Adipose-derived stem cells (ASCs) are promising seed cells for regenerative medicine due to their bountiful source, low immunogenicity and lack of ethical issues. Their anti-fibrosis, immunomodulation, angiogenesis and other therapeutic effects have made them suitable for treating fibrosis-related diseases. Here, we review the literature on ASCs treating fibrosis, elaborate and discuss their mechanisms of action, changes in disease environment, ways to enhance therapeutic effects, as well as current preclinical and clinical studies, in order to provide a general picture of ASCs treating fibrotic diseases.
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Affiliation(s)
- Zhu-Jun Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Li-Quan Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun-Zhu Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Chen-Yu Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jiu-Zuo Huang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Nan-Ze Yu
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, 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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Nojiri S, Tsuchiya A, Natsui K, Takeuchi S, Watanabe T, Kojima Y, Watanabe Y, Kamimura H, Ogawa M, Motegi S, Iwasawa T, Sato T, Kumagai M, Ishii Y, Kitayama T, Li YT, Ouchi Y, Shimbo T, Takamura M, Tamai K, Terai S. Synthesized HMGB1 peptide attenuates liver inflammation and suppresses fibrosis in mice. Inflamm Regen 2021; 41:28. [PMID: 34565478 PMCID: PMC8474861 DOI: 10.1186/s41232-021-00177-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 08/25/2021] [Indexed: 11/20/2022] Open
Abstract
The liver has a high regenerative ability and can induce spontaneous regression of fibrosis when early liver damage occurs; however, these abilities are lost when chronic liver damage results in decompensated cirrhosis. Cell therapies, such as mesenchymal stem cell (MSC) and macrophage therapies, have attracted attention as potential strategies for mitigating liver fibrosis. Here, we evaluated the therapeutic effects of HMGB1 peptide synthesized from box A of high mobility group box 1 protein. Liver damage and fibrosis were evaluated using a carbon tetrachloride (CCl4)-induced cirrhosis mouse model. The effects of HMGB1 peptide against immune cells were evaluated by single-cell RNA-seq using liver tissues, and those against monocytes/macrophages were further evaluated by in vitro analyses. Administration of HMGB1 peptide did not elicit a rapid response within 36 h, but attenuated liver damage after 1 week and suppressed fibrosis after 2 weeks. Fibrosis regression developed over time, despite continuous liver damage, suggesting that administration of this peptide could induce fibrolysis. In vitro analyses could not confirm a direct effect of HMGB1 peptide against monocyte/macrophages. However, macrophages were the most affected immune cells in the liver, and the number of scar-associated macrophages (Trem2+Cd9+ cells) with anti-inflammatory markers increased in the liver following HMGB1 treatment, suggesting that indirect effects of monocytes/macrophages were important for therapeutic efficacy. Overall, we established a new concept for cell-free therapy using HMGB1 peptide for cirrhosis through the induction of anti-inflammatory macrophages.
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Affiliation(s)
- Shunsuke Nojiri
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Kazuki Natsui
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Suguru Takeuchi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takayuki Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yuichi Kojima
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yusuke Watanabe
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Hiroteru Kamimura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Satoko Motegi
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takahiro Iwasawa
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Takeki Sato
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Masaru Kumagai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Yui Ishii
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Tomomi Kitayama
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Inc., Saito Bio-Incubator 3F 7-7-15, Saito-Asagi, Ibaraki City, Osaka, 567-0085 Japan
| | - Yu-Tung Li
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Yuya Ouchi
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Inc., Saito Bio-Incubator 3F 7-7-15, Saito-Asagi, Ibaraki City, Osaka, 567-0085 Japan
| | - Takashi Shimbo
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
- StemRIM Institute of Regeneration-Inducing Medicine, Osaka University, 2-8, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Masaaki Takamura
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
| | - Katsuto Tamai
- Department of Stem Cell Therapy Science, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka, 565-0871 Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, 1-757, Asahimachi-dori, Chuo-ku, Niigata, 951-8510 Japan
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50
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Muto H, Ito T, Tanaka T, Yokoyama S, Yamamoto K, Imai N, Ishizu Y, Maeda K, Honda T, Ishikawa T, Kato A, Ohshiro T, Kano F, Yamamoto A, Sakai K, Hibi H, Ishigami M, Fujishiro M. Conditioned medium from stem cells derived from human exfoliated deciduous teeth ameliorates NASH via the Gut-Liver axis. Sci Rep 2021; 11:18778. [PMID: 34548598 PMCID: PMC8455642 DOI: 10.1038/s41598-021-98254-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 08/24/2021] [Indexed: 12/18/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) occurrence has been increasing and is becoming a major cause of liver cirrhosis and liver cancer. However, effective treatments for NASH are still lacking. We examined the benefits of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) on a murine non-alcoholic steatohepatitis (NASH) model induced by a combination of Western diet (WD) and repeated administration of low doses of carbon tetrachloride intraperitoneally, focusing on the gut-liver axis. We showed that repeated intravenous administration of SHED-CM significantly ameliorated histological liver fibrosis and inflammation in a murine NASH model. SHED-CM inhibited parenchymal cell apoptosis and reduced the activation of inflammatory macrophages. Gene expression of pro-inflammatory and pro-fibrotic mediators (such as Tnf-α, Tgf-β, and Ccl-2) in the liver was reduced in mice treated with SHED-CM. Furthermore, SHED-CM protected intestinal tight junctions and maintained intestinal barrier function, while suppressing gene expression of the receptor for endotoxin, Toll-like receptor 4, in the liver. SHED-CM promoted the recovery of Caco-2 monolayer dysfunction induced by IFN-γ and TNF-α in vitro. Our findings suggest that SHED-CM may inhibit NASH fibrosis via the gut-liver axis, in addition to its protective effect on hepatocytes and the induction of macrophages with unique anti-inflammatory phenotypes.
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Affiliation(s)
- Hisanori Muto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Taku Tanaka
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Shinya Yokoyama
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Kenta Yamamoto
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Norihiro Imai
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Yoji Ishizu
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Keiko Maeda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Takashi Honda
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Tetsuya Ishikawa
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
| | - Asuka Kato
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Taichi Ohshiro
- ITOCHU Collaborative Research-Molecular Targeted Cancer Treatment for Next Generation, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumiya Kano
- Department of Tissue Regeneration Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Akihito Yamamoto
- Department of Tissue Regeneration Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Kiyoshi Sakai
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideharu Hibi
- Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
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