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Marinescu-Colan CI, Nastase-Rusu EG, Neculachi CA, Martelli F, Cherry L, Preda MB, Burlacu A. From cancer to heart fibrosis - GLIPR1 highlights a subset of myofibroblasts responsive to mesenchymal stem cell therapy after myocardial infarction. Biomed Pharmacother 2025; 187:118087. [PMID: 40306172 DOI: 10.1016/j.biopha.2025.118087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Revised: 04/22/2025] [Accepted: 04/23/2025] [Indexed: 05/02/2025] Open
Abstract
Despite recent advances in pre-clinical research on cardiac remodeling following myocardial infarction (MI), the precise molecular pathways remain poorly understood and effective therapies for heart failure are still delayed in development. Aged animal models may more accurately reflect the clinical scenario, as aging alters the cellular identities and impedes cardiac repair. In this manuscript, we investigated the expression profile of mouse cardiac fibroblasts following myocardial infarction, using both young and aged animals to enhance the translational significance. The initial studies aimed to identify fibroblast changes common to both young and old animals. Additionally, a group of young animals that underwent mesenchymal stem cells (MSC) therapy after MI surgery was included to help identify the molecular changes amenable to therapeutic modulation. The analysis uncovered Glioma- Pathogenesis Related Protein 1 (GLIPR1) activation during the post-MI maturation phase in a subset of myofibroblasts, localized to the infarct zone in young subjects and widespread throughout the ventricle in aged animals. Further investigations indicated that the inflammatory environment post-MI induced the upregulation of GLIPR1, which in turn promoted increased TIMP3 expression. These findings provide valuable insights for future research aimed at exploring the therapeutic potential of targeting GLIPR1 to reduce cardiac fibrosis post-MI.
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Affiliation(s)
| | - Evelyn-Gabriela Nastase-Rusu
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Carmen-Alexandra Neculachi
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Fabio Martelli
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania; IRCCS Policlinico San Donato, Milan, Italy
| | - Laudy Cherry
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Mihai Bogdan Preda
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania
| | - Alexandrina Burlacu
- Department of Stem Cell Biology, Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
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2
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Ding Z, Wang L, Sun J, Zheng L, Tang Y, Tang H. Hepatocellular carcinoma: pathogenesis, molecular mechanisms, and treatment advances. Front Oncol 2025; 15:1526206. [PMID: 40265012 PMCID: PMC12011620 DOI: 10.3389/fonc.2025.1526206] [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: 11/11/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.
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Affiliation(s)
- Zhixian Ding
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lusheng Wang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Jiting Sun
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lijie Zheng
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Yu Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Heng Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
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3
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Gadour E. Lesson learnt from 60 years of liver transplantation: Advancements, challenges, and future directions. World J Transplant 2025; 15:93253. [PMID: 40104199 PMCID: PMC11612893 DOI: 10.5500/wjt.v15.i1.93253] [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: 02/22/2024] [Revised: 09/06/2024] [Accepted: 09/14/2024] [Indexed: 11/26/2024] Open
Abstract
Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.
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Affiliation(s)
- Eyad Gadour
- Department of Gastroenterology and Hepatology, King Abdulaziz National Guard Hospital, Ahsa 36428, Saudi Arabia
- Internal Medicine, Zamzam University College, Khartoum 11113, Sudan
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4
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Li L, Jiao Q, Yang Q, Lu H, Zhou X, Zhang Q, Zhang F, Li H, Tian Z, Zeng Z. A bladder-blood immune barrier constituted by suburothelial perivascular macrophages restrains uropathogen dissemination. Immunity 2025; 58:568-584.e6. [PMID: 40015270 DOI: 10.1016/j.immuni.2025.02.002] [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: 10/23/2023] [Revised: 09/29/2024] [Accepted: 02/03/2025] [Indexed: 03/01/2025]
Abstract
Urinary tract infections (UTIs) predominantly occur in the bladder and can potentially progress into life-threatening sepsis if uropathogens spread unconstrainedly into the bloodstream. Here, we identified a subset of suburothelial perivascular macrophages (suPVMs) in the bladder that exerted a pivotal barrier function to prevent systemic bacterial dissemination during acute cystitis. During the initial phase of uropathogenic Escherichia coli (UPEC) infection, suPVMs actively captured UPEC invading the laminal propria and maintained the integrity of inflamed vessels. They subsequently underwent METosis to expel macrophage extracellular DNA traps (METs) into the urothelium to sequester bacteria within this avascular compartment. Matrix metallopeptidase-13 was released along with METs to promote neutrophil transuroepithelial migration. Replenished suPVMs from monocytes following a prior infection were functionally competent to confer protection against recurrent UTIs. Our study thus uncovers a bladder-blood immune barrier in restraining uropathogen dissemination, which could have implications for the prevention and treatment of urosepsis.
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Affiliation(s)
- Lu Li
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China
| | - Qiancheng Jiao
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qianqian Yang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Haisen Lu
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Xia Zhou
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Qing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Futing Zhang
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Hai Li
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhigang Tian
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
| | - Zhutian Zeng
- National Key Laboratory of Immune responses and Immunotherapy, Department of Oncology, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China.
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5
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de Zawadzki A, Leeming DJ, Sanyal AJ, Anstee QM, Schattenberg JM, Friedman SL, Schuppan D, Karsdal MA. Hot and cold fibrosis: The role of serum biomarkers to assess immune mechanisms and ECM-cell interactions in human fibrosis. J Hepatol 2025:S0168-8278(25)00148-5. [PMID: 40056933 DOI: 10.1016/j.jhep.2025.02.039] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 02/18/2025] [Accepted: 02/23/2025] [Indexed: 05/24/2025]
Abstract
Fibrosis is a pathological condition characterised by excessive accumulation of extracellular matrix (ECM) components, particularly collagens, leading to tissue scarring and organ dysfunction. In fibrosis, an imbalance between collagen synthesis (fibrogenesis) and degradation (fibrolysis) results in the deposition of fibrillar collagens disrupting the structural integrity of the ECM and, consequently, tissue architecture. Fibrosis is associated with a wide range of chronic diseases, including cirrhosis, kidney fibrosis, pulmonary fibrosis, and autoimmune diseases. Recently, the concept of "hot" and "cold" fibrosis has emerged, referring to the immune status within fibrotic tissues and the nature of fibrogenic signalling. Hot fibrosis is characterised by active immune cell infiltration and inflammation, while cold fibrosis is associated with auto- and paracrine myofibroblast activation, immune cell exclusion and quiescence. In this article, we explore the relationship between hot and cold fibrosis, the role of various types of collagens and their biologically active fragments in modulating the immune system, and how serological ECM biomarkers can help improve our understanding of the disease-relevant interactions between immune and mesenchymal cells in fibrotic tissues. Additionally, we draw lessons from immuno-oncology research in solid tumours to shed light on potential strategies for fibrosis treatment and highlight the advantage of having a "hot fibrotic environment" to treat fibrosis by enhancing collagen degradation through modulation of the immune system.
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Affiliation(s)
| | - Diana J Leeming
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Arun J Sanyal
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health and Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK; Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Centre, Homburg, Germany
| | - Scott L Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Harvard Medical School, MA, USA
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6
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Brennan PN, MacMillan M, Manship T, Moroni F, Glover A, Troland D, MacPherson I, Graham C, Aird R, Semple SIK, Morris DM, Fraser AR, Pass C, McGowan NWA, Turner ML, Manson L, Lachlan NJ, Dillon JF, Kilpatrick AM, Campbell JDM, Fallowfield JA, Forbes SJ. Autologous macrophage therapy for liver cirrhosis: a phase 2 open-label randomized controlled trial. Nat Med 2025; 31:979-987. [PMID: 39794616 PMCID: PMC11922741 DOI: 10.1038/s41591-024-03406-8] [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: 06/05/2024] [Accepted: 11/11/2024] [Indexed: 01/13/2025]
Abstract
Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial ( ISRCTN10368050 ) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy (n = 27) compared to standard medical care (n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was -0.87 (95% confidence interval: -1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.
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Affiliation(s)
- Paul N Brennan
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Mark MacMillan
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Thomas Manship
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK
| | | | - Alison Glover
- Scottish National Blood Transfusion Service (SNBTS), Edinburgh, UK
| | - Debbie Troland
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Iain MacPherson
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - Catriona Graham
- Wellcome Trust Clinical Research Facility, University of Edinburgh, Edinburgh, UK
| | - Rhona Aird
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Scott I K Semple
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | - David M Morris
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
| | | | - Chloe Pass
- Scottish National Blood Transfusion Service (SNBTS), Edinburgh, UK
| | - Neil W A McGowan
- Scottish National Blood Transfusion Service (SNBTS), Edinburgh, UK
| | - Marc L Turner
- Scottish National Blood Transfusion Service (SNBTS), Edinburgh, UK
| | - Lynn Manson
- Scottish National Blood Transfusion Service (SNBTS), Edinburgh, UK
| | | | - John F Dillon
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK
| | - Alastair M Kilpatrick
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | | | - Jonathan A Fallowfield
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK.
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, Edinburgh, UK.
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7
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Maher JJ. Not the end of the road for macrophage therapy in liver cirrhosis. Nat Med 2025; 31:735-736. [PMID: 39901047 DOI: 10.1038/s41591-025-03490-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2025]
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8
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Uhlig M, Billig S, Wienhold J, Schumacher D. Pro-Fibrotic Macrophage Subtypes: SPP1+ Macrophages as a Key Player and Therapeutic Target in Cardiac Fibrosis? Cells 2025; 14:345. [PMID: 40072075 PMCID: PMC11898914 DOI: 10.3390/cells14050345] [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: 01/13/2025] [Revised: 02/21/2025] [Accepted: 02/26/2025] [Indexed: 03/15/2025] Open
Abstract
Cardiac fibrosis is a major driver of heart failure, a leading cause of morbidity and mortality worldwide. Advances in single-cell transcriptomics have revealed the pivotal role of SPP1+ macrophages in the pathogenesis of cardiac fibrosis, positioning them as critical mediators and promising therapeutic targets. SPP1+ macrophages, characterized by elevated expression of secreted phosphoprotein 1 (SPP1) and often co-expressing Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), localize to fibrotic niches in the heart and other organs. These cells interact with activated fibroblasts and myofibroblasts, driving extracellular matrix remodeling and fibrosis progression. Their differentiation is orchestrated by signals such as CXCL4, GM-CSF, and IL-17A, further emphasizing their regulatory complexity. Therapeutic strategies targeting SPP1+ macrophages have shown encouraging preclinical results. Approaches include silencing Spp1 using antibody-siRNA conjugates and modulating key pathways involved in macrophage differentiation. These interventions have effectively reduced fibrosis and improved cardiac function in animal models. The mechanisms underlying SPP1+ macrophage function in cardiac fibrosis provide a foundation for innovative therapies aimed at mitigating pathological remodeling and improving outcomes in patients with heart failure. This emerging field has significant potential to transform the treatment of fibrotic heart disease.
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Affiliation(s)
- Moritz Uhlig
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Sebastian Billig
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - Jan Wienhold
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
| | - David Schumacher
- Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
- Department of Medicine 2 (Nephrology, Rheumatology, Clinical Immunology and Hypertension), Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany
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9
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Zhao W, Li Z, Ma S, Chen W, Wan Z, Zhu L, Li L, Wang D. Identification of pro-fibrotic cellular subpopulations in fascia of gluteal muscle contracture using single-cell RNA sequencing. J Transl Med 2025; 23:192. [PMID: 39962491 PMCID: PMC11834283 DOI: 10.1186/s12967-024-05889-y] [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: 08/05/2024] [Accepted: 11/15/2024] [Indexed: 02/20/2025] Open
Abstract
Fibrosis is a common and integral pathological feature in various chronic diseases, capable of affecting any tissue or organ. Fibrosis within deep fascia is implicated in many myofascial disorders, including gluteal muscle contracture (GMC), Dupuytren's disease, plantar fasciitis, iliotibial band syndrome, and chronic muscle pain. Despite its clinical significance, deep fascia fibrosis remains considerably under-researched compared to other fibrotic conditions. Single-cell RNA-sequencing (scRNA-seq) has been used to investigate cellular heterogeneity in fibrotic tissues. However, to our knowledge, only a few studies have applied scRNA-seq to explore cellular heterogeneity in deep fascia, and none have specifically examined fibrotic fascia. In this study, we performed scRNA-seq analysis on fibrotic fascia associated with GMC and compared them to nonfibrotic control fascial samples. Our findings show that fibroblast and macrophage cells play critical roles in pathological tissue remodeling within fibrotic deep fascia. We observed an upregulation of various collagens, proteoglycans, and extracellular matrix (ECM) glycoproteins in contracture deep fascia, attributed to the widespread activation of fibroblast subclusters. Additionally, two pro-fibrotic macrophage subpopulations, SPP1+ MP and ECM-like MP, appear to facilitate ECM deposition in fibrotic deep fascia by either regulating fibroblast activation or directly contributing to ECM production. The SPP1+ MP and ECM-like MP cells, as well as the signal interaction between SPP1+ MP and fibroblast cells, present potential therapeutic target for treating GMC and other related myofascial disorders.
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Affiliation(s)
- Weizhi Zhao
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China
- Institute for Future Sciences, University of South China, Changsha, Hunan, China
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China
| | - Zongchao Li
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China
- Institute for Future Sciences, University of South China, Changsha, Hunan, China
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China
| | - Suzhen Ma
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China
- Institute for Future Sciences, University of South China, Changsha, Hunan, China
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China
| | - Wen Chen
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China
- Institute for Future Sciences, University of South China, Changsha, Hunan, China
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China
| | - Zhengqing Wan
- Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China
| | - Lin Zhu
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China
- Institute for Future Sciences, University of South China, Changsha, Hunan, China
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China
| | - Liangjun Li
- The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, China.
| | - Danling Wang
- Hengyang Medical School, University of South China, Hengyang, Hunan, 421200, China.
- Institute for Future Sciences, University of South China, Changsha, Hunan, China.
- MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, University of South China, Changsha, Hunan, China.
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10
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Chang ACC, Schlegel BT, Carleton N, McAuliffe PF, Oesterreich S, Schwartz R, Lee AV. CITEgeist: Cellular Indexing of Transcriptomes and Epitopes for Guided Exploration of Intrinsic Spatial Trends. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.15.638331. [PMID: 40027773 PMCID: PMC11870549 DOI: 10.1101/2025.02.15.638331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/05/2025]
Abstract
Spatial transcriptomics provides insights into tissue architecture by linking gene expression with spatial localization. Current deconvolution methods rely heavily on single-cell RNA sequencing (scRNA-seq) references, which are costly and often unavailable, mainly if the tissue under evaluation is limited, such as in a core biopsy specimen. We present a novel tool, CITEgeist, that deconvolutes spatial transcriptomics data using antibody capture from the same slide as the reference, directly leveraging cell surface protein measurements from the same tissue section. This approach circumvents the limitations of scRNA-seq as a reference, offering a cost-effective and biologically grounded alternative. Our method employs mathematical optimization to estimate cell type proportions and gene expression profiles, incorporating sparsity constraints for robustness and interpretability. Benchmarks against state-of-the-art deconvolution methods show improved accuracy in cell type resolution, particularly in dense tumor microenvironments, while maintaining computational efficiency. This antibody-based tool advances spatial transcriptomics by providing a scalable, accurate, and reference-independent solution for deconvolution in complex tissues. We validate this tool by using a combined approach of simulated data and clinical samples by applying CITEgeist to translational pre-treatment and post-treatment ER+ breast tumors from an ongoing clinical trial, emphasizing the applicability and robustness of CITEgeist.
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Affiliation(s)
- Alexander Chih-Chieh Chang
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Brent T. Schlegel
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Neil Carleton
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Priscilla F. McAuliffe
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- Department of Surgery, Division of Breast Surgical Oncology, University of Pittsburgh School of Medicine, Pittsburgh PA, USA
| | - Steffi Oesterreich
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh PA, USA
| | - Russell Schwartz
- Ray and Stephanie Lane Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA, USA
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, USA
| | - Adrian V. Lee
- Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh PA, USA
- Institute of Precision Medicine, Pittsburgh PA, USA
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11
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Reinecke JB, Jimenez Garcia L, Gross AC, Cam M, Cannon MV, Gust MJ, Sheridan JP, Gryder BE, Dries R, Roberts RD. Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells. Clin Cancer Res 2025; 31:414-429. [PMID: 39540841 PMCID: PMC11739783 DOI: 10.1158/1078-0432.ccr-24-0049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 09/12/2024] [Accepted: 11/11/2024] [Indexed: 11/16/2024]
Abstract
PURPOSE Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation. EXPERIMENTAL DESIGN Using single-cell RNA sequencing, we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multiparameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics were used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and nontumor cells within the metastatic microenvironment. RESULTS Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. Single-cell RNA sequencing demonstrated that the surrounding lung stroma adopts a chronic, nonresolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, the metastasis-associated lung demonstrated marked fibrosis, likely because of the accumulation of pathogenic, profibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. CONCLUSIONS Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a prometastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the antifibrotic tyrosine kinase inhibitor (TKI) nintedanib. Our data shed light on the non-cell-autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.
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Affiliation(s)
- James B. Reinecke
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
- Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children’s Hospital, Columbus, Ohio
| | - Leyre Jimenez Garcia
- Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, Ohio
| | - Amy C. Gross
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
| | - Maren Cam
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
| | - Matthew V. Cannon
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
| | - Matthew J. Gust
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
| | - Jeffrey P. Sheridan
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
- Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts
| | - Berkley E. Gryder
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ruben Dries
- Section of Hematology and Medical Oncology, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts
- Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts
| | - Ryan D. Roberts
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, Ohio
- Department of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children’s Hospital, Columbus, Ohio
- The Ohio State University James Comprehensive Cancer Center, Columbus, Ohio
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Di X, Li Y, Wei J, Li T, Liao B. Targeting Fibrosis: From Molecular Mechanisms to Advanced Therapies. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410416. [PMID: 39665319 PMCID: PMC11744640 DOI: 10.1002/advs.202410416] [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] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/27/2024] [Indexed: 12/13/2024]
Abstract
As the final stage of disease-related tissue injury and repair, fibrosis is characterized by excessive accumulation of the extracellular matrix. Unrestricted accumulation of stromal cells and matrix during fibrosis impairs the structure and function of organs, ultimately leading to organ failure. The major etiology of fibrosis is an injury caused by genetic heterogeneity, trauma, virus infection, alcohol, mechanical stimuli, and drug. Persistent abnormal activation of "quiescent" fibroblasts that interact with or do not interact with the immune system via complicated signaling cascades, in which parenchymal cells are also triggered, is identified as the main mechanism involved in the initiation and progression of fibrosis. Although the mechanisms of fibrosis are still largely unknown, multiple therapeutic strategies targeting identified molecular mechanisms have greatly attenuated fibrotic lesions in clinical trials. In this review, the organ-specific molecular mechanisms of fibrosis is systematically summarized, including cardiac fibrosis, hepatic fibrosis, renal fibrosis, and pulmonary fibrosis. Some important signaling pathways associated with fibrosis are also introduced. Finally, the current antifibrotic strategies based on therapeutic targets and clinical trials are discussed. A comprehensive interpretation of the current mechanisms and therapeutic strategies targeting fibrosis will provide the fundamental theoretical basis not only for fibrosis but also for the development of antifibrotic therapies.
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Affiliation(s)
- Xingpeng Di
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Ya Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Jingwen Wei
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Tianyue Li
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
| | - Banghua Liao
- Department of Urology and Institute of UrologyWest China HospitalSichuan UniversityChengduP.R. China
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13
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Kim M, Park Y, Kim YS, Ko S. Cellular Plasticity in Gut and Liver Regeneration. Gut Liver 2024; 18:949-960. [PMID: 39081200 PMCID: PMC11565004 DOI: 10.5009/gnl240005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 11/16/2024] Open
Abstract
The intestine and liver share a unique regenerative property that sets them apart from other mammalian visceral organs. The intestinal epithelium exhibits rapid renewal, making it one of the fastest renewing tissues in humans. Under physiological conditions, intestinal stem cells within each intestinal crypt continuously differentiate into the different types of intestinal epithelial cells to maintain intestinal homeostasis. However, when exposed to tissue damage or stressful conditions such as inflammation, intestinal epithelial cells in the gastrointestinal tract exhibit plasticity, allowing fully differentiated cells to regain their stem cell properties. Likewise, hepatic epithelial cells possess a remarkable regenerative capacity to restore lost liver mass through proliferation-mediated liver regeneration. When the proliferation-mediated regenerative capacity is impaired, hepatocytes and biliary epithelial cells (BECs) can undergo plasticity-mediated regeneration and replenish each other. The transition of mammalian liver progenitor cells to hepatocytes/BECs can be observed under tightly controlled experimental conditions such as severe hepatocyte injury accompanied by the loss of regenerative capacity. In this review, we will discuss the mechanism by which cellular plasticity contributes to the regeneration process and the potential therapeutic implications of understanding and harnessing cellular plasticity in the gut and liver.
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Affiliation(s)
- Minwook Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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14
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Li J, Yuan Y, Fu Q, Chen M, Liang H, Chen X, Long X, Zhang B, Zhao J, Chen Q. Novel insights into the role of immunomodulatory extracellular vesicles in the pathogenesis of liver fibrosis. Biomark Res 2024; 12:119. [PMID: 39396032 PMCID: PMC11470730 DOI: 10.1186/s40364-024-00669-8] [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: 06/28/2024] [Accepted: 10/07/2024] [Indexed: 10/14/2024] Open
Abstract
Liver fibrosis, a chronic and long-term disease, can develop into hepatocellular carcinoma (HCC) and ultimately lead to liver failure. Early diagnosis and effective treatment still face significant challenges. Liver inflammation leads to liver fibrosis through continuous activation of hepatic stellate cells (HSCs) and the accumulation of immune cells. Intracellular communication among various immune cells is important for mediating the inflammatory response during fibrogenesis. Extracellular vesicles (EVs), which are lipid bilayer membrane-enclosed particles naturally secreted by cells, make great contributions to cell-cell communication and the transport of bioactive molecules. Nearly all the cells that participate in liver fibrosis release EVs loaded with lipids, proteins, and nucleic acids. EVs from hepatocytes, immune cells and stem cells are involved in mediating the inflammatory microenvironment of liver fibrosis. Recently, an increasing number of extracellular vesicle-based clinical applications have emerged, providing promising cell-free diagnostic and therapeutic tools for liver fibrosis because of their crucial role in immunomodulation during pathogenesis. The advantages of extracellular vesicle-based therapies include stability, biocompatibility, low cytotoxicity, and minimal immunogenicity, which highlight their great potential for drug delivery and specific treatments for liver fibrosis. In this review, we summarize the complex biological functions of EVs in the inflammatory response in the pathogenesis of liver fibrosis and evaluate the potential of EVs in the diagnosis and treatment of liver fibrosis.
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Affiliation(s)
- Jiaxuan Li
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yue Yuan
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Qinggang Fu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Min Chen
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Xin Long
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China
| | - Jianping Zhao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
| | - Qian Chen
- Division of Gastroenterology, Department of Internal Medicine at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Diwan R, Gaytan SL, Bhatt HN, Pena-Zacarias J, Nurunnabi M. Liver fibrosis pathologies and potentials of RNA based therapeutics modalities. Drug Deliv Transl Res 2024; 14:2743-2770. [PMID: 38446352 DOI: 10.1007/s13346-024-01551-8] [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: 02/14/2024] [Indexed: 03/07/2024]
Abstract
Liver fibrosis (LF) occurs when the liver tissue responds to injury or inflammation by producing excessive amounts of scar tissue, known as the extracellular matrix. This buildup stiffens the liver tissue, hinders blood flow, and ultimately impairs liver function. Various factors can trigger this process, including bloodborne pathogens, genetic predisposition, alcohol abuse, non-steroidal anti-inflammatory drugs, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. While some existing small-molecule therapies offer limited benefits, there is a pressing need for more effective treatments that can truly cure LF. RNA therapeutics have emerged as a promising approach, as they can potentially downregulate cytokine levels in cells responsible for liver fibrosis. Researchers are actively exploring various RNA-based therapeutics, such as mRNA, siRNA, miRNA, lncRNA, and oligonucleotides, to assess their efficacy in animal models. Furthermore, targeted drug delivery systems hold immense potential in this field. By utilizing lipid nanoparticles, exosomes, nanocomplexes, micelles, and polymeric nanoparticles, researchers aim to deliver therapeutic agents directly to specific biomarkers or cytokines within the fibrotic liver, increasing their effectiveness and reducing side effects. In conclusion, this review highlights the complex nature of liver fibrosis, its underlying causes, and the promising potential of RNA-based therapeutics and targeted delivery systems. Continued research in these areas could lead to the development of more effective and personalized treatment options for LF patients.
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Affiliation(s)
- Rimpy Diwan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Samantha Lynn Gaytan
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Himanshu Narendrakumar Bhatt
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA
| | - Jacqueline Pena-Zacarias
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA
- Department of Biological Sciences, College of Science, The University of Texas El Paso, El Paso, Texas, 79968, USA
| | - Md Nurunnabi
- Department of Pharmaceutical Sciences, School of Pharmacy, The University of Texas El Paso, El Paso, TX, 79902, USA.
- Department of Biomedical Engineering, College of Engineering, The University of Texas El Paso, El Paso, TX, 79968, USA.
- Department of Interdisciplinary Health Sciences, College of Health Sciences, The University of Texas El Paso, El Paso, Texas, 79968, USA.
- Border Biomedical Research Center, The University of Texas El Paso, El Paso, TX, 79968, USA.
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16
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Reinecke JB, Jimenez Garcia L, Gross AC, Cam M, Cannon MV, Gust MJ, Sheridan JP, Gryder BE, Dries R, Roberts RD. Aberrant activation of wound healing programs within the metastatic niche facilitates lung colonization by osteosarcoma cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.10.575008. [PMID: 38260361 PMCID: PMC10802507 DOI: 10.1101/2024.01.10.575008] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
PURPOSE Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation. EXPERIMENTAL DESIGN Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics was used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and non-tumor cells within the metastatic microenvironment. RESULTS Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis. CONCLUSIONS Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a pro-metastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the anti-fibrotic TKI nintedanib. Our data shed light on the non-cell autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.
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17
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Tsamou M, Kremers FAC, Samaritakis KA, Roggen EL. Identifying microRNAs Possibly Implicated in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Review. Int J Mol Sci 2024; 25:9551. [PMID: 39273498 PMCID: PMC11395538 DOI: 10.3390/ijms25179551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/28/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are chronic syndromes of unknown etiology, accompanied by numerous symptoms affecting neurological and physical conditions. Despite frequent revisions of the diagnostic criteria, clinical practice guidelines are often outdated, leading to underdiagnosis and ineffective treatment. Our aim was to identify microRNA (miRNA) biomarkers implicated in pathological mechanisms underlying these diseases. A comprehensive literature review using publicly accessible databases was conducted. Interesting miRNAs were extracted from relevant publications on ME/CFS and/or FM, and were then linked to pathophysiological processes possibly manifesting these chronic diseases. Dysregulated miRNAs in ME/CFS and FM may serve as promising biomarkers for these diseases. Key identified miRNAs, such as miR-29c, miR-99b, miR-128, miR-374b, and miR-766, were frequently mentioned for their roles in immune response, mitochondrial dysfunction, oxidative stress, and central sensitization, while miR-23a, miR-103, miR-152, and miR-320 were implicated in multiple crucial pathological processes for FM and/or ME/CFS. In summary, both ME/CFS and FM seem to share many dysregulated biological or molecular processes, which may contribute to their commonly shared symptoms. This miRNA-based approach offers new angles for discovering molecular markers urgently needed for early diagnosis or therapeutics to tackle the pathology of these medically unexplained chronic diseases.
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Affiliation(s)
- Maria Tsamou
- ToxGenSolutions (TGS), 6229 EV Maastricht, The Netherlands
| | | | | | - Erwin L Roggen
- ToxGenSolutions (TGS), 6229 EV Maastricht, The Netherlands
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18
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Mata-Martínez E, Ramírez-Ledesma MG, Vázquez-Victorio G, Hernández-Muñoz R, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic Signaling in Non-Parenchymal Liver Cells. Int J Mol Sci 2024; 25:9447. [PMID: 39273394 PMCID: PMC11394727 DOI: 10.3390/ijms25179447] [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: 08/15/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/15/2024] Open
Abstract
Purinergic signaling has emerged as an important paracrine-autocrine intercellular system that regulates physiological and pathological processes in practically all organs of the body. Although this system has been thoroughly defined since the nineties, recent research has made substantial advances regarding its role in aspects of liver physiology. However, most studies have mainly targeted the entire organ, 70% of which is made up of parenchymal cells or hepatocytes. Because of its physiological role, the liver is exposed to toxic metabolites, such as xenobiotics, drugs, and fatty acids, as well as to pathogens such as viruses and bacteria. Under injury conditions, all cell types within the liver undergo adaptive changes. In this context, the concentration of extracellular ATP has the potential to increase dramatically. Indeed, this purinergic response has not been studied in sufficient detail in non-parenchymal liver cells. In the present review, we systematize the physiopathological adaptations related to the purinergic system in chronic liver diseases of non-parenchymal liver cells, such as hepatic stellate cells, Kupffer cells, sinusoidal endothelial cells, and cholangiocytes. The role played by non-parenchymal liver cells in these circumstances will undoubtedly be strategic in understanding the regenerative activities that support the viability of this organ under stressful conditions.
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Affiliation(s)
- Esperanza Mata-Martínez
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - María Guadalupe Ramírez-Ledesma
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Genaro Vázquez-Victorio
- Departamento de Física, Facultad de Ciencias, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior S/N, Ciudad Universitaria, Mexico City 04510, Mexico
| | - Rolando Hernández-Muñoz
- Departamento de Biología Celular y Desarrollo, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Mexico City 04510, Mexico
| | - Mauricio Díaz-Muñoz
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
| | - Francisco G Vázquez-Cuevas
- Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Boulevard Juriquilla #3001, Querétaro 76230, Mexico
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Duan Y, Yang Y, Zhao S, Bai Y, Yao W, Gao X, Yin J. Crosstalk in extrahepatic and hepatic system in NAFLD/NASH. Liver Int 2024; 44:1856-1871. [PMID: 38717072 DOI: 10.1111/liv.15967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/28/2024] [Accepted: 04/26/2024] [Indexed: 07/17/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most prevalent chronic liver disease globally. Non-alcoholic steatohepatitis (NASH) represents an extremely progressive form of NAFLD, which, without timely intervention, may progress to cirrhosis or hepatocellular carcinoma. Presently, a definitive comprehension of the pathogenesis of NAFLD/NASH eludes us, and pharmacological interventions targeting NASH specifically remain constrained. The aetiology of NAFLD encompasses a myriad of external factors including environmental influences, dietary habits and gender disparities. More significantly, inter-organ and cellular interactions within the human body play a role in the development or regression of the disease. In this review, we categorize the influences affecting NAFLD both intra- and extrahepatically, elaborating meticulously on the mechanisms governing the onset and progression of NAFLD/NASH. This exploration delves into progress in aetiology and promising therapeutic targets. As a metabolic disorder, the development of NAFLD involves complexities related to nutrient metabolism, liver-gut axis interactions and insulin resistance, among other regulatory functions of extraneous organs. It further encompasses intra-hepatic interactions among hepatic cells, Kupffer cells (KCs) and hepatic stellate cells (HSCs). A comprehensive understanding of the pathogenesis of NAFLD/NASH from a macroscopic standpoint is instrumental in the formulation of future therapies for NASH.
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Affiliation(s)
- Yiliang Duan
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Yan Yang
- The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Shuqiang Zhao
- Jiangsu Institute for Food and Drug Control, NMPA Key Laboratory for Impurity Profile of Chemical Drugs, Nanjing, Jiangsu, China
| | - Yuesong Bai
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Wenbing Yao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Xiangdong Gao
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
| | - Jun Yin
- Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China
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Chen Y, Hu Y, Zhou H, Jiang N, Wang Y, Zhang J, Shen Y, Yu G, Cao J. Induction of hepatic fibrosis in mice with schistosomiasis by extracellular microRNA-30 derived from Schistosoma japonicum eggs. Front Immunol 2024; 15:1425384. [PMID: 39139565 PMCID: PMC11319242 DOI: 10.3389/fimmu.2024.1425384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 06/24/2024] [Indexed: 08/15/2024] Open
Abstract
Background Schistosomiasis is a zoonotic parasitic disorder induced by the infestation of schistosomes, a genus of trematodes. MicroRNAs (miRNAs) in egg-derived exosomes are crucial for modulating the host's immune responses and orchestrating the pathophysiological mechanisms. Although the exosomes secreted by S. japonicum contain abundant miRNAs, the specific roles of these miRNAs in the pathogenesis of schistosomiasis-induced hepatic fibrosis are yet to be comprehensively elucidated. The egg exosomes of S. japonicum secrete miRNA-30, a novel miRNA. Methods In vitro, the effect of miRNA-30 was evaluated by transfecting HSCs with miRNA mimics. The target gene biosignature for miRNA-30 was predicted using the miRDB software. The effect of miRNA-30 in hepatic fibrosis was evaluated by either elevating its expression in healthy mice or by inhibiting its activity in infected mice by administration of recombinant adeno-associated virus serotype eight vectors expressing miRNA-30 or miRNA sponges. Results This novel miRNA can activate hepatic stellate cells (HSCs), the prinary effector cells of hepatic fibrosis, in vitro, i.e., it significantly increases the fibrogenic factors Col1(α1), Col3(α1), and α-SMA at both mRNA and protein levels. In addition, miRNA-30 may activate HSCs by targeting the host RORA gene. In addition, in vivo experiments were conducted by administering a recombinant adeno-associated viral vector to modulate the expression levels of miRNA-30. The overexpression of miRNA-30 in healthy mice significantly elevated the expression of Col1(α1), Col3(α1), and α-SMA at both the transcriptomic and proteomic scales. This overexpression was coupled with a pronounced augmentation in the hepatic hydroxyproline content. Conversely, the in vivo silencing of miRNA-30 in infected mice induced a considerable reduction in the size of hepatic granulomas and areas of collagen deposition. Hence, in vivo, modulation of miRNA-30 expression may play a pivotal role in ameliorating the severity of hepatic fibrosis in mice afflicted with S. japonica. Conclusions The study results suggest that miRNA-30 may augment schistosomiasis-induced hepatic fibrosis through a probable interaction with the host RORA. Our study may improve the current theoretical framework regarding cross-species regulation by miRNAs of hepatic fibrosis in schistosomiasis.
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Affiliation(s)
- Yang Chen
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yuan Hu
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Hao Zhou
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Nan Jiang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yiluo Wang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Jing Zhang
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Yujuan Shen
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
| | - Guoying Yu
- State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Pingyuan Laboratory, Henan Normal University, Xinxiang, China
| | - Jianping Cao
- National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute of Parasitic Diseases at Chinese Center for Disease Control and Prevention, Chinese Center for Tropical Diseases Research, Shanghai, China
- Key Laboratory of Parasite and Vector Biology, National Health Commission of the People’s Republic of China, Shanghai, China
- World Health Organization Collaborating Centre for Tropical Diseases, Shanghai, China
- The School of Global Health, Chinese Center for Tropical Diseases Research, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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21
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Tadokoro T, Murata S, Kato M, Ueno Y, Tsuchida T, Okumura A, Kuse Y, Konno T, Uchida Y, Yamakawa Y, Zushi M, Yajima M, Kobayashi T, Hasegawa S, Kawakatsu-Hatada Y, Hayashi Y, Osakabe S, Maeda T, Kimura K, Mori A, Tanaka M, Kamishibahara Y, Matsuo M, Nie YZ, Okamoto S, Oba T, Tanimizu N, Taniguchi H. Human iPSC-liver organoid transplantation reduces fibrosis through immunomodulation. Sci Transl Med 2024; 16:eadg0338. [PMID: 39047116 DOI: 10.1126/scitranslmed.adg0338] [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: 12/19/2022] [Revised: 01/31/2024] [Accepted: 07/01/2024] [Indexed: 07/27/2024]
Abstract
Donor organ shortages for transplantation remain a serious global concern, and alternative treatment is in high demand. Fetal cells and tissues have considerable therapeutic potential as, for example, organoid technology that uses human induced pluripotent stem cells (hiPSCs) to generate unlimited human fetal-like cells and tissues. We previously reported the in vivo vascularization of early fetal liver-like hiPSC-derived liver buds (LBs) and subsquent improved survival of recipient mice with subacute liver failure. Here, we show hiPSC-liver organoids (LOs) that recapitulate midgestational fetal liver promote de novo liver generation when grafted onto the surface of host livers in chemical fibrosis models, thereby recovering liver function. We found that fetal liver, a hematopoietic tissue, highly expressed macrophage-recruiting factors and antifibrotic M2 macrophage polarization factors compared with the adult liver, resulting in fibrosis reduction because of CD163+ M2-macrophage polarization. Next, we created midgestational fetal liver-like hiPSC-LOs by fusion of hiPSC-LBs to induce static cell-cell interactions and found that these contained complex structures such as hepatocytes, vasculature, and bile ducts after transplantation. This fusion allowed the generation of a large human tissue suitable for transplantation into immunodeficient rodent models of liver fibrosis. hiPSC-LOs showed superior liver function compared with hiPSC-LBs and improved survival and liver function upon transplantation. In addition, hiPSC-LO transplantation ameliorated chemically induced liver fibrosis, a symptom of liver cirrhosis that leads to organ dysfunction, through immunomodulatory effects, particularly on CD163+ phagocytic M2-macrophage polarization. Together, our results suggest hiPSC-LO transplantation as a promising therapeutic option for liver fibrosis.
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Affiliation(s)
- Tomomi Tadokoro
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Soichiro Murata
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Mimoko Kato
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yasuharu Ueno
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Tomonori Tsuchida
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Ayumu Okumura
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Yoshiki Kuse
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Takahiro Konno
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yutaro Uchida
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yuriko Yamakawa
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Marina Zushi
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Megumi Yajima
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Tatsuya Kobayashi
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Shunsuke Hasegawa
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yumi Kawakatsu-Hatada
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yoshihito Hayashi
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Shun Osakabe
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Takuji Maeda
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Kodai Kimura
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Akihiro Mori
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Maiko Tanaka
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Yu Kamishibahara
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Megumi Matsuo
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Yun-Zhong Nie
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Satoshi Okamoto
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Takayoshi Oba
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Naoki Tanimizu
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
| | - Hideki Taniguchi
- Department of Regenerative Medicine, Yokohama City University School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regeneration Medicine, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
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22
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Guillot A, Tacke F. Liver macrophages revisited: The expanding universe of versatile responses in a spatiotemporal context. Hepatol Commun 2024; 8:e0491. [PMID: 38967563 PMCID: PMC11227356 DOI: 10.1097/hc9.0000000000000491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 05/23/2024] [Indexed: 07/06/2024] Open
Abstract
The liver is a vital organ that continuously adapts to a wide and dynamic diversity of self-antigens and xenobiotics. This involves the active contribution of immune cells, particularly by the liver-resident macrophages, the Kupffer cells (KCs), which exert a variety of central functions in liver homeostasis and disease. As such, KCs interact with their microenvironment to shape the hepatic cellular landscape, control gut-derived signal integration, and modulate metabolism. On injury, the rapid recruitment of bone marrow monocyte-derived macrophages alters this status quo and, when unrestrained, drastically compromises liver homeostasis, immune surveillance, and tissue organization. Several factors determine the functional roles of liver macrophages in these processes, such as their ontogeny, activation/polarization profile and, importantly, spatial distribution within the liver. Loss of tolerance and adaptability of the hepatic immune environment may result in persistent inflammation, hepatic fibrosis, cirrhosis, and a tumorigenic niche promoting liver cancer. In this review, we aim at providing the most recent breakthroughs in our understanding of liver macrophage biology, particularly their diversity and adaptability in the hepatic spatiotemporal context, as well as on potential therapeutic interventions that may hold the key to tackling remaining clinical challenges of varying etiologies in hepatology.
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23
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Dai H, Zhu C, Huai Q, Xu W, Zhu J, Zhang X, Zhang X, Sun B, Xu H, Zheng M, Li X, Wang H. Chimeric antigen receptor-modified macrophages ameliorate liver fibrosis in preclinical models. J Hepatol 2024; 80:913-927. [PMID: 38340812 DOI: 10.1016/j.jhep.2024.01.034] [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: 06/21/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024]
Abstract
BACKGROUND & AIMS Treatments directly targeting fibrosis remain limited. Given the unique intrinsic features of macrophages and their capacity to engraft in the liver, we genetically engineered bone marrow-derived macrophages with a chimeric antigen receptor (CAR) to direct their phagocytic activity against hepatic stellate cells (HSCs) in multiple mouse models. This study aimed to demonstrate the therapeutic efficacy of CAR macrophages (CAR-Ms) in mouse models of fibrosis and cirrhosis and to elucidate the underlying mechanisms. METHODS uPAR expression was studied in patients with fibrosis/cirrhosis and in murine models of liver fibrosis, including mice treated with carbon tetrachloride, a 5-diethoxycarbonyl-1, 4-dihydrocollidine diet, or a high-fat/cholesterol/fructose diet. The safety and efficacy of CAR-Ms were evaluated in vitro and in vivo. RESULTS Adoptive transfer of CAR-Ms resulted in a significant reduction in liver fibrosis and the restoration of function in murine models of liver fibrosis. CAR-Ms modulated the hepatic immune microenvironment to recruit and modify the activation of endogenous immune cells to drive fibrosis regression. These CAR-Ms were able to recruit and present antigens to T cells and mount specific antifibrotic T-cell responses to reduce fibroblasts and liver fibrosis in mice. CONCLUSION Collectively, our findings demonstrate the potential of using macrophages as a platform for CAR technology to provide an effective treatment option for liver fibrosis. CAR-Ms might be developed for treatment of patients with liver fibrosis. IMPACT AND IMPLICATIONS Liver fibrosis is an incurable condition that afflicts millions of people globally. Despite the clear clinical need, therapies for liver fibrosis are limited. Our findings provide the first preclinical evidence that chimeric antigen receptor (CAR)-macrophages (CAR-Ms) targeting uPAR can attenuate liver fibrosis and cirrhosis. We show that macrophages expressing this uPAR CAR exert a direct antifibrotic effect and elicit a specific T-cell response that augments the immune response against liver fibrosis. These findings demonstrate the potential of using CAR-Ms as an effective cell-based therapy for the treatment of liver fibrosis.
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Affiliation(s)
- Hanren Dai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Cheng Zhu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Qian Huai
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Wentao Xu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Jiejie Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xu Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Xianzheng Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Honghai Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Minghua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiaolei Li
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China; Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China.
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24
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Ashmore-Harris C, Antonopoulou E, Finney SM, Vieira MR, Hennessy MG, Muench A, Lu WY, Gadd VL, El Haj AJ, Forbes SJ, Waters SL. Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside. NPJ Regen Med 2024; 9:19. [PMID: 38724586 PMCID: PMC11081951 DOI: 10.1038/s41536-024-00361-3] [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: 07/05/2023] [Accepted: 04/18/2024] [Indexed: 05/12/2024] Open
Abstract
Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies.
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Affiliation(s)
- Candice Ashmore-Harris
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | | | - Simon M Finney
- Mathematical Institute, University of Oxford, Oxford, OX2 6GG, UK
| | - Melissa R Vieira
- Healthcare Technologies Institute (HTI), Institute of Translational Medicine, University of Birmingham, Birmingham, B15 2TH, UK
- School of Chemical Engineering, College of Engineering and Physical Sciences, University of Birmingham, Birmingham, B15 2TH, UK
| | - Matthew G Hennessy
- Department of Engineering Mathematics, University of Bristol, BS8 1TW, Bristol, UK
| | - Andreas Muench
- Mathematical Institute, University of Oxford, Oxford, OX2 6GG, UK
| | - Wei-Yu Lu
- Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Victoria L Gadd
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Alicia J El Haj
- Healthcare Technologies Institute (HTI), Institute of Translational Medicine, University of Birmingham, Birmingham, B15 2TH, UK
- School of Chemical Engineering, College of Engineering and Physical Sciences, University of Birmingham, Birmingham, B15 2TH, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Sarah L Waters
- Mathematical Institute, University of Oxford, Oxford, OX2 6GG, UK.
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25
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Meizlish ML, Kimura Y, Pope SD, Matta R, Kim C, Philip NH, Meyaard L, Gonzalez A, Medzhitov R. Mechanosensing regulates tissue repair program in macrophages. SCIENCE ADVANCES 2024; 10:eadk6906. [PMID: 38478620 PMCID: PMC10936955 DOI: 10.1126/sciadv.adk6906] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 01/29/2024] [Indexed: 03/17/2024]
Abstract
Tissue-resident macrophages play important roles in tissue homeostasis and repair. However, how macrophages monitor and maintain tissue integrity is not well understood. The extracellular matrix (ECM) is a key structural and organizational component of all tissues. Here, we find that macrophages sense the mechanical properties of the ECM to regulate a specific tissue repair program. We show that macrophage mechanosensing is mediated by cytoskeletal remodeling and can be performed in three-dimensional environments through a noncanonical, integrin-independent mechanism analogous to amoeboid migration. We find that these cytoskeletal dynamics also integrate biochemical signaling by colony-stimulating factor 1 and ultimately regulate chromatin accessibility to control the mechanosensitive gene expression program. This study identifies an "amoeboid" mode of ECM mechanosensing through which macrophages may regulate tissue repair and fibrosis.
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Affiliation(s)
- Matthew L. Meizlish
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Yoshitaka Kimura
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Scott D. Pope
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Rita Matta
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Catherine Kim
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Naomi H. Philip
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Linde Meyaard
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
- Oncode Institute, Utrecht, Netherlands
| | - Anjelica Gonzalez
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Ruslan Medzhitov
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA
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26
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Ahmadi Badi S, Bereimipour A, Rohani P, Khatami S, Siadat SD. Interplay between gut microbiota and the master iron regulator, hepcidin, in the pathogenesis of liver fibrosis. Pathog Dis 2024; 82:ftae005. [PMID: 38555503 PMCID: PMC10990161 DOI: 10.1093/femspd/ftae005] [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: 10/23/2023] [Revised: 02/12/2024] [Accepted: 03/28/2024] [Indexed: 04/02/2024] Open
Abstract
INTRODUCTION There is a proven role for hepcidin and the composition of gut microbiota and its derivatives in the pathophysiology of liver fibrosis. AREA COVERED This review focuses on the literature search regarding the effect of hepcidin and gut microbiota on regulating liver physiology. We presented the regulating mechanisms of hepcidin expression and discussed the possible interaction between gut microbiota and hepcidin regulation. Furthermore, we investigated the importance of the hepcidin gene in biological processes and bacterial interactions using bioinformatics analysis. EXPERT OPINION One of the main features of liver fibrosis is iron accumulation in hepatic cells, including hepatocytes. This accumulation can induce an oxidative stress response, inflammation, and activation of hepatic stellate cells. Hepcidin is a crucial regulator of iron by targeting ferroportin expressed on hepatocytes, macrophages, and enterocytes. Various stimuli, such as iron load and inflammatory signals, control hepcidin regulation. Furthermore, a bidirectional relationship exists between iron and the composition and metabolic activity of gut microbiota. We explored the potential of gut microbiota to influence hepcidin expression and potentially manage liver fibrosis, as the regulation of iron metabolism plays a crucial role in this context.
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Affiliation(s)
- Sara Ahmadi Badi
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Ahmad Bereimipour
- Department of Biological Sciences and BioDiscovery Institute, University of North Texas, Denton, TX 76203, USA
| | - Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, 1416753955, Iran
| | - Shohreh Khatami
- Biochemistry Department, Pasteur Institute of Iran, Tehran, 1963737611, Iran
| | - Seyed Davar Siadat
- Microbiology Research Center, Pasteur Institute of Iran, Tehran, 1963737611, Iran
- Department of Mycobacteriology and Pulmonary Research, Pasteur Institute of Iran, Tehran,1963737611, Iran
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27
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Egorov D, Kopaliani I, Ameln AKV, Speier S, Deussen A. Mechanism of pro-MMP9 activation in co-culture of pro-inflammatory macrophages and cardiomyocytes. Exp Cell Res 2024; 434:113868. [PMID: 38043722 DOI: 10.1016/j.yexcr.2023.113868] [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: 08/10/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/05/2023]
Abstract
OBJECTIVE A wide range of cardiac diseases is associated with inflammation. "Inflamed" heart tissue is infiltrated with pro-inflammatory macrophages which extensively secrete matrix metalloproteinase 9 (MMP9), a regulator of extracellular matrix turnover. As MMP9 is released from macrophages in a latent form, it requires activation. The present study addresses the role of cardiomyocytes in the course of this activation process. METHODS AND RESULTS In mono- and co-cultures of pro-inflammatory rat macrophages (bone marrow-derived and peritoneal) and cardiomyocytes (H9C2 cell line) gelatin zymography demonstrated that activated macrophages robustly secreted latent pro-MMP9, whereas cardiomyocytes could not produce the enzyme. Co-culturing of the two cell species was critical for pro-MMP9 activation and was also accompanied by processing of cardiomyocyte-secreted pro-MMP2. A cascade of pro-MMP9 activation was initiated on macrophage membrane with pro-MMP2 cleavage. Namely, pro-inflammatory macrophages expressed an active membrane type 1 MMP (MT1MMP), which activated pro-MMP2, which in turn converted pro-MMP9. Downregulation of MT1MMP in macrophages by siRNA abolished activation of both pro-MMP2 and pro-MMP9 in co-culture. In addition, both cell species secreted MMP13 as a further pro-MMP9 activator. In co-culture, activation of pro-MMP13 occurred on membranes of macrophages and was enhanced in presence of active MMP2. Using incubations with recombinant MMPs and isolated macrophage membranes, we demonstrated that while both MMP2 and MMP13 individually had the ability to activate pro-MMP9, their combined action provided a synergistic effect. CONCLUSION Activation of pro-MMP9 in a co-culture of pro-inflammatory macrophages and cardiomyocytes was the result of a complex interaction of several MMPs on the cell membrane and in the extracellular space. Both cell types contributed critically to pro-MMP9 processing.
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Affiliation(s)
- Dmitry Egorov
- Institute of Physiology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
| | - Irakli Kopaliani
- Institute of Physiology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Anne Klotzsche-von Ameln
- Institute of Physiology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Stephan Speier
- Institute of Physiology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; Paul Langerhans Institute Dresden (PLID) of the Helmholtz Zenrtum München at University Clinic Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Andreas Deussen
- Institute of Physiology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Cates WT, Denbeigh JM, Salvagno RT, Kakar S, van Wijnen AJ, Eaton C. Inflammatory Markers Involved in the Pathogenesis of Dupuytren's Contracture. Crit Rev Eukaryot Gene Expr 2024; 34:1-35. [PMID: 38912961 DOI: 10.1615/critreveukaryotgeneexpr.2024052889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2024]
Abstract
Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.
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Affiliation(s)
- William T Cates
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Janet M Denbeigh
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Sanjeev Kakar
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Andre J van Wijnen
- Department of Biochemistry, University of Vermont, Burlington, VT 05405, USA
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Casari M, Siegl D, Deppermann C, Schuppan D. Macrophages and platelets in liver fibrosis and hepatocellular carcinoma. Front Immunol 2023; 14:1277808. [PMID: 38116017 PMCID: PMC10728659 DOI: 10.3389/fimmu.2023.1277808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/13/2023] [Indexed: 12/21/2023] Open
Abstract
During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible process, however, from the cirrhotic stage, there is significant progression to hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) and monocyte-derived macrophages are important drivers of fibrosis progression, but can also induce its regression once triggers of chronic inflammation are eliminated. In liver cancer, they are attracted to the tumor site to become tumor-associated macrophages (TAMs) polarized towards a M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis and hemostasis, platelets can also stimulate fibrosis and tumor development by secreting profibrogenic factors and regulating the innate immune response, e.g., by interacting with monocytes and macrophages. Here, we review recent literature on the role of macrophages and platelets and their interplay in liver fibrosis and hepatocellular carcinoma.
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Affiliation(s)
- Martina Casari
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Dominik Siegl
- Institute for Translational Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Research Center for Immune Therapy Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Detlef Schuppan
- Institute for Translational Immunology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Research Center for Immune Therapy Forschungszentrum für Immuntherapie (FZI), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
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Long H, Lichtnekert J, Andrassy J, Schraml BU, Romagnani P, Anders HJ. Macrophages and fibrosis: how resident and infiltrating mononuclear phagocytes account for organ injury, regeneration or atrophy. Front Immunol 2023; 14:1194988. [PMID: 37868987 PMCID: PMC10587486 DOI: 10.3389/fimmu.2023.1194988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 09/22/2023] [Indexed: 10/24/2023] Open
Abstract
Mononuclear phagocytes (MP), i.e., monocytes, macrophages, and dendritic cells (DCs), are essential for immune homeostasis via their capacities to clear pathogens, pathogen components, and non-infectious particles. However, tissue injury-related changes in local microenvironments activate resident and infiltrating MP towards pro-inflammatory phenotypes that contribute to inflammation by secreting additional inflammatory mediators. Efficient control of injurious factors leads to a switch of MP phenotype, which changes the microenvironment towards the resolution of inflammation. In the same way, MP endorses adaptive structural responses leading to either compensatory hypertrophy of surviving cells, tissue regeneration from local tissue progenitor cells, or tissue fibrosis and atrophy. Under certain circumstances, MP contribute to the reversal of tissue fibrosis by clearance of the extracellular matrix. Here we give an update on the tissue microenvironment-related factors that, upon tissue injury, instruct resident and infiltrating MP how to support host defense and recover tissue function and integrity. We propose that MP are not intrinsically active drivers of organ injury and dysfunction but dynamic amplifiers (and biomarkers) of specific tissue microenvironments that vary across spatial and temporal contexts. Therefore, MP receptors are frequently redundant and suboptimal targets for specific therapeutic interventions compared to molecular targets upstream in adaptive humoral or cellular stress response pathways that influence tissue milieus at a contextual level.
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Affiliation(s)
- Hao Long
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
- Sichuan Clinical Research Center for Nephropathy, Luzhou, China
| | - Julia Lichtnekert
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Joachim Andrassy
- Department of General, Visceral and Transplant Surgery, University Hospital of Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
| | - Barbara U. Schraml
- Institute for Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-University (LMU), Munich, Germany
- Walter-Brendel-Centre of Experimental Medicine, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
| | - Paola Romagnani
- Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, University of Firenze, Nephrology and Dialysis Unit, Meyer Children’s Hospital, Firenze, Italy
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU), Munich, Germany
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Wang S, Friedman SL. Found in translation-Fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). Sci Transl Med 2023; 15:eadi0759. [PMID: 37792957 PMCID: PMC10671253 DOI: 10.1126/scitranslmed.adi0759] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 09/15/2023] [Indexed: 10/06/2023]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of liver disease that poses a global health threat because of its potential to progress to advanced fibrosis, leading to cirrhosis and liver cancer. Recent advances in single-cell methodologies, refined disease models, and genetic and epigenetic insights have provided a nuanced understanding of MASH fibrogenesis, with substantial cellular heterogeneity in MASH livers providing potentially targetable cell-cell interactions and behavior. Unlike fibrogenesis, mechanisms underlying fibrosis regression in MASH are still inadequately understood, although antifibrotic targets have been recently identified. A refined antifibrotic treatment framework could lead to noninvasive assessment and targeted therapies that preserve hepatocellular function and restore the liver's architectural integrity.
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Affiliation(s)
- Shuang Wang
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Scott L. Friedman
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029
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Abstract
Chronic liver diseases such as nonalcoholic fatty liver disease (NAFLD) or viral hepatitis are characterized by persistent inflammation and subsequent liver fibrosis. Liver fibrosis critically determines long-term morbidity (for example, cirrhosis or liver cancer) and mortality in NAFLD and nonalcoholic steatohepatitis (NASH). Inflammation represents the concerted response of various hepatic cell types to hepatocellular death and inflammatory signals, which are related to intrahepatic injury pathways or extrahepatic mediators from the gut-liver axis and the circulation. Single-cell technologies have revealed the heterogeneity of immune cell activation concerning disease states and the spatial organization within the liver, including resident and recruited macrophages, neutrophils as mediators of tissue repair, auto-aggressive features of T cells as well as various innate lymphoid cell and unconventional T cell populations. Inflammatory responses drive the activation of hepatic stellate cells (HSCs), and HSC subsets, in turn, modulate immune mechanisms via chemokines and cytokines or transdifferentiate into matrix-producing myofibroblasts. Current advances in understanding the pathogenesis of inflammation and fibrosis in the liver, mainly focused on NAFLD or NASH owing to the high unmet medical need, have led to the identification of several therapeutic targets. In this Review, we summarize the inflammatory mediators and cells in the diseased liver, fibrogenic pathways and their therapeutic implications.
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Affiliation(s)
- Linda Hammerich
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
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Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
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35
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Ouyang JF, Mishra K, Xie Y, Park H, Huang KY, Petretto E, Behmoaras J. Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis. eLife 2023; 12:e85530. [PMID: 37706477 PMCID: PMC10547479 DOI: 10.7554/elife.85530] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 09/13/2023] [Indexed: 09/15/2023] Open
Abstract
Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1) associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single-cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin, and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarisation state within SPP1+ macrophages. Importantly, the MAM polarisation state follows a differentiation trajectory from SPP1+ macrophages and is associated with a core set of regulon activity. SPP1+ macrophages without the MAM polarisation state (SPP1+MAM-) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarisation state of SPP1+ macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.
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Affiliation(s)
- John F Ouyang
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Kunal Mishra
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Yi Xie
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Harry Park
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Kevin Y Huang
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Enrico Petretto
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
- Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University (CPU)NanjingChina
| | - Jacques Behmoaras
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College LondonLondonUnited Kingdom
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Bhattacharya M, Ramachandran P. Immunology of human fibrosis. Nat Immunol 2023; 24:1423-1433. [PMID: 37474654 DOI: 10.1038/s41590-023-01551-9] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 06/08/2023] [Indexed: 07/22/2023]
Abstract
Fibrosis, defined by the excess deposition of structural and matricellular proteins in the extracellular space, underlies tissue dysfunction in multiple chronic diseases. Approved antifibrotics have proven modest in efficacy, and the immune compartment remains, for the most part, an untapped therapeutic opportunity. Recent single-cell analyses have interrogated human fibrotic tissues, including immune cells. These studies have revealed a conserved profile of scar-associated macrophages, which localize to the fibrotic niche and interact with mesenchymal cells that produce pathological extracellular matrix. Here we review recent advances in the understanding of the fibrotic microenvironment in human diseases, with a focus on immune cell profiles and functional immune-stromal interactions. We also discuss the key role of the immune system in mediating fibrosis regression and highlight avenues for future study to elucidate potential approaches to targeting inflammatory cells in fibrotic disorders.
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Affiliation(s)
- Mallar Bhattacharya
- Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
| | - Prakash Ramachandran
- University of Edinburgh Centre for Inflammation Research, Institute for Regeneration and Repair, Edinburgh BioQuarter, Edinburgh, UK.
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Liu H, Yang C, Gao Y, Zhang X, Wang M, Yu X, Wang W, Xie L, Tang P, Yin X, Bai C, Zhang L. Macrophage-based delivery of anti-fibrotic proteins alleviates bleomycin-induced pulmonary fibrosis in mice. Bioeng Transl Med 2023; 8:e10555. [PMID: 37693057 PMCID: PMC10486326 DOI: 10.1002/btm2.10555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 05/03/2023] [Accepted: 05/16/2023] [Indexed: 09/12/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by chronic, progressive, and fibrotic lung injury. Although remarkable progress has been made toward understanding the pathogenesis of PF, finding more effective treatments for this fatal disease remains a challenge. In this study, we describe an innovative macrophage-based approach to deliver anti-fibrotic protein to the lung and inhibit PF in a mouse model of bleomycin (BLM)-induced lung injury. We engineered macrophages to continuously secrete three types of proteins: interleukin-10, which prevents inflammation; TGFRcFc, a soluble truncated TGF-βR2 that blocks TGF-β; and CD147, which induces matrix metalloproteinases (MMPs) and causes collagen degradation. Infusing these engineered macrophages into the lungs of BLM-induced PF mouse models in an optimal pattern significantly ameliorated PF in mice. Specifically, the most effective therapeutic outcome was achieved by infusing IL-10-secreting macrophages on day 1, followed by TGFRcFc-secreting macrophages on day 7 and CD147-secreting macrophages on day 14 into the same mice after BLM treatment. Our data suggest that macrophage-based delivery of anti-fibrotic proteins to the lungs is a promising therapy for fibrotic lung disorders.
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Affiliation(s)
- Huiying Liu
- College of Pulmonary and Critical Medicine, The 8th Medical CentreChinese PLA General HospitalBeijingChina
- Medical School of Chinese PLABeijingChina
| | - Cuiping Yang
- College of Pulmonary and Critical Medicine, The 8th Medical CentreChinese PLA General HospitalBeijingChina
- Medical School of Chinese PLABeijingChina
| | - Yun Gao
- College of Pharmaceutical and Biological EngineeringShenyang University of Chemical TechnologyShenyangLiaoningChina
| | - Xueli Zhang
- Department of PathologyThe 5th Medical Centre, Chinese PLA General HospitalBeijingChina
| | - Min Wang
- Graduate School of Dalian Medical UniversityDalianLiaoningChina
| | - Xinting Yu
- Department of Respiratory and Critical Care Medicine307 Clinical College, Anhui Medical UniversityBeijingChina
| | - Weidong Wang
- Medical School of Chinese PLABeijingChina
- Research Center of BioengineeringThe Medical Innovation Research Division of Chinese PLA General HospitalBeijingChina
| | - Lixin Xie
- College of Pulmonary and Critical Medicine, The 8th Medical CentreChinese PLA General HospitalBeijingChina
- Medical School of Chinese PLABeijingChina
| | - Ping Tang
- Department of RespiratoryShenzhen University General Hospital, Shenzhen University Clinical Medical AcademyShenzhenChina
| | - Xiushan Yin
- College of Pharmaceutical and Biological EngineeringShenyang University of Chemical TechnologyShenyangLiaoningChina
- RocRock Biotechnology (Shenzhen) Co., Ltd.ShenzhenChina
| | - Changqing Bai
- Department of RespiratoryShenzhen University General Hospital, Shenzhen University Clinical Medical AcademyShenzhenChina
| | - Luo Zhang
- Medical School of Chinese PLABeijingChina
- Research Center of BioengineeringThe Medical Innovation Research Division of Chinese PLA General HospitalBeijingChina
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Yao L, Hu X, Yuan M, Zhang Q, Liu P, Yang L, Dai K, Jiang Y. IGF2-NR4A2 Signaling Regulates Macrophage Subtypes to Attenuate Liver Cirrhosis. J Clin Transl Hepatol 2023; 11:787-799. [PMID: 37408817 PMCID: PMC10318280 DOI: 10.14218/jcth.2022.00392] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/18/2022] [Accepted: 11/20/2022] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND AND AIMS Liver cirrhosis can lead to liver failure and eventually death. Macrophages are the main contributors to cirrhosis and have a bidirectional role in regulating matrix deposition and degradation. Macrophage-based cell therapy has been developed as an alternative to liver transplantation. However, there is insufficient evidence regarding its safety and efficacy. In this study, we aimed to explore the effect of combining insulin-like growth factor 2 (IGF2) with bone marrow-derived macrophages (BMDMs) to treat mice with liver cirrhosis. METHODS We assessed liver inflammation, fibrosis regression, liver function, and liver regeneration in mice with CCl4-induced cirrhosis and treated with BMDM only or IGF2 + BMDM. We performed in vitro experiments in which activated hepatic stellate cells (HSCs) were co-cultured with macrophages in the presence or absence of IGF2. The polarity of macrophages and the degree of inhibition of HSCs were examined. The effect of IGF2 on macrophages was also verified by the overexpression of IGF2. RESULTS Combining IGF2 with BMDM reduced liver inflammation and fibrosis and increased hepatocyte proliferation. Combining IGF2 with BMDM was more effective than using BMDM alone. In vitro experiments demonstrated that IGF2 inhibited HSCs activation by upregulating NR4A2 to promote the anti-inflammatory macrophages phenotype. IGF2 also increased the synthesis of matrix metalloproteinases (MMPs) by macrophages, which may explain why administering IGF2 combined with BMDM was more effective than administering BMDM only. CONCLUSIONS Our study provides a theoretical basis for the future use of BMDM-based cell therapy to treat liver cirrhosis.
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Affiliation(s)
- Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qiuling Zhang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Pingji Liu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Lian Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Kai Dai
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
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Yu L, Gao Y, Aaron N, Qiang L. A glimpse of the connection between PPARγ and macrophage. Front Pharmacol 2023; 14:1254317. [PMID: 37701041 PMCID: PMC10493289 DOI: 10.3389/fphar.2023.1254317] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/31/2023] [Indexed: 09/14/2023] Open
Abstract
Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies.
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Affiliation(s)
- Lexiang Yu
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Yuen Gao
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Nicole Aaron
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, United States
| | - Li Qiang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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40
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Tao H, Liu Q, Zeng A, Song L. Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging. Int Immunopharmacol 2023; 121:110497. [PMID: 37329808 DOI: 10.1016/j.intimp.2023.110497] [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: 04/20/2023] [Revised: 05/30/2023] [Accepted: 06/11/2023] [Indexed: 06/19/2023]
Abstract
Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.
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Affiliation(s)
- Hongxia Tao
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Qianglin Liu
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China
| | - Anqi Zeng
- Institute of Translational Pharmacology and Clinical Application, Sichuan Academy of Chinese Medical Science, Chengdu, Sichuan 610041, PR China.
| | - Linjiang Song
- School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, PR China.
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41
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Sharma A, Wang J, Gandhi CR. CD14 is not required for carbon tetrachloride-induced hepatic inflammation and fibrosis with or without lipopolysaccharide challenge. J Cell Physiol 2023; 238:1530-1541. [PMID: 37098757 DOI: 10.1002/jcp.31030] [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: 10/17/2022] [Revised: 04/05/2023] [Accepted: 04/11/2023] [Indexed: 04/27/2023]
Abstract
Binding of lipopolysaccharide (LPS) to CD14 is required for its cellular effects via TLR4. A role of LPS/TLR4-mediated signaling in activated hepatic stellate cells (aHSCs), the major fibrogenic cells, in liver fibrosis has been reported. We investigated effects of LPS on carbon tetrachloride (CCl4)-induced fibrosis in CD14-knockout (KO) mice in vivo, and culture-activated HSCs in vitro. CCl4 (biweekly; 4 weeks)-treated wild type (WT) and CD14-KO mice were challenged with single LPS administration for 24 h. Liver injury, inflammation and fibrosis were determined. Culture-activated HSCs from WT or CD14-KO mice were stimulated with LPS. Parameters of fibrogenic activity (expression of collagen1a1 [Col1a1], α-smooth muscle actin [αSMA] and TGFβ1) and inflammatory cytokines/chemokines were measured. CCl4 treatment caused similar liver injury and fibrosis in WT and CD14-KO mice. LPS increased liver injury and inflammation similarly in CCl4-treated WT and CD14-KO mice, but downregulated Timp1 and upregulated Mmp13. LPS elicited similar NFκB activation and inflammatory response in WT and CD14-KO aHSCs. LPS similarly downregulated Acta2 (encodes αSMA), Pdgfrb, Col1a1 and Mmp13 expression but did not affect Timp1 expression in WT and CD14-KO aHSCs. LPS did not alter Tgfb1 but increased expression of decorin (Dcn) (inhibitor of TGFβ1) expression in WT and CD14-KO aHSCs. The results indicate that the effects of LPS on HSCs are CD14-independent, and CD14 is not required for hepatic fibrosis. LPS-induced down-modulation of fibrogenic markers in aHSCs is also CD14-independent.
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Affiliation(s)
- Akanksha Sharma
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jiang Wang
- Department of Pathology, University of Cincinnati, Cincinnati, Ohio, USA
| | - Chandrashekhar R Gandhi
- Cincinnati Veterans Administration Medical Center, Cincinnati, Ohio, USA
- Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA
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42
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Lee YS, Seki E. In Vivo and In Vitro Models to Study Liver Fibrosis: Mechanisms and Limitations. Cell Mol Gastroenterol Hepatol 2023; 16:355-367. [PMID: 37270060 PMCID: PMC10444957 DOI: 10.1016/j.jcmgh.2023.05.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/05/2023]
Abstract
Liver fibrosis is a common result of liver injury owing to various kinds of chronic liver diseases. A deeper understanding of the pathophysiology of liver fibrosis and identifying potential therapeutic targets of liver fibrosis is important because liver fibrosis may progress to advanced liver diseases, such as cirrhosis and hepatocellular carcinoma. Despite numerous studies, the underlying mechanisms of liver fibrosis remain unclear. Mechanisms of the development and progression of liver fibrosis differ according to etiologies. Therefore, appropriate liver fibrosis models should be selected according to the purpose of the study and the type of underlying disease. Many in vivo animal and in vitro models have been developed to study liver fibrosis. However, there are no perfect preclinical models for liver fibrosis. In this review, we summarize the current in vivo and in vitro models for studying liver fibrosis and highlight emerging in vitro models, including organoids and liver-on-a-chip models. In addition, we discuss the mechanisms and limitations of each model.
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Affiliation(s)
- Young-Sun Lee
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Department of Internal Medicine, Korea University College of Medicine, Seoul, South Korea
| | - Ekihiro Seki
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
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43
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Carvalho TL, Mertens Brainer de Queiroz Lima AC, de Araújo NS, de Sousa Fernandes MS, Lira GB, de Melo MMM, Vasconcelos LRS, de Moura PMMF, da Cunha Correia C. Aspects of cognitive assessments and spectroscopic magnetic resonance imaging in people with chronic hepatitis C: a systematic review. PSYCHOL HEALTH MED 2023; 28:1013-1029. [PMID: 35075963 DOI: 10.1080/13548506.2022.2029915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Extrahepatic manifestations are common in people with hepatitis C virus (HCV). Cognitive changes are pointed out, but the mechanisms are still uncertain. The aim of this systematic review was to analyze studies involving spectroscopic magnetic resonance in people infected with HCV, which also included cognitive tests. The research occurred in six databases (Directory of Open Access Journals, Lilacs, Medcaribe, Medline, Scielo and ScienceDirect) and the selection of studies was carried out in two stages: search for titles and abstracts, then reading of the full articles, excluding those that did not meet the eligibility criteria. 12,888 titles and abstracts were selected, but only 6 articles were included in the review. Impairments in attention, concentration, speed of information processing, memory, verbal fluency and executive functions were identified as well as an increase in the Cho/Cr and mI/Cr ratios and a reduction in the NAA/Cr ratio in some included studies. Longitudinal studies, with more homogeneous samples and methods, as well as with better controlled confounding factors, are necessary to adequately identify the effect of HCV on the brain.
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Affiliation(s)
- Tatiana Lins Carvalho
- Hospital Universitário Oswaldo Cruz, Pós-Graduação em Ciências da Saúde, Universidade de Pernambuco (UPE), Recife, Brazil
| | | | | | - Matheus Santos de Sousa Fernandes
- Departamento de Fisiologia e Farmacologia, Pós-graduação Em Neuropsiquiatria e Ciências do Comportamento, Universidade Federal de Pernambuco (UFPE), Recife, Brazil
| | - Gabriela Barza Lira
- Programa de Pós-graduação de Saúde da Criança e do Adolescente, Universidade Federal de Pernambuco (UFPE), Recife, PE, Brazil
| | | | | | | | - Carolina da Cunha Correia
- Professor of Neurology and Post Graduate Course in Health Sciences, Universidade de Pernambuco (UPE), Recife, PE, Brazil
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44
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Guo Y, Tian G, Chen X, Hou Y, Zhang X, Xue X, Zhao L, Wu Y. GL-V9 ameliorates liver fibrosis by inhibiting TGF-β/smad pathway. Exp Cell Res 2023; 425:113521. [PMID: 36841325 DOI: 10.1016/j.yexcr.2023.113521] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 02/12/2023] [Accepted: 02/13/2023] [Indexed: 02/27/2023]
Abstract
Liver fibrosis is a wound-healing response that arises from various aetiologies. Flavonoid compounds have been proved of their anti-liver fibrosis effects. This study aimed to elucidate the protective effect and mechanism of flavonoid compound GL-V9 on CCl4-induced and DDC-induced liver fibrosis. Treatment with GL-V9 alleviated hepatic injury and exhibited a dramatic protection effect of liver fibrosis. Further experiments found that GL-V9 treatment inhibited extracellular matrix (ECM) expression. Activation of hepatic stellate cells (HSCs) is a central driver of fibrosis. GL-V9 could inhibit the activation of HSCs through directly binding to TGFβRI, subsequently inhibit TGF-β/Smad pathway. In conclusion, this study proved that GL-V9 executed a protective effect on liver fibrosis by inhibiting TGF-β/Smad pathway.
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Affiliation(s)
- Yabing Guo
- Pharmaceutical Animal Experimental Center of China Pharmaceutical University, Nanjing, 211198, China
| | - Geng Tian
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Chen
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Yingjian Hou
- Center of Cellular and Molecular Biology, China Pharmaceutical University, Nanjing, 211198, China
| | - Xinyu Zhang
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Xin Xue
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China
| | - Li Zhao
- Pathology and Patient Derived Xenograft Efficacy Evaluation Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
| | - Yun Wu
- Yancheng Third People's Hospital, Yancheng School of Clinical Medicine of Nanjing Medical University, Yancheng, 224001, China.
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Singh S, Sharma N, Shukla S, Behl T, Gupta S, Anwer MK, Vargas-De-La-Cruz C, Bungau SG, Brisc C. Understanding the Potential Role of Nanotechnology in Liver Fibrosis: A Paradigm in Therapeutics. Molecules 2023; 28:molecules28062811. [PMID: 36985782 PMCID: PMC10057127 DOI: 10.3390/molecules28062811] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 03/15/2023] [Accepted: 03/17/2023] [Indexed: 03/30/2023] Open
Abstract
The liver is a vital organ that plays a crucial role in the physiological operation of the human body. The liver controls the body's detoxification processes as well as the storage and breakdown of red blood cells, plasma protein and hormone production, and red blood cell destruction; therefore, it is vulnerable to their harmful effects, making it more prone to illness. The most frequent complications of chronic liver conditions include cirrhosis, fatty liver, liver fibrosis, hepatitis, and illnesses brought on by alcohol and drugs. Hepatic fibrosis involves the activation of hepatic stellate cells to cause persistent liver damage through the accumulation of cytosolic matrix proteins. The purpose of this review is to educate a concise discussion of the epidemiology of chronic liver disease, the pathogenesis and pathophysiology of liver fibrosis, the symptoms of liver fibrosis progression and regression, the clinical evaluation of liver fibrosis and the research into nanotechnology-based synthetic and herbal treatments for the liver fibrosis is summarized in this article. The herbal remedies summarized in this review article include epigallocathechin-3-gallate, silymarin, oxymatrine, curcumin, tetrandrine, glycyrrhetinic acid, salvianolic acid, plumbagin, Scutellaria baicalnsis Georgi, astragalosides, hawthorn extract, and andrographolides.
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Affiliation(s)
- Sukhbir Singh
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Neelam Sharma
- Department of Pharmaceutics, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Saurabh Shukla
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India
| | - Tapan Behl
- School of Health Sciences &Technology, University of Petroleum and Energy Studies, Dehradun 248007, Uttarakhand, India
| | - Sumeet Gupta
- Department of Pharmacology, MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133207, Haryana, India
| | - Md Khalid Anwer
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Alkharj 11942, Saudi Arabia
| | - Celia Vargas-De-La-Cruz
- Department of Pharmacology, Bromatology and Toxicology, Faculty of Pharmacy and Biochemistry, Universidad Nacional Mayor de San Marcos, Lima 150001, Peru
- E-Health Research Center, Universidad de Ciencias y Humanidades, Lima 15001, Peru
| | - Simona Gabriela Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Cristina Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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Lee KJ, An S, Kim MY, Kim SM, Jeong WI, Ko HJ, Yang YM, Noh M, Han YH. Hepatic TREM2 + macrophages express matrix metalloproteinases to control fibrotic scar formation. Immunol Cell Biol 2023; 101:216-230. [PMID: 36529983 DOI: 10.1111/imcb.12616] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 12/11/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022]
Abstract
Liver cirrhosis is characterized by the extensive deposition of extracellular matrix such as fibril collagen, causing dysfunction and failure of the liver. Hepatic macrophages play pivotal roles in the transition from inflammatory to restorative properties upon hepatic injury. In particular, scar-associated macrophages (SAMacs) control liver fibrosis with the representative expression of matrix metalloproteinase (MMP). However, the heterogenic SAMac population has not been well characterized yet. This study profiled heterogeneous liver macrophages using public databases of single-cell transcriptomics and found T-cell immunoglobulin and mucin containing (TIM)4- macrophages exhibited elevated expression of MMPs. Scar-associated triggering receptor expressed on myeloid cells (TREM)2 was positively correlated with MMP expression, suggesting that TREM2+ subsets exert their fibrotic role via MMPs. During the progression of diet-induced nonalcoholic steatohepatitis and drug-induced liver cirrhosis, monocyte-derived TREM2+ macrophages accumulate in the liver with the distinct expression of MMPs. A noticeable expansion of MMP- and TREM2- double positive macrophages was observed in fibrotic scar regions. Consistently, the analysis of single-cell transcriptomics for human cirrhotic livers supported the theory that TREM2+ SAMacs are strongly associated with MMPs. The results could expand the understanding of liver fibrosis and SAMac, offering potential therapeutic approaches for liver cirrhosis.
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Affiliation(s)
- Kyeong-Jin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.,College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Seungchan An
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea.,College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Sun Myoung Kim
- College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon, South Korea
| | - Hyun-Jeong Ko
- College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Yoon Mee Yang
- College of Pharmacy, Kangwon National University, Chuncheon, South Korea
| | - Minsoo Noh
- Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon, South Korea
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Li S, Zhou B, Xue M, Zhu J, Tong G, Fan J, Zhu K, Hu Z, Chen R, Dong Y, Chen Y, Lee KY, Li X, Jin L, Cong W. Macrophage-specific FGF12 promotes liver fibrosis progression in mice. Hepatology 2023; 77:816-833. [PMID: 35753047 DOI: 10.1002/hep.32640] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Chronic liver diseases are associated with the development of liver fibrosis. Without treatment, liver fibrosis commonly leads to cirrhosis and HCC. FGF12 is an intracrine factor belonging to the FGF superfamily, but its role in liver homeostasis is largely unknown. This study aimed to investigate the role of FGF12 in the regulation of liver fibrosis. APPROACH AND RESULTS FGF12 was up-regulated in bile duct ligation (BDL)-induced and CCL 4 -induced liver fibrosis mouse models. Expression of FGF12 was specifically up-regulated in nonparenchymal liver cells, especially in hepatic macrophages. By constructing myeloid-specific FGF12 knockout mice, we found that deletion of FGF12 in macrophages protected against BDL-induced and CCL 4 -induced liver fibrosis. Further results revealed that FGF12 deletion dramatically decreased the population of lymphocyte antigen 6 complex locus C high macrophages in mouse fibrotic liver tissue and reduced the expression of proinflammatory cytokines and chemokines. Meanwhile, loss-of-function and gain-of-function approaches revealed that FGF12 promoted the proinflammatory activation of macrophages, thus inducing HSC activation mainly through the monocyte chemoattractant protein-1/chemokine (C-C motif) receptor 2 axis. Further experiments indicated that the regulation of macrophage activation by FGF12 was mainly mediated through the Janus kinase-signal transducer of activators of transcription pathway. Finally, the results revealed that FGF12 expression correlates with the severity of fibrosis across the spectrum of fibrogenesis in human liver samples. CONCLUSIONS FGF12 promotes liver fibrosis progression. Therapeutic approaches to inhibit macrophage FGF12 may be used to combat liver fibrosis in the future.
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Affiliation(s)
- Santie Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China.,College of Pharmacy and Research Institute of Drug Development , Chonnam National University , Gwangju , Republic of Korea
| | - Bin Zhou
- Department of Hepatobiliary Surgery , The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Mei Xue
- Central Laboratory , The First Affiliated Hospital of Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Junjie Zhu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Gaozan Tong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Junfu Fan
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Kunxuan Zhu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Zijing Hu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Rui Chen
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Yonggan Dong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Yiming Chen
- Department of Hepatobiliary Surgery , The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Kwang Youl Lee
- College of Pharmacy and Research Institute of Drug Development , Chonnam National University , Gwangju , Republic of Korea
| | - Xiaokun Li
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China.,Haihe Laboratory of Cell Ecosystem , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Litai Jin
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
| | - Weitao Cong
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health) , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China.,Haihe Laboratory of Cell Ecosystem , School of Pharmaceutical Science , Wenzhou Medical University , Wenzhou , People's Republic of China
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48
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Hildreth AD, Padilla ET, Tafti RY, Legala AR, O'Sullivan TE. Sterile liver injury induces a protective tissue-resident cDC1-ILC1 circuit through cDC1-intrinsic cGAS-STING-dependent IL-12 production. Cell Rep 2023; 42:112141. [PMID: 36807146 PMCID: PMC10435668 DOI: 10.1016/j.celrep.2023.112141] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 11/02/2022] [Accepted: 02/06/2023] [Indexed: 02/22/2023] Open
Abstract
Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.
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Affiliation(s)
- Andrew D Hildreth
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eddie T Padilla
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Rana Yakhshi Tafti
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Akshara R Legala
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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49
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Qin L, Liu N, Bao CLM, Yang DZ, Ma GX, Yi WH, Xiao GZ, Cao HL. Mesenchymal stem cells in fibrotic diseases-the two sides of the same coin. Acta Pharmacol Sin 2023; 44:268-287. [PMID: 35896695 PMCID: PMC9326421 DOI: 10.1038/s41401-022-00952-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Accepted: 06/29/2022] [Indexed: 02/06/2023]
Abstract
Fibrosis is caused by extensive deposition of extracellular matrix (ECM) components, which play a crucial role in injury repair. Fibrosis attributes to ~45% of all deaths worldwide. The molecular pathology of different fibrotic diseases varies, and a number of bioactive factors are involved in the pathogenic process. Mesenchymal stem cells (MSCs) are a type of multipotent stem cells that have promising therapeutic effects in the treatment of different diseases. Current updates of fibrotic pathogenesis reveal that residential MSCs may differentiate into myofibroblasts which lead to the fibrosis development. However, preclinical and clinical trials with autologous or allogeneic MSCs infusion demonstrate that MSCs can relieve the fibrotic diseases by modulating inflammation, regenerating damaged tissues, remodeling the ECMs, and modulating the death of stressed cells after implantation. A variety of animal models were developed to study the mechanisms behind different fibrotic tissues and test the preclinical efficacy of MSC therapy in these diseases. Furthermore, MSCs have been used for treating liver cirrhosis and pulmonary fibrosis patients in several clinical trials, leading to satisfactory clinical efficacy without severe adverse events. This review discusses the two opposite roles of residential MSCs and external MSCs in fibrotic diseases, and summarizes the current perspective of therapeutic mechanism of MSCs in fibrosis, through both laboratory study and clinical trials.
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Affiliation(s)
- Lei Qin
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Nian Liu
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Chao-le-meng Bao
- CASTD Regengeek (Shenzhen) Medical Technology Co. Ltd, Shenzhen, 518000 China
| | - Da-zhi Yang
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Gui-xing Ma
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Wei-hong Yi
- grid.33199.310000 0004 0368 7223Department of Orthopedics, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, 518000 China
| | - Guo-zhi Xiao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
| | - Hui-ling Cao
- grid.263817.90000 0004 1773 1790Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Shenzhen, 518055 China
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Wang Y, Yang M, Zhang J, Ren J, Liu N, Liu B, Lu L, Yang B. S-Doped carbonized polymer dots inhibit early myocardial fibrosis by regulating mitochondrial function. Biomater Sci 2023; 11:894-907. [PMID: 36524407 DOI: 10.1039/d2bm00578f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Myocardial fibrosis (MF) is a critical pathological lesion in the progression of various acute and chronic cardiovascular diseases. However, there is still a lack of clinically effective drugs and treatments for MF therapies. Herein, for the first time, we developed fluorescent sulfur-doped carbonized polymer dots (S-CPDs) as new nano-antioxidants to reduce the cardiomyocyte damage caused by reactive oxygen species (ROS) in the early stage of fibrotic lesions. In vitro results suggested that the pre-protection of S-CPDs significantly increased the survival rate of H9c2 cells under severe oxidative stress, inhibited the isoproterenol (ISO)-induced hypertrophy of myocardial cells through improving the content of mitochondria related proteins and adenosine triphosphate (ATP) in cells. Moreover, S-CPD administration could effectively decrease cardiac hypertrophy and promote heart function in MF rat models. The rapid internalization, high biocompatibility and fluorescence imaging potential of S-CPDs revealed their promising application prospects in the diagnoses and treatments of cardiovascular diseases.
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Affiliation(s)
- Yiran Wang
- Department of Cardiology, The Second Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Mingxi Yang
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun 130021, P.R. China. .,State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P.R. China.
| | - Jiayi Zhang
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Jingyan Ren
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Ning Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Bin Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Laijin Lu
- Department of Hand Surgery, The First Hospital of Jilin University, Changchun 130021, P.R. China.
| | - Bai Yang
- State Key Laboratory of Supramolecular Structure and Materials, College of Chemistry, Jilin University, Changchun 130012, P.R. China.
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