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1
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Poudineh M, Mohammadyari F, Parsamanesh N, Jamialahmadi T, Kesharwani P, Sahebkar A. Cell and gene therapeutic approaches in non-alcoholic fatty liver disease. Gene 2025; 956:149466. [PMID: 40189164 DOI: 10.1016/j.gene.2025.149466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/14/2025] [Accepted: 03/31/2025] [Indexed: 04/11/2025]
Abstract
Non-Alcoholic Fatty Liver Disease (NAFLD) refers to a range of conditions marked by the buildup of triglycerides in liver cells, accompanied by inflammation, which contributes to liver damage, clinical symptoms, and histopathological alterations. Multiple molecular pathways contribute to NAFLD pathogenesis, including immune dysregulation, endoplasmic reticulum stress, and tissue injury. Both the innate and adaptive immune systems play crucial roles in disease progression, with intricate crosstalk between liver and immune cells driving NAFLD development. Among emerging therapeutic strategies, cell and gene-based therapies have shown promise. This study reviews the pathophysiological mechanisms of NAFLD and explores the therapeutic potential of cell-based interventions, highlighting their immunomodulatory effects, inhibition of hepatic stellate cells, promotion of hepatocyte regeneration, and potential for hepatocyte differentiation. Additionally, we examine gene delivery vectors designed to target NAFLD, focusing on their role in engineering hepatocytes through gene addition or editing to enhance therapeutic efficacy.
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Affiliation(s)
| | | | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran; Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Tananz Jamialahmadi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Toxicology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh 470003, India.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Centre for Research Impact and Outcome, Chitkara University, Rajpura 140417, Punjab, India; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Xiang YY, Won JH, Kim JS, Baek KW. Transplantation of Exercise-Enhanced Mesenchymal Stem Cells Improves Obesity and Glucose Tolerance via Immune Modulation in Adipose Tissue. Stem Cell Rev Rep 2025:10.1007/s12015-025-10881-0. [PMID: 40227488 DOI: 10.1007/s12015-025-10881-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 04/15/2025]
Abstract
Exercise-conditioned mesenchymal stem cells (MSCs) may modulate immune responses and improve white adipose tissue (WAT) function. While MSCs are known to reduce inflammation, it remains unclear if exercise-stimulated MSCs can improve obesity-related dysfunctions. This study is the first to explore how exercise-conditioned MSCs may influence adipose tissue inflammation and remodeling in the context of obesity. MSCs were isolated from exercised- and sedentary donor mice, then cultured in vitro. After culture, MSCs were assessed for differentiation capacity and cytokine gene expression, including Il10, as indicators of immune modulation. Exercise-conditioned MSCs were then transplanted into obese recipient mice. Following transplantation, immune cell profiles, inflammatory markers, and adipocyte morphology in recipient WAT were analyzed. Flow cytometry was used to quantify macrophage subtypes (pro-inflammatory and anti-inflammatory), and histological analysis was performed to measure changes in adipocyte size. Exercise-activated MSCs showed a ± 35% increase in Il10 expression and a ± 20% enhancement in differentiation capacity compared to controls, indicating improved immunomodulatory potential. In recipient mice, transplantation led to a ± 25% reduction in pro-inflammatory macrophages (CD86+ CD206-) and a 15% decrease in adipocyte size within WAT. Additionally, WAT in treated mice showed balanced inflammatory profiles and reduced adipose hypertrophy, suggesting restored immune balance and metabolic health. These findings suggest that exercise-modified MSCs exhibit enhanced immunomodulatory and metabolic regulatory properties. This study provides evidence that exercise enhances MSC characteristics, potentially improving their capacity to modulate adipose tissue immune balance and metabolic function in obesity. Exercise-conditioned MSCs may serve as a foundation for future strategies that integrate exercise-induced stem cell modifications to modulate obesity-related metabolic dysfunction.
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Affiliation(s)
- Ying-Ying Xiang
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea
| | - Jong-Hwa Won
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea
| | - Ji-Seok Kim
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea
- Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 52828, Korea
| | - Kyung-Wan Baek
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea.
- Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 52828, Korea.
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Zhang Z, Wang J, Li H, Niu Q, Tao Y, Zhao X, Zeng Z, Dong H. The role of the interleukin family in liver fibrosis. Front Immunol 2025; 16:1497095. [PMID: 39995661 PMCID: PMC11847652 DOI: 10.3389/fimmu.2025.1497095] [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: 09/16/2024] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
Liver fibrosis represents a wound-healing response to chronic liver injury caused by viral infections, alcohol, and chemicals agents. It is a critical step in the progression from chronic liver disease to cirrhosis and hepatocellular carcinoma. No chemical or biological drugs have been approved for the treatment of liver fibrosis. Relevant studies have demonstrated that effective inhibition of hepatitis B virus (HBV) replication by nucleoside (acid) analogs or polyethylene glycol alpha-interferon can lead to recovery in some patients with hepatitis B liver fibrosis, However, some patients with liver fibrosis do not show improvement, even after achieving a complete serologic and virologic response. A similar situation occurs in patients with hepatitis C-related liver fibrosis. The liver, with its unique anatomical and immunological structure, is the largest immune organ and produces a large number of cytokines in response to external stimuli, which are crucial for the progression of liver fibrosis. cytokines can act either by directly affecting hepatic stellate cells (HSCs) or by indirectly regulating immune target cells. Among these, the interleukin family activates a complex cascade of responses, including cytokines, chemokines, adhesion molecules, and lipid mediators, playing a key role in the initiation and regulation of inflammation, as well as innate and adaptive immunity. In this paper, we systematically summarize recent literature to elucidate the pathogenesis of interleukin-mediated liver fibrosis and explore potential therapeutic targets for liver fibrosis treatment.
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Affiliation(s)
- Zixin Zhang
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jiahui Wang
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qun Niu
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yujing Tao
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xin Zhao
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zijian Zeng
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Haijian Dong
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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D’Angeli F, Granata G, Romano IR, Distefano A, Lo Furno D, Spila A, Leo M, Miele C, Ramadan D, Ferroni P, Li Volti G, Accardo P, Geraci C, Guadagni F, Genovese C. Biocompatible Poly(ε-Caprolactone) Nanocapsules Enhance the Bioavailability, Antibacterial, and Immunomodulatory Activities of Curcumin. Int J Mol Sci 2024; 25:10692. [PMID: 39409022 PMCID: PMC11476408 DOI: 10.3390/ijms251910692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 09/28/2024] [Accepted: 10/02/2024] [Indexed: 10/20/2024] Open
Abstract
Curcumin (Cur), the primary curcuminoid found in Curcuma longa L., has garnered significant attention for its potential anti-inflammatory and antibacterial properties. However, its hydrophobic nature significantly limits its bioavailability. Additionally, adipose-derived stem cells (ADSCs) possess immunomodulatory properties, making them useful for treating inflammatory and autoimmune conditions. This study aims to verify the efficacy of poly(ε-caprolactone) nanocapsules (NCs) in improving Cur's bioavailability, antibacterial, and immunomodulatory activities. The Cur-loaded nanocapsules (Cur-NCs) were characterized for their physicochemical properties (particle size, polydispersity index, Zeta potential, and encapsulation efficiency) and stability over time. A digestion test simulated the behavior of Cur-NCs in the gastrointestinal tract. Micellar phase analyses evaluated the Cur-NCs' bioaccessibility. The antibacterial activity of free Cur, NCs, and Cur-NCs against various Gram-positive and Gram-negative strains was determined using the microdilution method. ADSC viability, treated with Cur-NCs and Cur-NCs in the presence or absence of lipopolysaccharide, was analyzed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assay. Additionally, ADSC survival was assessed through the Muse apoptotic assay. The expression of both pro-inflammatory (interleukin-1β and tumor necrosis factor-α) and anti-inflammatory (IL-10 and transforming growth factor-β) cytokines on ADSCs was evaluated by real-time polymerase chain reaction. The results demonstrated high stability post-gastric digestion of Cur-NCs and elevated bioaccessibility of Cur post-intestinal digestion. Moreover, Cur-NCs exhibited antibacterial activity against Escherichia coli without affecting Lactobacillus growth. No significant changes in the viability and survival of ADSCs were observed under the experimental conditions. Finally, Cur-NCs modulated the expression of both pro- and anti-inflammatory cytokines in ADSCs exposed to inflammatory stimuli. Collectively, these findings highlight the potential of Cur-NCs to enhance Cur's bioavailability and therapeutic efficacy, particularly in cell-based treatments for inflammatory diseases and intestinal dysbiosis.
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Affiliation(s)
- Floriana D’Angeli
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
| | - Giuseppe Granata
- CNR-Institute of Biomolecular Chemistry, Via Paolo Gaifami 18, 95126 Catania, Italy; (G.G.); (P.A.); (C.G.)
| | - Ivana Roberta Romano
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy; (I.R.R.); (D.L.F.)
| | - Alfio Distefano
- Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, 95123 Catania, Italy; (A.D.); (G.L.V.)
| | - Debora Lo Furno
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95123 Catania, Italy; (I.R.R.); (D.L.F.)
| | - Antonella Spila
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
| | - Mariantonietta Leo
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
| | - Chiara Miele
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
| | - Dania Ramadan
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
| | - Patrizia Ferroni
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
- InterInstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele, 00166 Rome, Italy
| | - Giovanni Li Volti
- Department of Biomedical and Biotechnological Sciences, Section of Biochemistry, University of Catania, 95123 Catania, Italy; (A.D.); (G.L.V.)
| | - Paolo Accardo
- CNR-Institute of Biomolecular Chemistry, Via Paolo Gaifami 18, 95126 Catania, Italy; (G.G.); (P.A.); (C.G.)
| | - Corrada Geraci
- CNR-Institute of Biomolecular Chemistry, Via Paolo Gaifami 18, 95126 Catania, Italy; (G.G.); (P.A.); (C.G.)
| | - Fiorella Guadagni
- Department of Promotion of Human Sciences and Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy; (A.S.); (M.L.); (C.M.); (D.R.); (P.F.); (F.G.)
- InterInstitutional Multidisciplinary Biobank (BioBIM), IRCCS San Raffaele, 00166 Rome, Italy
| | - Carlo Genovese
- Department of Medicine and Surgery, “Kore” University of Enna, Contrada Santa Panasia, 94100 Enna, Italy;
- Nacture S.r.l, Spin-Off University of Catania, Via Santa Sofia 97, 95123 Catania, Italy
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5
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Xiang YY, Won JH, Lee SJ, Baek KW. The Effect of Exercise on Mesenchymal Stem Cells and their Application in Obesity Treatment. Stem Cell Rev Rep 2024; 20:1732-1751. [PMID: 38954390 DOI: 10.1007/s12015-024-10755-x] [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: 06/22/2024] [Indexed: 07/04/2024]
Abstract
Mesenchymal stem cells (MSCs) have demonstrated considerable potential in tissue repair and the treatment of immune-related diseases, but there are problems with homing efficiency during MSCs transplantation. Exercise, as an intervention, has been shown to have an important impact on the properties of MSCs. This review summarizes the effects of exercise on the properties (including proliferation, apoptosis, differentiation, and homing) of bone marrow-derived MSCs and adipose-derived MSCs. Studies indicated that exercise enhances bone marrow-derived MSCs proliferation, osteogenic differentiation, and homing while reducing adipogenic differentiation. For adipose-derived MSCs, exercise enhances proliferation and reduces adipogenic differentiation. In addition, studies have investigated the therapeutic effects of combined therapy of MSCs transplantation with exercise on diseases of the bone, cardiac, and nervous systems. The combined therapy improves tissue repair by increasing the homing of transplanted MSCs and cytokine secretion (such as neurotrophin 4). Furthermore, MSCs transplantation also has potential for the treatment of obesity. Although the effect is not significant in weight loss, MSCs transplantation shows effects in controlling blood glucose, improving dyslipidemia, reducing inflammation, and improving liver disease. Finally, the potential role of combined MSCs transplantation and exercise therapy in addressing obesity is discussed.
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Affiliation(s)
- Ying-Ying Xiang
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea
| | - Jong-Hwa Won
- Department of Physical Education, Gyeongsang National University, Jinju, 52828, Korea
| | - Sam-Jun Lee
- Department of Sport Rehabilitation, College of Health, Tongmyong University, Welfare, and Education, Busan, 48520, Korea
| | - Kyung-Wan Baek
- Research Institute of Pharmaceutical Sciences, Gyeongsang National University, Jinju, 52828, Korea.
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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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7
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Cebi M, Yilmaz Y. Immune system dysregulation in the pathogenesis of non-alcoholic steatohepatitis: unveiling the critical role of T and B lymphocytes. Front Immunol 2024; 15:1445634. [PMID: 39148730 PMCID: PMC11324455 DOI: 10.3389/fimmu.2024.1445634] [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: 06/07/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.
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Affiliation(s)
- Merve Cebi
- Department of Medical Biology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
| | - Yusuf Yilmaz
- Department of Gastroenterology, School of Medicine, Recep Tayyip Erdoğan University, Rize, Türkiye
- The Global NASH Council, Washington, DC, United States
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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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9
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Navarro-Perez J, Carobbio S. Adipose tissue-derived stem cells, in vivo and in vitro models for metabolic diseases. Biochem Pharmacol 2024; 222:116108. [PMID: 38438053 DOI: 10.1016/j.bcp.2024.116108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/15/2024] [Accepted: 03/01/2024] [Indexed: 03/06/2024]
Abstract
The primary role of adipose tissue stem cells (ADSCs) is to support the function and homeostasis of adipose tissue in physiological and pathophysiological conditions. However, when ADSCs become dysfunctional in diseases such as obesity and cancer, they become impaired, undergo signalling changes, and their epigenome is altered, which can have a dramatic effect on human health. In more recent years, the therapeutic potential of ADSCs in regenerative medicine, wound healing, and for treating conditions such as cancer and metabolic diseases has been extensively investigated with very promising results. ADSCs have also been used to generate two-dimensional (2D) and three-dimensional (3D) cellular and in vivo models to study adipose tissue biology and function as well as intracellular communication. Characterising the biology and function of ADSCs, how it is altered in health and disease, and its therapeutic potential and uses in cellular models is key for designing intervention strategies for complex metabolic diseases and cancer.
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10
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Chen HJ, Huang TX, Jiang YX, Chen X, Wang AF. Multifunctional roles of inflammation and its causative factors in primary liver cancer: A literature review. World J Hepatol 2023; 15:1258-1271. [PMID: 38223416 PMCID: PMC10784815 DOI: 10.4254/wjh.v15.i12.1258] [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: 08/21/2023] [Revised: 11/06/2023] [Accepted: 11/24/2023] [Indexed: 12/25/2023] Open
Abstract
Primary liver cancer is a severe and complex disease, leading to 800000 global deaths annually. Emerging evidence suggests that inflammation is one of the critical factors in the development of hepatocellular carcinoma (HCC). Patients with viral hepatitis, alcoholic hepatitis, and steatohepatitis symptoms are at higher risk of developing HCC. However, not all inflammatory factors have a pathogenic function in HCC development. The current study describes the process and mechanism of hepatitis development and its progression to HCC, particularly focusing on viral hepatitis, alcoholic hepatitis, and steatohepatitis. Furthermore, the roles of some essential inflammatory cytokines in HCC progression are described in addition to a summary of future research directions.
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Affiliation(s)
- Hong-Jin Chen
- Department of Pharmacology, School of Basic Medical Sciences, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Ting-Xiong Huang
- School of Clinical Medical, Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Yu-Xi Jiang
- Zhejiang Provincial Key Laboratory of Medical Genetics, Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou 325035, Zhejiang Province, China
| | - Xiong Chen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China
| | - Ai-Fang Wang
- Department of Endocrinology, The People's Hospital of Yuhuan, The Yuhuan Branch of The First Affiliated Hospital of Wenzhou Medical University, Yuhuan 317600, Zhejiang Province, China.
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11
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Sosa RA, Terry AQ, Ito T, Naini BV, Zheng Y, Pickering H, Nevarez-Mejia J, Busuttil RW, Gjertson DW, Kupiec-Weglinski JW, Reed EF, Kaldas FM. Immune Features of Disparate Liver Transplant Outcomes in Female Hispanics With Nonalcoholic Steatohepatitis. Transplant Direct 2023; 9:e1550. [PMID: 37876917 PMCID: PMC10593264 DOI: 10.1097/txd.0000000000001550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 08/26/2023] [Indexed: 10/26/2023] Open
Abstract
Background Nonalcoholic steatohepatitis (NASH) is a severe immune-mediated stage of nonalcoholic fatty liver disease that is rapidly becoming the most common etiology requiring liver transplantation (LT), with Hispanics bearing a disproportionate burden. This study aimed to uncover the underlying immune mechanisms of the disparities experienced by Hispanic patients undergoing LT for NASH. Methods We enrolled 164 LT recipients in our institutional review board-approved study, 33 of whom presented with NASH as the primary etiology of LT (20%), with 16 self-reported as Hispanic (48%). We investigated the histopathology of prereperfusion and postreperfusion biopsies, clinical liver function tests, longitudinal soluble cytokines via 38-plex Luminex, and immune cell phenotypes generated by prereperfusion and postreperfusion blood using 14-color flow cytometry and enzyme-linked immunosorbent assay. Results Hispanic LT recipients transplanted for NASH were disproportionately female (81%) and disproportionately suffered poor outcomes in the first year posttransplant, including rejection (26%) and death (38%). Clinically, we observed increased pro-inflammatory and apoptotic histopathological features in biopsies, increased AST/international normalized ratio early posttransplantation, and a higher incidence of presensitization to mismatched HLA antigens expressed by the donor allograft. Experimental investigations revealed that blood from female Hispanic NASH patients showed significantly increased levels of leukocyte-attracting chemokines, innate-to-adaptive switching cytokines and growth factors, HMGB1 release, and TLR4/TLR8/TLR9/NOD1 activation, and produced a pro-inflammatory, pro-apoptotic macrophage phenotype with reduced CD14/CD68/CD66a/TIM-3 and increased CD16/CD11b/HLA-DR/CD80. Conclusions A personalized approach to reducing immunological risk factors is urgently needed for this endotype in Hispanics with NASH requiring LT, particularly in females.
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Affiliation(s)
- Rebecca A. Sosa
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Allyson Q. Terry
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Takahiro Ito
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Bita V. Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Ying Zheng
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Jessica Nevarez-Mejia
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Ronald W. Busuttil
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - David W. Gjertson
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Jerzy W. Kupiec-Weglinski
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Elaine F. Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA
- UCLA Immunogenetics Center, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA
| | - Fady M. Kaldas
- Dumont-UCLA Transplantation Center, Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
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12
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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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13
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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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14
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Takamura S, Teraki Y, Katayama E, Kawaguchi T, Kawaguchi M, Nakano D, Tsutsumi T, Nagoshi S, Nakama T, Torimura T. Effects of IL-17 inhibitors on Hepatic Fibrosis Index in Patients with Psoriasis and MAFLD: Directed Acyclic Graphs. Clin Mol Hepatol 2022; 28:269-272. [PMID: 35164434 PMCID: PMC9013613 DOI: 10.3350/cmh.2022.0040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Saori Takamura
- Department of Dermatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Yuichi Teraki
- Department of Dermatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Eri Katayama
- Department of Dermatology, Kurume University School of Medicine, Kurume, Japan
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Machiko Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Dan Nakano
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Tsubasa Tsutsumi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Sumiko Nagoshi
- Department of Gastroenterology and Hepatology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Takekuni Nakama
- Department of Dermatology, Kurume University School of Medicine, Kurume, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
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15
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Yano M, Nasti A, Seki A, Ishida K, Yamato M, Inui H, Ogawa N, Inagaki S, Ho TTB, Kawaguchi K, Yamashita T, Arai K, Yamashita T, Mizukoshi E, Inoue O, Takashima S, Usui S, Takamura M, Honda M, Wada T, Kaneko S, Sakai Y. Characterization of adipose tissue-derived stromal cells of mice with nonalcoholic fatty liver disease and their use for liver repair. Regen Ther 2021; 18:497-507. [PMID: 34926735 PMCID: PMC8649123 DOI: 10.1016/j.reth.2021.11.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/01/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
Introduction Freshly isolated uncultured adipose tissue-derived stromal cells (u-ADSCs), containing miscellaneous cells like the relatively abundant mesenchymal stem cells, are attractive for repair and regenerative therapy. However, the detailed characteristics and therapeutic efficacy of u-ADSCs obtained from disease-affected hosts are unknown. We compared the properties of u-ADSCs obtained from wild-type mice and from a mouse model of non-alcoholic steatohepatitis (NASH). Methods The NASH model was established by feeding C57BL/6J mice an atherogenic high-fat diet for 4 (NASH (4w)) or 12 weeks (NASH (12w)), followed by the isolation and characterization of u-ADSCs. Wild-type u-ADSCs or NASH-derived u-ADSCs were administered to mice with NASH cirrhosis, followed by analyses of hepatic inflammatory cells, antigen profiles, fibrosis, and gene expression. Results Wild-type u-ADSCs and NASH-derived u-ADSCs did not show marked differences in surface antigen profiles. In NASH (4w) u-ADSCs, but not NASH (12w) u-ADSCs, the frequencies of the leukocyte markers CD11b, CD45, and CD44 were elevated; furthermore, we observed an increase in the M1/M2 macrophage ratio only in NASH (12w) u-ADSCs. Only in NASH-4w u-ADSCs, the expression levels cell cycle-related genes were higher than those in u-ADSCs. Wild-type u-ADSCs administered to mice with NASH-related cirrhosis decreased the infiltration of CD11b+, F4/80+, and Gr-1+ inflammatory cells, ameliorated fibrosis, and had a restorative effect on liver tissues, as determined by gene expression profiles and the NAFLD activity score. The therapeutic effects of NASH (4w) u-ADSCs and NASH (12w) u-ADSCs on NASH-related cirrhosis were highly similar to the effect of wild-type u-ADSCs, including reductions in inflammation and fibrosis. Conclusions NASH-derived u-ADSCs, similar to wild-type u-ADSCs, are applicable for reparative and regenerative therapy in mice with NASH.
Uncultured adipose tissue-derived stromal cells (u-ADSCs) in regenerative therapy. Nonalcoholic steatohepatitis (NASH) mice model was established. We confirmed the efficacy of u-ADSCs for treatment of cirrhotic mice. We studied the NASH mouse model-derived u-ADSCs for treatment of cirrhotic mice. NASH-u-ADSCs and wild-type u-ADSCs are anti-inflammatory and effective for cirrhosis.
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Key Words
- AST, aspartate aminotransferase
- AT-HF, atherogenic high-fat
- Adipose tissue
- FCM, flow cytometry
- HICs, hepatic inflammatory cells
- LD, lactate dehydrogenase
- MSCs, mesenchymal stem cells
- Mesenchymal stem cells
- NAFLD, nonalcoholic fatty liver disease
- NAS, NAFLD activity score
- NASH (12 w) u-ADSCs, NASH (12 weeks)-derived u-ADSCs
- NASH (4w) u-ADSCs, NASH (4 weeks)-derived u-ADSCs
- NASH, nonalcoholic steatohepatitis
- Non-alcoholic fatty liver disease
- Stromal cells
- qRT-PCR, quantitative real-time polymerase chain reaction
- u-ADSCs, uncultured adipose tissue-derived stromal cells
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Affiliation(s)
- Masaaki Yano
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Alessandro Nasti
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kosuke Ishida
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Masatoshi Yamato
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Hiiro Inui
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Norihiko Ogawa
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shingo Inagaki
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tuyen Thuy Bich Ho
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Oto Inoue
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinichiro Takashima
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Soichiro Usui
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
- Corresponding author. Department of Gastroenterology, Kanazawa University Hospital, 13-1 Takara-machi, Kanazawa, 920-8641, Japan. Fax: +81 76 234 4250.
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16
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Gallego-Durán R, Montero-Vallejo R, Maya-Miles D, Lucena A, Martin F, Ampuero J, Romero-Gómez M. Analysis of Common Pathways and Markers From Non-Alcoholic Fatty Liver Disease to Immune-Mediated Diseases. Front Immunol 2021; 12:667354. [PMID: 34899679 PMCID: PMC8652219 DOI: 10.3389/fimmu.2021.667354] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 11/01/2021] [Indexed: 12/13/2022] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is the most prevalent form of liver disease worldwide, accounting for a high liver-related mortality and morbidity with extensive multi-organ involvement. This entity has displaced viral hepatitis as the main cause of severe forms of hepatic diseases, although the onset and transition of MAFLD stages still remains unclear. Nevertheless, innate and adaptive immune responses seem to play an essential role in the establishment and further progression of this disease. The immune system is responsible of safeguard and preserves organs and systems function, and might be altered under different stimuli. Thus, the liver suffers from metabolic and immune changes leading to different injuries and loss of function. It has been stablished that cell-cell crosstalk is a key process in the hepatic homeostasis maintenance. There is mounting evidence suggesting that MAFLD pathogenesis is determined by a complex interaction of environmental, genetic and host factors that leads to a full plethora of outcomes. Therefore, herein we will revisit and discuss the interplay between immune mechanisms and MAFLD, highlighting the potential role of immunological markers in an attempt to clarify its relationship.
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Affiliation(s)
- Rocío Gallego-Durán
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Rocío Montero-Vallejo
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Douglas Maya-Miles
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
| | - Ana Lucena
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Franz Martin
- Andalusian Center for Molecular Biology and Regenerative Medicine (CABIMER), University of Pablo de Olavide-University of Sevilla-Consejo Superior de Investigaciones Científicas, Sevilla, Spain.,Biomedical Research Network on Diabetes and Related Metabolic Diseases (CIBERDEM), Madrid, Spain
| | - Javier Ampuero
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Manuel Romero-Gómez
- SeLiver Group, Instituto de Biomedicina de Sevilla/Consejo Superior de Investigaciones Científicas (CSIC)/Hospital Virgen del Rocío, Sevilla, Spain.,Biomedical Research Network on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.,Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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17
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Adipose-Derived Stem Cell-Derived Extracellular Vesicles Inhibit the Fibrosis of Fibrotic Buccal Mucosal Fibroblasts via the MicroRNA-375/FOXF1 Axis. Stem Cells Int 2021; 2021:9964159. [PMID: 34257670 PMCID: PMC8245228 DOI: 10.1155/2021/9964159] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/25/2021] [Accepted: 06/07/2021] [Indexed: 01/05/2023] Open
Abstract
Oral submucous fibrosis (OSF) is a precancerous lesion. Adipose-derived stem cell- (ADSC-) derived extracellular vesicles (EVs) (ADSC-EVs) regulate multiple oral diseases. Hence, this study explored the mechanism of ADSC-EVs in OSF. ADSCs were transduced with microRNA- (miR-) 375 mimic. ADSC-EVs and miR-375-overexpressed ADSC-EVs (EVs-miR-375) were extracted and identified. miR-375 expression in EVs and fibrotic buccal mucosal fibroblasts (fBMFs) was detected. EV uptake by fBMFs was observed. The targeted relationship between miR-375 and forkhead box protein F1 (FOXF1) was predicted and verified. After EVs-miR-375 treatment or FOXF1 overexpression, fBMF cell proliferation, migration, invasion, and apoptosis were evaluated, and levels of apoptosis-related proteins (cleaved-caspase-3, Bax, and Bcl-2) and fibrosis markers (α-SMA, collagen I, and collagen III) were detected. Functional rescue experiments were further performed to verify the role of the miR-375/FOXF1 axis in OSF. miR-375 was notably upregulated in EVs-miR-375 and EVs-miR-375-treated fBMFs (all P < 0.001). ADSC-EVs carried miR-375 into fBMFs. fBMFs can internalize ADSC-EVs. EVs-miR-375 treatment markedly inhibited fBMF cell proliferation, migration, invasion, and fibrosis and promoted apoptosis (all P < 0.01). Moreover, miR-375 targeted FOXF1 in fBMFs. FOXF1 overexpression promoted fBMF cell biological behaviors and fibrosis, which were reversed after EVs-miR-375 treatment (P < 0.01 or P < 0.001). We highlighted that ADSC-EVs inhibited fBMF fibrosis and then suppressed OSF progression via the miR-375/FOXF1 axis.
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18
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Sakai Y, Fukunishi S, Takamura M, Kawaguchi K, Inoue O, Usui S, Takashima S, Seki A, Asai A, Tsuchimoto Y, Nasti A, Bich Ho TT, Imai Y, Yoshimura K, Murayama T, Yamashita T, Arai K, Yamashita T, Mizukoshi E, Honda M, Wada T, Harada K, Higuchi K, Kaneko S. Clinical trial of autologous adipose tissue-derived regenerative (stem) cells therapy for exploration of its safety and efficacy. Regen Ther 2021; 18:97-101. [PMID: 34095367 PMCID: PMC8165289 DOI: 10.1016/j.reth.2021.04.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 04/03/2021] [Accepted: 04/27/2021] [Indexed: 12/14/2022] Open
Abstract
Introduction Liver cirrhosis is the ultimate condition of chronic liver diseases. Non-alcoholic steatohepatitis and fatty liver diseases are emerging in association with metabolic syndrome largely due to excess nutrition. Stromal cells of adipose tissue are enriched mesenchymal stem cells which are pluripotent and immunomodulatory, which are expected to be applied for repairing/regenerative therapy of the impaired organs. Methods We conducted the multi-institutional clinical trial (Japanese UMIN Clinical Trial Registry: UMIN000022601) of cell therapy using freshly isolated autologous adipose tissue-derived regenerative (stem) cells (ADRCs), which are obtained by the investigational trial device, adipose tissue dissociation device, for liver cirrhosis patients due to non-alcoholic steatohepatitis or fatty liver disease, to exploratory assess efficacy as well as safety of this trial. We completed treatment and 24 weeks follow-up for 7 patients. Results We observed that 6 out of 7 patients' serum albumin concentration was improved. As for prothrombin activity, 5 out of 7 patients showed improvement. No trial-related adverse events, which were serious or non-serious, was observed. Besides, no malfunction of the investigational trial device was encountered. Conclusion Thus, treatment with autologous ADRCs obtained with the investigational trial device in steatohepatitis-related cirrhosis was confirmed to be safely conductible and potentially promising for the retaining or improving the impaired hepatic reserve.
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Affiliation(s)
- Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
- Corresponding author. 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. Fax: +81 76 234 4250.
| | - Shinya Fukunishi
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Oto Inoue
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Soichiro Usui
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinichiro Takashima
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Akira Asai
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Yusuke Tsuchimoto
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Alessandro Nasti
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Tuyen Thuy Bich Ho
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
| | - Yasuhito Imai
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Kenichi Yoshimura
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Toshinori Murayama
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Kuniaki Arai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kazuhide Higuchi
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
- System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Kanazawa, Japan
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19
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Adipose-Derived Stem Cells: Current Applications and Future Directions in the Regeneration of Multiple Tissues. Stem Cells Int 2020; 2020:8810813. [PMID: 33488736 PMCID: PMC7787857 DOI: 10.1155/2020/8810813] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/04/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022] Open
Abstract
Adipose-derived stem cells (ADSCs) can maintain self-renewal and enhanced multidifferentiation potential through the release of a variety of paracrine factors and extracellular vesicles, allowing them to repair damaged organs and tissues. Consequently, considerable attention has increasingly been paid to their application in tissue engineering and organ regeneration. Here, we provide a comprehensive overview of the current status of ADSC preparation, including harvesting, isolation, and identification. The advances in preclinical and clinical evidence-based ADSC therapy for bone, cartilage, myocardium, liver, and nervous system regeneration as well as skin wound healing are also summarized. Notably, the perspectives, potential challenges, and future directions for ADSC-related researches are discussed. We hope that this review can provide comprehensive and standardized guidelines for the safe and effective application of ADSCs to achieve predictable and desired therapeutic effects.
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Liao N, Shi Y, Wang Y, Liao F, Zhao B, Zheng Y, Zeng Y, Liu X, Liu J. Antioxidant preconditioning improves therapeutic outcomes of adipose tissue-derived mesenchymal stem cells through enhancing intrahepatic engraftment efficiency in a mouse liver fibrosis model. Stem Cell Res Ther 2020; 11:237. [PMID: 32546282 PMCID: PMC7298967 DOI: 10.1186/s13287-020-01763-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 05/25/2020] [Accepted: 06/08/2020] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Although it has been preclinically suggested that adipose tissue-derived mesenchymal stem cell (ADSC)-based therapy could effectively treat chronic liver diseases, the hepatic engraftment of ADSCs is still extremely low, which severely limits their long-term efficacy for chronic liver diseases. This study was designed to investigate the impact of antioxidant preconditioning on hepatic engraftment efficiency and therapeutic outcomes of ADSC transplantation in liver fibrotic mice. METHODS Liver fibrosis model was established by using intraperitoneal injection of carbon tetrachloride (CCl4) in the male C57BL/6 mice. Subsequently, the ADSCs with or without antioxidant pretreatment (including melatonin and reduced glutathione (GSH)) were administrated into fibrotic mice via tail vein injection. Afterwards, the ADSC transplantation efficiency was analyzed by ex vivo imaging, and the liver functions were assessed by biochemical analysis and histopathological examination, respectively. Additionally, a typical hydrogen peroxide (H2O2)-induced cell injury model was applied to mimic the cell oxidative injury to further investigate the protective effects of antioxidant preconditioning on cell migration, proliferation, and apoptosis of ADSCs. RESULTS Our data showed that antioxidant preconditioning could enhance the therapeutic effects of ADSCs on liver function recovery by reducing the level of AST, ALT, and TBIL, as well as the content of hepatic hydroxyproline and fibrotic area in liver tissues. Particularly, we also found that antioxidant preconditioning could enhance hepatic engraftment efficiency of ADSCs in liver fibrosis model through inhibiting oxidative injury. CONCLUSIONS Antioxidant preconditioning could effectively improve therapeutic effects of ADSC transplantation for liver fibrosis through enhancing intrahepatic engraftment efficiency by reducing oxidative injuries. These findings might provide a practical strategy for enhancing ADSC transplantation and therapeutic efficiency.
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Affiliation(s)
- Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yingjun Shi
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Fangyu Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Youshi Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Yongyi Zeng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025 People’s Republic of China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025 People’s Republic of China
- Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350007 People’s Republic of China
- Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116 People’s Republic of China
- The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025 People’s Republic of China
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Sakai Y, Fukunishi S, Takamura M, Inoue O, Takashima S, Usui S, Seki A, Nasti A, Ho TTB, Kawaguchi K, Asai A, Tsuchimoto Y, Yamashita T, Yamashita T, Mizukoshi E, Honda M, Imai Y, Yoshimura K, Murayama T, Wada T, Harada K, Higuchi K, Kaneko S. Regenerative Therapy for Liver Cirrhosis Based on Intrahepatic Arterial Infusion of Autologous Subcutaneous Adipose Tissue-Derived Regenerative (Stem) Cells: Protocol for a Confirmatory Multicenter Uncontrolled Clinical Trial. JMIR Res Protoc 2020; 9:e17904. [PMID: 32229470 PMCID: PMC7319609 DOI: 10.2196/17904] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 03/02/2020] [Accepted: 03/11/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Liver cirrhosis results from chronic hepatitis, and is characterized by advanced fibrosis due to long-term hepatic inflammation. Cirrhosis ultimately leads to manifestations of jaundice, ascites, and encephalopathy, and increases the risk of hepatocellular carcinoma. Once cirrhosis is established, resulting in hepatic failure, no effective treatment is available. Therefore, novel therapies to inhibit disease progression of cirrhosis are needed. OBJECTIVE The objective of this investigator-initiated clinical trial is to assess the safety and efficacy of autologous adipose tissue-derived regenerative (stem) cell therapy delivered to the liver via the hepatic artery in patients with liver cirrhosis. METHODS Through consultation with the Japan Pharmaceuticals and Medical Devices Agency, we designed a clinical trial to assess a therapy for liver cirrhosis based on autologous adipose tissue-derived regenerative (stem) cells, which are extracted using an adipose tissue dissociation device. The primary endpoints of the trial are the serum albumin concentration, prothrombin activity, harmful events, and device malfunction. RESULTS Enrollment and registration were initiated in November 2017, and the follow-up period ended in November 2019. Data analysis and the clinical study report will be completed by the end of March 2020. CONCLUSIONS Completion of this clinical trial, including data analysis, will provide data on the safety and efficacy of this novel liver repair therapy based on autologous adipose tissue-derived regenerative (stem) cells using an adipose tissue dissociation device. TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000022601; https://tinyurl.com/w9uqw3q. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/17904.
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Affiliation(s)
- Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinya Fukunishi
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Masayuki Takamura
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Oto Inoue
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Shinichiro Takashima
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Soichiro Usui
- Department of Cardiovascular Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | | | | | - Kazunori Kawaguchi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Akira Asai
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Yusuke Tsuchimoto
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Eishiro Mizukoshi
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan
| | - Yasuhito Imai
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Kenichi Yoshimura
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan.,Center for Integrated Medical Research, Hiroshima University Hospital, Hiroshima, Japan
| | - Toshinori Murayama
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Takashi Wada
- Department of Nephrology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kazuhide Higuchi
- Department of Gastroenterology, Osaka Medical College, Takatsuki, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Japan.,System Biology, Kanazawa University, Kanazawa, Japan
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