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Tian C, Wang Y, Wang R, Pan L, Xu T. Pharmacological and therapeutic effects of natural products on liver regeneration-a comprehensive research. Chin Med 2025; 20:57. [PMID: 40329344 PMCID: PMC12057117 DOI: 10.1186/s13020-025-01108-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/12/2025] [Indexed: 05/08/2025] Open
Abstract
Liver regeneration (LR) refers to the physiological process by which hepatocytes undergo cellular proliferation to restore the structure and function of the liver following significant hepatocyte loss due to injury or partial hepatectomy (PH). While the liver possesses a remarkable regenerative capacity, this process is tightly regulated to ensure appropriate cessation once homeostasis is reestablished. Various strategies, including technological interventions and pharmacological agents, have been explored to enhance LR. Among these, natural products have emerged as promising candidates for promoting LR. For instance, quercetin, a natural compound, has been shown to enhance LR following PH by maintaining redox homeostasis and stimulating hepatocyte proliferation. However, natural products present certain limitations, such as poor solubility and low bioavailability, which may hinder their clinical application. Modifications in the formulation and mode of administration have demonstrated potential in overcoming these challenges and optimizing their pharmacological effects. Recent advancements in research have further highlighted the growing relevance of natural products, including traditional Chinese medicine (TCM), in the context of LR. Despite this progress, a comprehensive and systematic review of their roles, mechanisms, and therapeutic potential remains lacking. This review aims to bridge this gap by summarizing natural products with demonstrated potential to promote LR. Drawing on data from PubMed, Web of Science, and CNKI databases, it elucidates their pharmacological effects and regulatory mechanisms, providing a valuable reference for future research and clinical application in the field of LR.
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Affiliation(s)
- Chang Tian
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China
- Anhui Key Lab of Bioactivity of Natural Products, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China
| | - Yuhan Wang
- International Cooperation and Exchange Department, Shanghai General Hospital, 85/86 Wujin Road, Hongkou District, Shanghai, 200434, China
| | - Ran Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China
- Anhui Key Lab of Bioactivity of Natural Products, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China
| | - Linxin Pan
- College of Life Sciences, Anhui Medical University, Hefei, 230032, China.
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, School of Pharmaceutical Sciences, Anhui Medical University, Hefei, 230032, China.
- Anhui Key Lab of Bioactivity of Natural Products, Institute for Liver Diseases of Anhui Medical University, Anhui Medical University, Hefei, 230032, China.
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Liu G, Tang F, Wang T, Yan JQ, Li FH, Ha FS, Zhang X, Jing L, Liang J. Efficacy of recombinant human thrombopoietin in patients with acute-on-chronic liver failure and thrombocytopenia: A prospective, open-label study. World J Gastroenterol 2025; 31:105004. [PMID: 40248371 PMCID: PMC12001200 DOI: 10.3748/wjg.v31.i14.105004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/24/2025] [Accepted: 03/24/2025] [Indexed: 04/11/2025] Open
Abstract
BACKGROUND Patients with acute-on-chronic liver failure (ACLF) have a high mortality rate, poor prognosis, and often experience concurrent thrombocytopenia and bleeding events. AIM To evaluate the efficacy and safety of recombinant human thrombopoietin (rhTPO) in patients with ACLF with concomitant severe thrombocytopenia. METHODS This was a prospective, open-label study. We assigned 70 ACLF patients with severe thrombocytopenia into the rhTPO group and control group, with 35 patients in each group. Patients in the rhTPO group received subcutaneous injections of rhTPO at a dose of 15000 IU/day for 7 consecutive days, while patients in the control group did not receive rhTPO treatment. The primary endpoint was the proportion of patients with platelet count > 50 × 109/L on day 14. RESULTS The proportion of patients with platelet count > 50 × 109/L on day 14 was 60.7% in the rhTPO group, which was significantly higher than that (12.0%) in the control group (P < 0.001). The platelet count in the rhTPO group on day 14 was 64 × 109/L, exceeding the baseline of 28 × 109/L. Compared to the control group, the rhTPO group exhibited a significant increase in platelet count from baseline (P < 0.05). Model for end-stage liver disease score, albumin level and international normalized ratio improved significantly from baseline on day 14 after rhTPO injection. The concentrations of serum thrombopoietin and hepatocyte growth factor in the rhTPO group after 7 days were 143.7 and 195.4 pg/mL, respectively, showing a significant increase from baseline (P < 0.05). Eight (22.9%) patients had bleeding events in the control group compared with four (11.4%) in the rhTPO group. The incidence of 90-day mortality was also higher in the control group (6, 17.1%) than that in the rhTPO group (3, 8.6%). CONCLUSION rhTPO significantly increased the platelet count in ACLF patients with thrombocytopenia and reduce the occurrence of bleeding events, with a good safety profile.
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Affiliation(s)
- Gang Liu
- Department of Internal Medicine, The Third Central Clinical College of Tianjin Medical University, Tianjin 300300, China
- Department of Internal Medicine, Tianjin Dongli Hospital, Tianjin 300300, China
| | - Fei Tang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Tao Wang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Jun-Qing Yan
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Feng-Hui Li
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Fu-Shuang Ha
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Xu Zhang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Li Jing
- Department of Medical Laboratory, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Jing Liang
- Department of Gastroenterology and Hepatology, The Third Central Hospital of Tianjin, Tianjin 300170, China
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Sun Y, Shan X, Li M, Niu Y, Sun Z, Ma X, Wang T, Zhang J, Niu D. Autoimmune mechanisms and inflammation in obesity-associated type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease. Funct Integr Genomics 2025; 25:84. [PMID: 40205260 DOI: 10.1007/s10142-025-01587-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 03/19/2025] [Accepted: 03/20/2025] [Indexed: 04/11/2025]
Abstract
Obesity, characterized by the excessive accumulation of white adipose tissue, is a significant global health burden and a major risk factor for a range of diseases, including malignancies and metabolic disorders. Individuals with high visceral fat content are particularly susceptible to severe complications such as type 2 diabetes, cardiovascular diseases, and liver disorders. However, the pathogenesis of obesity-related metabolic diseases extends beyond simple adiposity. Chronic obesity triggers a prolonged inflammatory response, which leads to tissue fibrosis and sustained organ damage, contributing to multi-organ dysfunction. This review explores the autoimmune mechanisms and inflammatory pathways underlying obesity-induced type 2 diabetes, atherosclerosis, and non-alcoholic fatty liver disease, with an emphasis on their interrelated pathophysiology and the potential for therapeutic interventions.
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Grants
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- LZ22C010003 Key Project of Zhejiang Provincial Natural Science Foundation of China
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 2021R52043 Scientific and Technological Innovation Leading Talents Project of Zhejiang Provincial "High-level Talents Special Support Plan"
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- 32202656, 32402753 National Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- LQ23C170003, LQ23C180003 & LQ24C170001 Zhejiang Provincial Natural Science Foundation of China
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
- 2021C02068-4 Zhejiang Science and Technology Major Program on Agricultural New Variety Breeding
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Affiliation(s)
- Yuanyuan Sun
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Xueting Shan
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Mingyang Li
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Yifan Niu
- College of Animal Sciences, Zhejiang University, Hangzhou, 310058, Zhejiang, China
| | - Zhongxin Sun
- Department of Plastic, Reconstructive & Hand Microsurgery, Ningbo NO.6 Hospital, Ningbo, 315000, Zhejiang, China
| | - Xiang Ma
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China
| | - Tao Wang
- Nanjing Kgene Genetic Engineering Co., Ltd, Nanjing, 211300, Jiangsu, China.
| | - Jufang Zhang
- Department of Plastic and Aesthetic Surgery, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, 310006, Zhejiang, China.
| | - Dong Niu
- College of Animal Science and Technology & College of Veterinary Medicine, Key Laboratory of Applied Technology on Green-Eco-Healthy Animal Husbandry of Zhejiang Province, Provincial Engineering Research Center for Animal Health Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, China Australia Joint Laboratory for Animal Health Big Data Analytics, Zhejiang A&F University, Hangzhou, 311300, Zhejiang, China.
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He W, Yan L, Hu D, Hao J, Liou Y, Luo G. Neutrophil heterogeneity and plasticity: unveiling the multifaceted roles in health and disease. MedComm (Beijing) 2025; 6:e70063. [PMID: 39845896 PMCID: PMC11751288 DOI: 10.1002/mco2.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/04/2024] [Accepted: 12/11/2024] [Indexed: 01/24/2025] Open
Abstract
Neutrophils, the most abundant circulating leukocytes, have long been recognized as key players in innate immunity and inflammation. However, recent discoveries unveil their remarkable heterogeneity and plasticity, challenging the traditional view of neutrophils as a homogeneous population with a limited functional repertoire. Advances in single-cell technologies and functional assays have revealed distinct neutrophil subsets with diverse phenotypes and functions and their ability to adapt to microenvironmental cues. This review provides a comprehensive overview of the multidimensional landscape of neutrophil heterogeneity, discussing the various axes along which diversity manifests, including maturation state, density, surface marker expression, and functional polarization. We highlight the molecular mechanisms underpinning neutrophil plasticity, focusing on the complex interplay of signaling pathways, transcriptional regulators, and epigenetic modifications that shape neutrophil responses. Furthermore, we explore the implications of neutrophil heterogeneity and plasticity in physiological processes and pathological conditions, including host defense, inflammation, tissue repair, and cancer. By integrating insights from cutting-edge research, this review aims to provide a framework for understanding the multifaceted roles of neutrophils and their potential as therapeutic targets in a wide range of diseases.
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Affiliation(s)
- Weifeng He
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Lingfeng Yan
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
| | - Dongxue Hu
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
| | - Jianlei Hao
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and TreatmentZhuhai Institute of Translational MedicineZhuhai People's Hospital (Zhuhai Clinical Medical College of Jinan University)Jinan UniversityZhuhaiGuangdongChina
- The Biomedical Translational Research InstituteFaculty of Medical ScienceJinan UniversityGuangzhouGuangdongChina
| | - Yih‐Cherng Liou
- Department of Biological SciencesFaculty of ScienceNational University of SingaporeSingaporeSingapore
- National University of Singapore (NUS) Graduate School for Integrative Sciences and EngineeringNational University of SingaporeSingaporeSingapore
| | - Gaoxing Luo
- Institute of Burn ResearchState Key Laboratory of Trauma and Chemical Poisoningthe First Affiliated Hospital of Army Medical University (the Third Military Medical University)ChongqingChina
- Chongqing Key Laboratory for Wound Repair and Tissue RegenerationChongqingChina
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Zhao Y, Zhao S, Liu S, Ye W, Chen WD. Kupffer cells, the limelight in the liver regeneration. Int Immunopharmacol 2025; 146:113808. [PMID: 39673997 DOI: 10.1016/j.intimp.2024.113808] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 11/25/2024] [Accepted: 12/04/2024] [Indexed: 12/16/2024]
Abstract
Kupffer cells are pivotal in initiating hepatocyte proliferation and establishing connections between different cell types during liver regeneration following partial hepatectomy. As resident macrophages within the liver, Kupffer cells collaborate with hepatocytes and non-parenchymal cells to release various inflammatory mediators that promote hepatocyte proliferation through induction signals like STAT3 phosphorylation. Additionally, the regeneration and replenishment of Kupffer cells themselves are integral components of liver regeneration. The supplementation of the Kupffer cell pool primarily occurs through two pathways: one involves local proliferation of Kupffer cells in their original location, while the other entails infiltration of circulating monocytes into the liver, followed by acquiring Kupffer cell phenotypes under the combined influence of multiple inducing factors. Extensive research has focused on intercellular crosstalk among various types of liver cells during liver regeneration, highlighting the crucial role played by Kupffer cells. This article aims to introduce Kupffer cells and their involvement in liver regeneration, as well as discuss the steady-state balance of Kupffer cell pools during this process.
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Affiliation(s)
- Yang Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China; Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Shizhen Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China; The First Affiliated Hospital of Henan University, Kaifeng, China
| | - Shiwei Liu
- Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, Henan University, Kaifeng, China
| | - Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China; Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, Henan University, Kaifeng, China.
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China; Key Laboratory of Receptors-Mediated Gene Regulation, Hebi Key Laboratory of Liver Disease, School of Basic Medical Sciences, Henan University, Kaifeng, China.
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Dhayanithy G, Radhakrishnan S, Ann Martin C, Caroline Martin J, Hakeem AR, Jothimani D, Kalkura SN, Rela M. Understanding immunological insights of liver transplantation: a practice for attaining operational tolerance. Clin Exp Immunol 2025; 219:uxae125. [PMID: 39973343 PMCID: PMC11878573 DOI: 10.1093/cei/uxae125] [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: 04/17/2024] [Revised: 11/15/2024] [Accepted: 02/19/2025] [Indexed: 02/21/2025] Open
Abstract
Liver transplantation has been at the forefront of medical research, with efforts concentrated on understanding the intricate cellular and molecular dynamics involved this complex procedure. This body of work has chronicled critical clinical advancements, identified challenges, and highlighted progressive improvements in surgical practices. These concerted efforts have significantly contributed to the evolution and enhancement of liver transplantation, elevating it to its current level of sophistication. A successful liver transplant now demands an integrated, multidisciplinary approach that includes not only expanding the donor pool from deceased to living donors but also embracing advances in surgical methods, efficiently managing post-transplant complications, and, importantly, achieving operational tolerance. The latter, operational tolerance, is a state wherein the recipient's immune system is coaxed into accepting the transplanted organ without the long-term use of immunosuppressive drugs, thereby minimizing potential side effects, and improving quality of life. Understanding the critical immune mechanisms that aim to prevent graft rejection is essential from an immunological perspective. This review aims to highlight the crucial areas of host versus graft immune responses, making a clear distinction between organs received from living and deceased donors. It examines how these immune responses, both innate and adaptive, are initiated and proposes the exploration of molecular docking sites as a strategy to curb unwanted immune reactions. Additionally, this review explores the promising potential of biomarkers in predicting graft rejection, and emphasizes the importance of achieving tolerance and the continuous quest for innovative strategies to enhance the success and longevity of liver transplants.
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Affiliation(s)
| | | | | | - Josette Caroline Martin
- Department of Pathology, Sri Venkateshwara Medical College Hospital and Research Institute, Pondicherry, India
| | | | - Dinesh Jothimani
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
| | - Subbaraya Narayana Kalkura
- Crystal Growth Centre, Anna University, Guindy, Chennai, India
- National Foundation for Liver Research, Chromepet, Chennai, India
| | - Mohamed Rela
- National Foundation for Liver Research, Chromepet, Chennai, India
- Dr. Rela Institute and Medical Centre, Chromepet, Chennai, India
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Eldafashi N, Waaz S, Ali TFS, Zaki MYW, Nazmy MH, Fathy M. The protective role of two oxindole derivatives is mediated by modulating NLRP3/caspase-1 and PI3K/AKT pathways in a preclinical animal model of hepatic ischemia reperfusion injury. Life Sci 2024; 352:122872. [PMID: 38942361 DOI: 10.1016/j.lfs.2024.122872] [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: 04/25/2024] [Revised: 06/05/2024] [Accepted: 06/23/2024] [Indexed: 06/30/2024]
Abstract
Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. MAIN METHODS HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. KEY FINDINGS HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1β, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. SIGNIFICANCE Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.
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Affiliation(s)
- Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
| | - Shaimaa Waaz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
| | - Taha F S Ali
- Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
| | - Marco Y W Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
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Zhang X, Geng Q, Lin L, Zhang L, Shi C, Liu B, Yan L, Cao Z, Li L, Lu P, Tan Y, He X, Zhao N, Li L, Lu C. Insights gained into the injury mechanism of drug and herb induced liver injury in the hepatic microenvironment. Toxicology 2024; 507:153900. [PMID: 39079402 DOI: 10.1016/j.tox.2024.153900] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2024] [Revised: 07/25/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
Drug-Induced Liver Injury (DILI) and herb Induced Liver Injury (HILI) continues to pose a substantial challenge in both clinical practice and drug development, representing a grave threat to patient well-being. This comprehensive review introduces a novel perspective on DILI and HILI by thoroughly exploring the intricate microenvironment of the liver. The dynamic interplay among hepatocytes, sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, cholangiocytes, and the intricate vascular network assumes a central role in drug metabolism and detoxification. Significantly, this microenvironment is emerging as a critical determinant of susceptibility to DILI and HILI. The review delves into the multifaceted interactions within the liver microenvironment, providing valuable insights into the complex mechanisms that underlie DILI and HILI. Furthermore, we discuss potential strategies for mitigating drug-induced liver injury by targeting these influential factors, emphasizing their clinical relevance. By highlighting recent advances and future prospects, our aim is to shed light on the promising avenue of leveraging the liver microenvironment for the prevention and mitigation of DILI and HILI. This deeper understanding is crucial for advancing clinical practices and ensuring patient safety in the realm of DILI and HILI.
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Affiliation(s)
- Xiaomeng Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Qi Geng
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lin Lin
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lulu Zhang
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Changqi Shi
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Bin Liu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Lan Yan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhiwen Cao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Peipei Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yong Tan
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaojuan He
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ning Zhao
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Li Li
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
| | - Cheng Lu
- Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
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Cao Y, Wang S, Zhang M, Lai B, Liang Y. PFKFB3-mediated glycolysis in hepatic stellate cells promotes liver regeneration. Biochem Biophys Res Commun 2024; 712-713:149958. [PMID: 38640731 DOI: 10.1016/j.bbrc.2024.149958] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 04/21/2024]
Abstract
Hepatic stellate cells (HSCs) perform a significant function in liver regeneration (LR) by becoming active. We propose to investigate if activated HSCs enhance glycolysis via PFKFB3, an essential glycolytic regulator, and whether targeting this pathway could be beneficial for LR. The liver and isolated HSCs of mice subjected to 2/3 partial hepatectomy (PHx) exhibited a significant rise in PFKFB3 expression, as indicated by quantitative RT-PCR analyses and Western blotting. Also, the primary HSCs of mice subjected to PHx have a significant elevation of the glycolysis level. Knocking down PFKFB3 significantly diminished the enhancement of glycolysis by PDGF in human LX2 cells. The hepatocyte proliferation in mice treated with PHx was almost completely prevented when the PFKFB3 inhibitor 3PO was administered, emerging that PFKFB3 is essential in LR. Furthermore, there was a decline in mRNA expression of immediate early genes and proinflammatory cytokines. In terms of mechanism, both the p38 MAP kinase and ERK1/2 phosphorylation in LO2 cells and LO2 proliferation were significantly reduced by the conditioned medium (CM) obtained from LX2 cells with either PFKFB3 knockdown or inhibition. Compared to the control group, isolated hepatocytes from 3PO-treated mice showed decreased p38 MAP kinase and ERK1/2 phosphorylation and proliferation. Thus, LR after PHx involves the activation of PFKFB3 in HSCs, which enhances glycolysis and promotes lactate production, thereby facilitating hepatocyte proliferation via the p38/ERK MAPK signaling pathway.
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Affiliation(s)
- Yapeng Cao
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Siyu Wang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Min Zhang
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Baochang Lai
- Cardiovascular Research Center, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, 710061, China
| | - Yanni Liang
- Shaanxi Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xian Yang, 712046, China.
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10
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Chen Y, Yang Y, Lu J, Chen H, Shi Z, Wang X, Xu N, Xu X, Wang S. Neutrophil and macrophage crosstalk might be a potential target for liver regeneration. FEBS Open Bio 2024; 14:922-941. [PMID: 38710666 PMCID: PMC11148125 DOI: 10.1002/2211-5463.13803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/17/2024] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
The regenerative capability of the liver is remarkable, but further research is required to understand the role that neutrophils play in this process. In the present study, we reanalyzed single-cell RNA sequencing data from a mouse partial hepatectomy (PH) model to track the transcriptional changes in hepatocytes and non-parenchymal cells. Notably, we unraveled the regenerative capacity of hepatocytes at diverse temporal points after PH, unveiling the contributions of three distinct zones in the liver regeneration process. In addition, we observed that the depletion of neutrophils reduced the survival and liver volume after PH, confirming the important role of neutrophils in liver regeneration. CellChat analysis revealed an intricate crosstalk between neutrophils and macrophages promoting liver regeneration and, using weighted gene correlation network analysis, we identified the most significant genetic module associated with liver regeneration. Our study found that hepatocytes in the periportal zone of the liver are more active than in other zones, suggesting that the crosstalk between neutrophils and macrophages might be a potential target for liver regeneration treatment.
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Affiliation(s)
- Yiyuan Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
| | - Yijie Yang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
| | - Jinjiao Lu
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
| | - Huan Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
| | - Zhixiong Shi
- Zhejiang University School of MedicineHangzhouChina
| | - Xiaodong Wang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
| | - Nan Xu
- Zhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Institute of Organ TransplantationZhejiang UniversityHangzhouChina
| | - Shuai Wang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical University, Affiliated Hangzhou First People's HospitalHangzhouChina
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
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11
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Sedik AA, Elgohary R, Khalifa E, Khalil WKB, I Shafey H, B Shalaby M, S O Gouida M, M Tag Y. Lauric acid attenuates hepato-metabolic complications and molecular alterations in high-fat diet-induced nonalcoholic fatty liver disease in rats. Toxicol Mech Methods 2024; 34:454-467. [PMID: 38166588 DOI: 10.1080/15376516.2023.2301344] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 12/29/2023] [Indexed: 01/04/2024]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver illness characterized by increase of lipid content in the liver. This study investigated the role of lauric acid to treat NAFLD in male adult Sprague Dawley rats. In this study, to induce NAFLD in the rats, a high-fat diet (HFD) was administered for eight consecutive weeks. Lauric acid groups received lauric acid (250 and 500 mg/kg; orally), concurrently with HFD for eight consecutive weeks. Lauric acid could ameliorate the serum levels of TG, TC, ALT, AST, blood glucose, and insulin. Moreover, lauric acid significantly elevated the levels of SOD, GSH, catalase, and IL-10. Additionally, it lowered the hepatic levels of MDA, ROS, MPO, 4-HNE, interleukin (IL)-1β, and tumor necrosis factor (TNF-α). Furthermore, lauric acid significantly up-regulated the hepatic expression of IRS1, AMPK, PI3K, and SIRT1 genes. In parallel, lauric acid could improve the histopathological picture of the liver and reduce the liver apoptosis via decreasing the expression of annexin V (Anx V). Finally, our data proposed that lauric acid could be an effective candidate for the NAFLD treatment.
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Affiliation(s)
- Ahmed A Sedik
- Pharmacology Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Rania Elgohary
- Narcotics, Ergogenics and Poisons Department, Medical Research and Clinical Studies Institute, National Research Centre, Cairo, Egypt
| | - Eman Khalifa
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura, Egypt
| | | | - Heba I Shafey
- Cell Biology Department, National Research Centre, Giza, Egypt
| | - Mohamed B Shalaby
- Toxicology Research Department, Research Institute of Medical Entomology (RIME), General Organisation of Teaching Hospitals and Institutes (GOTHI), Ministry of Health and Population (MoHP), Cairo, Egypt
| | - Mona S O Gouida
- Genetics Unit, Faculty of Medicine, Children Hospital, Mansoura University, Mansoura, Egypt
| | - Yasmin M Tag
- Oral Biology Department, Faculty of Oral and Dental Medicine, Delta University for Science and Technology, Mansoura, Egypt
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12
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Ruz-Maldonado I, Gonzalez JT, Zhang H, Sun J, Bort A, Kabir I, Kibbey RG, Suárez Y, Greif DM, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nat Commun 2024; 15:1247. [PMID: 38341404 PMCID: PMC10858916 DOI: 10.1038/s41467-024-45439-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 01/24/2024] [Indexed: 02/12/2024] Open
Abstract
Midlobular hepatocytes are proposed to be the most plastic hepatic cell, providing a reservoir for hepatocyte proliferation during homeostasis and regeneration. However, other mechanisms beyond hyperplasia have been little explored and the contribution of other hepatocyte subpopulations to regeneration has been controversial. Thus, re-examining hepatocyte dynamics during regeneration is critical for cell therapy and treatment of liver diseases. Using a mouse model of hepatocyte- and non-hepatocyte- multicolor lineage tracing, we demonstrate that midlobular hepatocytes also undergo hypertrophy in response to chemical, physical, and viral insults. Our study shows that this subpopulation also combats liver impairment after infection with coronavirus. Furthermore, we demonstrate that pericentral hepatocytes also expand in number and size during the repair process and Galectin-9-CD44 pathway may be critical for driving these processes. Notably, we also identified that transdifferentiation and cell fusion during regeneration after severe injury contribute to recover hepatic function.
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Affiliation(s)
- Inmaculada Ruz-Maldonado
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - John T Gonzalez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Hanming Zhang
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Jonathan Sun
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Alicia Bort
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Inamul Kabir
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Richard G Kibbey
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Departments of Internal Medicine (Endocrinology) and Cellular & Molecular Physiology, Yale University, New Haven, CT, USA
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA
| | - Daniel M Greif
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06511, USA
- Department of Genetics, Yale University School of Medicine, New Haven, CT, 06511, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Yale Center of Molecular and Systems Metabolism, Yale University School of Medicine, New Haven, CT, 06520, USA.
- Department of Pathology, Yale University School of Medicine, New Haven, CT, 06520, USA.
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13
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Brunnthaler L, Pereyra D, Brenner M, Santol J, Herrmann L, Schrottmaier WC, Pirabe A, Schmuckenschlager A, Kim S, Kern AE, Huber FX, Michels LE, Brostjan C, Salzmann M, Hohensinner P, Kain R, Gruenberger T, Starlinger P, Assinger A. Intrahepatic neutrophil accumulation and extracellular trap formation are associated with posthepatectomy liver failure. Hepatol Commun 2024; 8:e0348. [PMID: 38099865 PMCID: PMC10727591 DOI: 10.1097/hc9.0000000000000348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/13/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Posthepatectomy liver failure (PHLF) represents a life-threatening complication with limited therapeutic options. Neutrophils play a critical and dynamic role during regeneratory processes, but their role in human liver regeneration is incompletely understood, especially as underlying liver disease, detectable in the majority of patients, critically affects hepatic regeneration. Here we explored intrahepatic neutrophil accumulation and neutrophil extracellular traps (NETs) in patients with PHLF and validated the functional relevance of NETs in a murine partial hepatectomy (PHx) model. METHODS We investigated the influx of neutrophils, macrophages, eosinophils, and mast cells and the presence of their respective extracellular traps in liver biopsies of 35 patients undergoing hepatectomy (10 patients with PHLF) before and after the initiation of liver regeneration by fluorescence microscopy. In addition, NET formation and neutrophil activation were confirmed by plasma analysis of 99 patients (24 patients with PHLF) before and up to 5 days after surgery. Furthermore, we inhibited NETs via DNase I in a murine PHx model of mice with metabolically induced liver disease. RESULTS We detected rapid intrahepatic neutrophil accumulation, elevated levels of myeloperoxidase release, and NET formation in regenerating human livers, with a significantly higher increase of infiltrating neutrophils and NETs in patients with PHLF. Circulating markers of neutrophil activation, including elastase, myeloperoxidase, and citrullinated histone H3, correlated with markers of liver injury. In a murine PHx model, we showed that the inhibition of NET accelerated hepatocyte proliferation and liver regeneration. CONCLUSIONS Patients with PHLF showed accelerated intrahepatic neutrophil infiltration and NET formation, which were associated with liver damage. Further, we identified postsurgical myeloperoxidase levels as predictive markers for adverse outcomes and observed that blocking NETs in a murine PHx model accelerated tissue regeneration.
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Affiliation(s)
- Laura Brunnthaler
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - David Pereyra
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Miriam Brenner
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jonas Santol
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Lukas Herrmann
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Waltraud C. Schrottmaier
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anita Pirabe
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Anna Schmuckenschlager
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Sarang Kim
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Anna Emilia Kern
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Felix Xaver Huber
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Lisa Emilie Michels
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Christine Brostjan
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Manuel Salzmann
- Department of Medicine II, Division of Cardiology, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Philipp Hohensinner
- Center for Biomedical Research, Division of Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Patrick Starlinger
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
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14
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Mun SJ, Hong YH, Shin Y, Lee J, Cho HS, Kim DS, Chung KS, Son MJ. Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling. Sci Rep 2023; 13:22935. [PMID: 38129682 PMCID: PMC10739970 DOI: 10.1038/s41598-023-50250-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/17/2023] [Indexed: 12/23/2023] Open
Abstract
Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvement for standardization and reproducible mass production. Here, we improved the method such that it is suitable for scalable expansion and relatively homogenous production, resulting in an efficient and reproducible process. Moreover, three medium components critical for long-term expansion were defined. Detailed transcriptome analysis revealed that fibroblast growth factor signaling, the essential pathway for hepatocyte proliferation during liver regeneration, was mainly enriched in proliferative liver organoids. Short hairpin RNA-mediated knockdown of FGFR4 impaired the generation and proliferation of organoids. Finally, glycogen storage disease type Ia (GSD1a) patient-specific liver organoids were efficiently and reproducibly generated using the new protocol. They well maintained disease-specific phenotypes such as higher lipid and glycogen accumulation in the liver organoids and lactate secretion into the medium consistent with the main pathologic characteristics of patients with GSD1a. Therefore, our newly established liver organoid platform can provide scalable and practical personalized disease models and help to find new therapies for incurable liver diseases including genetic liver diseases.
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Affiliation(s)
- Seon Ju Mun
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Yeon-Hwa Hong
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Yongbo Shin
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Jaeseo Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Hyun-Soo Cho
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Dae-Soo Kim
- Department of Bioinformatics, UST, 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
- Department of Digital Biotech Innovation Center, KRIBB, 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Kyung-Sook Chung
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea.
- Biomedical Translational Research Center, KRIBB, 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
| | - Myung Jin Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea.
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15
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Sharma P, Arora A. Basic Understanding of Liver Transplant Immunology. J Clin Exp Hepatol 2023; 13:1091-1102. [PMID: 37975047 PMCID: PMC10643508 DOI: 10.1016/j.jceh.2023.05.007] [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] [Received: 03/08/2023] [Accepted: 05/14/2023] [Indexed: 11/19/2023] Open
Abstract
The liver is a specialized organ and plays an important role in our immune system. The liver constitutes parenchymal cells which are hepatocytes and cholangiocytes (60-80%) and non-parenchymal cells like liver sinusoidal endothelial cells (LSECs), hepatic satellite/Ito cells, Kupffer cells, neutrophils, mononuclear cells, T and B lymphocytes (conventional and non-conventional), natural killer cells, and natural killer T (NKT) cells. The liver mounts a rapid and strong immune response, under unfavorable conditions and acts as an immune tolerance to a variety of non-pathogenic antigens. This delicate and dynamic interaction between different kinds of immune cells in the liver maintains a balance between immune screening and immune tolerance. The liver allografts are privileged immunologically; however, allograft rejection is not uncommon and is classified as cell or antibody-mediated. Advancements in transplant immunology help in the prevention of allografts rejection by immune reactions of the host thus leading to better graft and host survival. Fewer patients may not require immunosuppression due to systemic donor-specific T-cell tolerance. The liver tolerance mechanism is poorly studied, and LSEC and unconventional lymphocytes play an important role that dampens T cell response either by inducing apoptosis of cells or inhibiting co-stimulatory pathways. Newer cell-based therapy based on Treg, dendritic cells, and mesenchymal stromal cells will probably change the future of immunosuppression. Various invasive and non-invasive biomarkers and artificial intelligence have also been investigated to predict graft survival, post-transplant complications, and immunotolerance in the future.
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Affiliation(s)
- Praveen Sharma
- Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi, India
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16
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Wen Y. The Role of Immune Cells in Liver Regeneration. LIVERS 2023; 3:383-396. [DOI: 10.3390/livers3030029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2025] Open
Abstract
The liver is the only organ that can regenerate and regain its original tissue-to-body weight ratio within a short period of time after tissue loss. Insufficient liver regeneration in patients after partial hepatectomy or liver transplantation with partial liver grafts often leads to post-hepatectomy liver failure or small-for-size syndrome, respectively. Enhancing liver regeneration after liver injury might improve outcomes and increase patient survival. Liver regeneration comprises hepatocyte proliferation, and hepatic progenitor cell expansion and differentiation into hepatocytes. The immune system is intensively involved in liver regeneration. The current review provides a comprehensive overview of the diverse roles played by immune cells in liver regeneration. Macrophages, neutrophils, eosinophils, basophils, mast cells, platelets, dendritic cells, type 1 innate lymphoid cells, B cells, and T cells are implicated in promoting liver regeneration, while natural killer cells and overactivated natural killer T cells are supposed to inhibit hepatocyte proliferation. We also highlight the predominant underlying mechanisms mediated by immune cells, which may contribute to the development of novel strategies for promoting liver regeneration in patients with liver diseases.
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Affiliation(s)
- Yankai Wen
- Department of Anesthesiology, Critical Care and Pain Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
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17
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Wolf SD, Ehlting C, Müller-Dott S, Poschmann G, Petzsch P, Lautwein T, Wang S, Helm B, Schilling M, Saez-Rodriguez J, Vucur M, Stühler K, Köhrer K, Tacke F, Dooley S, Klingmüller U, Luedde T, Bode JG. Hepatocytes reprogram liver macrophages involving control of TGF-β activation, influencing liver regeneration and injury. Hepatol Commun 2023; 7:e0208. [PMID: 37486964 PMCID: PMC10368377 DOI: 10.1097/hc9.0000000000000208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/12/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Macrophages play an important role in maintaining liver homeostasis and regeneration. However, it is not clear to what extent the different macrophage populations of the liver differ in terms of their activation state and which other liver cell populations may play a role in regulating the same. METHODS Reverse transcription PCR, flow cytometry, transcriptome, proteome, secretome, single cell analysis, and immunohistochemical methods were used to study changes in gene expression as well as the activation state of macrophages in vitro and in vivo under homeostatic conditions and after partial hepatectomy. RESULTS We show that F4/80+/CD11bhi/CD14hi macrophages of the liver are recruited in a C-C motif chemokine receptor (CCR2)-dependent manner and exhibit an activation state that differs substantially from that of the other liver macrophage populations, which can be distinguished on the basis of CD11b and CD14 expressions. Thereby, primary hepatocytes are capable of creating an environment in vitro that elicits the same specific activation state in bone marrow-derived macrophages as observed in F4/80+/CD11bhi/CD14hi liver macrophages in vivo. Subsequent analyses, including studies in mice with a myeloid cell-specific deletion of the TGF-β type II receptor, suggest that the availability of activated TGF-β and its downregulation by a hepatocyte-conditioned milieu are critical. Reduction of TGF-βRII-mediated signal transduction in myeloid cells leads to upregulation of IL-6, IL-10, and SIGLEC1 expression, a hallmark of the activation state of F4/80+/CD11bhi/CD14hi macrophages, and enhances liver regeneration. CONCLUSIONS The availability of activated TGF-β determines the activation state of specific macrophage populations in the liver, and the observed rapid transient activation of TGF-β may represent an important regulatory mechanism in the early phase of liver regeneration in this context.
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Affiliation(s)
- Stephanie D Wolf
- Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Christian Ehlting
- Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Sophia Müller-Dott
- Institute for Computational Biomedicine, Faculty of Medicine & Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Gereon Poschmann
- Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Patrick Petzsch
- Genomics & Transcriptomics Laboratory, BMFZ, Heinrich Heine University, Düsseldorf, Germany
| | - Tobias Lautwein
- Genomics & Transcriptomics Laboratory, BMFZ, Heinrich Heine University, Düsseldorf, Germany
| | - Sai Wang
- Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Barbara Helm
- Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Marcel Schilling
- Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Julio Saez-Rodriguez
- Institute for Computational Biomedicine, Faculty of Medicine & Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, BMFZ, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Institute of Molecular Medicine, Proteome Research, Medical Faculty and University Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Karl Köhrer
- Genomics & Transcriptomics Laboratory, BMFZ, Heinrich Heine University, Düsseldorf, Germany
| | - Frank Tacke
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum (CVK) and Campus Charité Mitte (CCM), Berlin, Germany
| | - Steven Dooley
- Molecular Hepatology Section, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Johannes G Bode
- Department of Gastroenterology, Hepatology and Infectious Disease, Faculty of Medicine & Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
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18
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Jin Y, Guo YH, Li JC, Li Q, Ye D, Zhang XX, Li JT. Vascular endothelial growth factor protein and gene delivery by novel nanomaterials for promoting liver regeneration after partial hepatectomy. World J Gastroenterol 2023; 29:3748-3757. [PMID: 37426320 PMCID: PMC10324527 DOI: 10.3748/wjg.v29.i24.3748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/13/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Partial hepatectomy (PH) can lead to severe complications, including liver failure, due to the low regenerative capacity of the remaining liver, especially after extensive hepatectomy. Liver sinusoidal endothelial cells (LSECs), whose proliferation occurs more slowly and later than hepatocytes after PH, compose the lining of the hepatic sinusoids, which are the smallest blood vessels in the liver. Vascular endothelial growth factor (VEGF), secreted by hepatocytes, promotes LSEC proliferation. Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver, thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration. At present, some shortcomings exist in the methods of supplementing exogenous VEGF, such as a low drug concentration in the liver and the reaching of other organs. More-over, VEGF should be administered multiple times and in large doses because of its short half-life. This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.
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Affiliation(s)
- Yun Jin
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ying-Hao Guo
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jia-Cheng Li
- Department of General Surgery, Yuhuan Second People’s Hospital, Taizhou 317600, Zhejiang Province, China
| | - Qi Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Dan Ye
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Xiao-Xiao Zhang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jiang-Tao Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
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Li JH, Hepworth MR, O'Sullivan TE. Regulation of systemic metabolism by tissue-resident immune cell circuits. Immunity 2023; 56:1168-1186. [PMID: 37315533 PMCID: PMC10321269 DOI: 10.1016/j.immuni.2023.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/11/2023] [Accepted: 05/02/2023] [Indexed: 06/16/2023]
Abstract
Recent studies have demonstrated that tissue homeostasis and metabolic function are dependent on distinct tissue-resident immune cells that form functional cell circuits with structural cells. Within these cell circuits, immune cells integrate cues from dietary contents and commensal microbes in addition to endocrine and neuronal signals present in the tissue microenvironment to regulate structural cell metabolism. These tissue-resident immune circuits can become dysregulated during inflammation and dietary overnutrition, contributing to metabolic diseases. Here, we review the evidence describing key cellular networks within and between the liver, gastrointestinal tract, and adipose tissue that control systemic metabolism and how these cell circuits become dysregulated during certain metabolic diseases. We also identify open questions in the field that have the potential to enhance our understanding of metabolic health and disease.
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Affiliation(s)
- Joey H Li
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA; Medical Scientist Training Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Matthew R Hepworth
- Division of Immunology, Immunity to Infection and Respiratory Medicine, Faculty of Biology, Medicine and Health, Manchester Collaborative Centre for Inflammation Research, Lydia Becker Institute of Immunology and Inflammation, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Timothy E O'Sullivan
- Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 900953, USA.
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20
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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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21
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Starlinger P, Brunnthaler L, McCabe C, Pereyra D, Santol J, Steadman J, Hackl M, Skalicky S, Hackl H, Gronauer R, O’Brien D, Kain R, Hirsova P, Gores GJ, Wang C, Gruenberger T, Smoot RL, Assinger A. Transcriptomic landscapes of effective and failed liver regeneration in humans. JHEP Rep 2023; 5:100683. [PMID: 36950091 PMCID: PMC10025111 DOI: 10.1016/j.jhepr.2023.100683] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/19/2022] [Accepted: 01/08/2023] [Indexed: 03/24/2023] Open
Abstract
Background & Aims Although extensive experimental evidence on the process of liver regeneration exists, in humans, validation is largely missing. However, liver regeneration is critically affected by underlying liver disease. Within this project, we aimed to systematically assess early transcriptional changes during liver regeneration in humans and further assess how these processes differ in people with dysfunctional liver regeneration. Methods Blood samples of 154 patients and intraoperative tissue samples of 46 patients undergoing liver resection were collected and classified with regard to dysfunctional postoperative liver regeneration. Of those, a matched cohort of 21 patients were used for RNA sequencing. Samples were assessed for circulating cytokines, gene expression dynamics, intrahepatic neutrophil accumulation, and spatial transcriptomics. Results Individuals with dysfunctional liver regeneration demonstrated an aggravated transcriptional inflammatory response with higher intracellular adhesion molecule-1 induction. Increased induction of this critical leukocyte adhesion molecule was associated with increased intrahepatic neutrophil accumulation and activation upon induction of liver regeneration in individuals with dysfunctional liver regeneration. Comparing baseline gene expression profiles in individuals with and without dysfunctional liver regeneration, we found that dual-specificity phosphatase 4 (DUSP4) expression, a known critical regulator of intracellular adhesion molecule-1 expression in endothelial cells, was markedly reduced in patients with dysfunctional liver regeneration. Mimicking clinical risk factors for dysfunctional liver regeneration, we found liver sinusoidal endothelial cells of two liver disease models to have significantly reduced baseline levels of DUSP4. Conclusions Exploring the landscape of early transcriptional changes of human liver regeneration, we observed that people with dysfunctional regeneration experience overwhelming intrahepatic inflammation. Subclinical liver disease might account for DUSP4 reduction in liver sinusoidal endothelial cells, which ultimately primes the liver for an aggravated inflammatory response. Impact and implications Using a unique human biorepository, focused on liver regeneration (LR), we explored the landscape of circulating and tissue-level alterations associated with both functional and dysfunctional LR. In contrast to experimental animal models, people with dysfunctional LR demonstrated an aggravated transcriptional inflammatory response, higher intracellular adhesion molecule-1 (ICAM-1) induction, intrahepatic neutrophil accumulation and activation upon induction of LR. Although inflammatory responses appear rapidly after liver resection, people with dysfunctional LR have exaggerated inflammatory responses that appear to be related to decreased levels of LSEC DUSP4, challenging existing concepts of post-resectional LR.
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Key Words
- ALT, alanine aminotransferase
- AST, aspartate aminotransferase
- CASH, chemotherapy associated steatohepatitis
- DLR, dysfunctional LR
- DUSP-4
- DUSP4, dual-specificity phosphatase 4
- FDR, false discovery rate
- FLR, functional LR
- FPKM, fragments per kilobase of transcript per million mapped reads
- Human
- ICAM-1, intracellular adhesion molecule-1
- IPA, Ingenuity Pathway Analysis
- IVCL, inferior vena cava ligation
- Inflammation
- LPS, lipopolysaccharide
- LR, liver regeneration
- LSEC, liver sinusoidal endothelial cell
- Liver regeneration
- MFI, mean fluorescence intensity
- MPO, myeloperoxidase
- NASH, non-alcoholic steatohepatitis
- Neutrophils
- PCA, principal component analysis
- POD1, 1 day after liver resection
- POD5, 5 days after liver resection
- STRING, Search Tool for the Retrieval of Interacting Genes/Proteins
- TMM, trimmed mean of M values
- TNF, tumour necrosis factor
- logCPM, log counts per million
- pTPM, protein-coding transcripts per million
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Affiliation(s)
- Patrick Starlinger
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Laura Brunnthaler
- Center of Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria
| | - Chantal McCabe
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - David Pereyra
- Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria
| | - Jonas Santol
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Jessica Steadman
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | | | | | - Hubert Hackl
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Raphael Gronauer
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
| | - Daniel O’Brien
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Renate Kain
- Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
| | - Petra Hirsova
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Chen Wang
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
| | - Thomas Gruenberger
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Rory L. Smoot
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| | - Alice Assinger
- Center of Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria
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22
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Deng Y, Zhao Z, Sheldon M, Zhao Y, Teng H, Martinez C, Zhang J, Lin C, Sun Y, Yao F, Zhu H, Ma L. LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.18.533289. [PMID: 36993315 PMCID: PMC10055204 DOI: 10.1101/2023.03.18.533289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro . In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3- CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage- induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.
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23
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Parlar YE, Ayar SN, Cagdas D, Balaban YH. Liver immunity, autoimmunity, and inborn errors of immunity. World J Hepatol 2023; 15:52-67. [PMID: 36744162 PMCID: PMC9896502 DOI: 10.4254/wjh.v15.i1.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/23/2022] [Accepted: 12/23/2022] [Indexed: 01/16/2023] Open
Abstract
The liver is the front line organ of the immune system. The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens. This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens, such as food antigens or pathogens. As an immune active organ, the liver functions as a gatekeeping barrier from the outside world, and it can create a rapid and strong immune response, under unfavorable conditions. However, the liver's assumed immune status is anti-inflammatory or immuno-tolerant. Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance. The anatomical structure of the liver can facilitate the preparation of lymphocytes, modulate the immune response against hepatotropic pathogens, and contribute to some of its unique immunological properties, particularly its capacity to induce antigen-specific tolerance. Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane, circulating lymphocytes can closely contact with antigens, displayed by endothelial cells, Kupffer cells, and dendritic cells while passing through the sinusoids. Loss of immune tolerance, leading to an autoaggressive immune response in the liver, if not controlled, can lead to the induction of autoimmune or autoinflammatory diseases. This review mentions the unique features of liver immunity, and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.
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Affiliation(s)
- Yavuz Emre Parlar
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey.
| | - Sefika Nur Ayar
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| | - Deniz Cagdas
- Department of Pediatric Immunology, Hacettepe University Ihsan Dogramaci Children's Hospital, Ankara 06100, Turkey
| | - Yasemin H Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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24
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Di-Iacovo N, Pieroni S, Piobbico D, Castelli M, Scopetti D, Ferracchiato S, Della-Fazia MA, Servillo G. Liver Regeneration and Immunity: A Tale to Tell. Int J Mol Sci 2023; 24:1176. [PMID: 36674692 PMCID: PMC9864482 DOI: 10.3390/ijms24021176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
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Affiliation(s)
- Nicola Di-Iacovo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Marilena Castelli
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Damiano Scopetti
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Simona Ferracchiato
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Maria Agnese Della-Fazia
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, 06123 Perugia, Italy
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25
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Zhang Y, Huber P, Praetner M, Zöllner A, Holdt L, Khandoga A, Lerchenberger M. Serine proteases mediate leukocyte recruitment and hepatic microvascular injury in the acute phase following extended hepatectomy. Microcirculation 2023; 30:e12796. [PMID: 36577737 DOI: 10.1111/micc.12796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 12/13/2022] [Accepted: 12/22/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE Post-hepatectomy liver failure (PHLF) is the main limitation of extended liver resection. The molecular mechanism and the role of leukocytes in the development of PHLF remain to be unveiled. We aimed to address the impact of serine proteases (SPs) on the acute phase after liver resection by intravitally analyzing leukocyte recruitment and changes in hemodynamics and microcirculation of the liver. METHODS C57BL/6 mice undergoing 60% partial hepatectomy were treated with aprotinin (broad-spectrum SP inhibitor), tranexamic acid (plasmin inhibitor), or vehicle. Sham-operated animals served as controls. In vivo fluorescence microscopy was used to quantify leukocyte-endothelial interactions immediately after, as well as 120 min after partial hepatectomy in postsinusoidal venules, along with measurement of sinusoidal perfusion rate and postsinusoidal shear rate. Recruitment of leukocytes, neutrophils, T cells, and parameters of liver injury were assessed in tissue/blood samples. RESULTS Leukocyte recruitment, sinusoidal perfusion failure rate, and shear rate were significantly increased in mice after 60% partial hepatectomy compared to sham-operated animals. The inhibition of SPs or plasmin significantly attenuated leukocyte recruitment and improved the perfusion rate in the remnant liver. ICAM-1 expression and neutrophil recruitment significantly increased after 60% partial hepatectomy and were strongly reduced by plasmin inhibition. CONCLUSIONS Endothelial activation and leukocyte recruitment in the liver in response to the increment of sinusoidal shear rate were hallmarks in the acute phase after liver resection. SPs mediated leukocyte recruitment and contributed to the impairment of sinusoidal perfusion in an ICAM-1-dependent manner in the acute phase after liver resection.
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Affiliation(s)
- Yunjie Zhang
- Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Patrick Huber
- Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Marc Praetner
- Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Alice Zöllner
- Walter-Brendel Centre of Experimental Medicine, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Lesca Holdt
- Institute of Laboratory Medicine, LMU University Hospitals, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Andrej Khandoga
- Department of General, Visceral, and Transplant Surgery, LMU University Hospitals, Ludwig-Maximilians-Universität Munich, Munich, Germany
| | - Maximilian Lerchenberger
- Department of General, Visceral, and Transplant Surgery, LMU University Hospitals, Ludwig-Maximilians-Universität Munich, Munich, Germany
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26
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López-Gutierrez J, Ramos-Payán R, Romero-Quintana JG, Ayala-Ham A, Castro-Salazar Y, Castillo-Ureta H, Jiménez-Gastélum G, Bermúdez M, Aguilar-Medina M. Evaluation of biocompatibility and angiogenic potential of extracellular matrix hydrogel biofunctionalized with the LL-37 peptide. Biomed Mater Eng 2023; 34:545-560. [PMID: 37393490 DOI: 10.3233/bme-230022] [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] [Indexed: 07/03/2023]
Abstract
BACKGROUND Biomaterials must allow revascularization for a successful tissue regeneration process. Biomaterials formulated from the extracellular matrix (ECM) have gained popularity in tissue engineering because of their superior biocompatibility, and due to their rheological properties, ECM-hydrogels can be easily applied in damaged areas, allowing cell colonization and integration into the host tissue. Porcine urinary bladder ECM (pUBM) retains functional signaling and structural proteins, being an excellent option in regenerative medicine. Even some small molecules, such as the antimicrobial cathelicidin-derived LL-37 peptide have proven angiogenic properties. OBJECTIVE The objective of this study was to evaluate the biocompatibility and angiogenic potential of an ECM-hydrogel derived from the porcine urinary bladder (pUBMh) biofunctionalized with the LL-37 peptide (pUBMh/LL37). METHODS Macrophages, fibroblasts, and adipose tissue-derived mesenchymal stem cells (AD-MSC) were exposed pUBMh/LL37, and the effect on cell proliferation was evaluated by MTT assay, cytotoxicity by quantification of lactate dehydrogenase release and the Live/Dead Cell Imaging assays. Moreover, macrophage production of IL-6, IL-10, IL-12p70, MCP-1, INF-γ, and TNF-α cytokines was quantified using a bead-based cytometric array. pUBMh/LL37 was implanted directly by dorsal subcutaneous injection in Wistar rats for 24 h to evaluate biocompatibility, and pUBMh/LL37-loaded angioreactors were implanted for 21 days for evaluation of angiogenesis. RESULTS We found that pUBMh/LL37 did not affect cell proliferation and is cytocompatible to all tested cell lines but induces the production of TNF-α and MCP-1 in macrophages. In vivo, this ECM-hydrogel induces fibroblast-like cell recruitment within the material, without tissue damage or inflammation at 48 h. Interestingly, tissue remodeling with vasculature inside angioreactors was seen at 21 days. CONCLUSIONS Our results showed that pUBMh/LL37 is cytologically compatible, and induces angiogenesis in vivo, showing potential for tissue regeneration therapies.
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Affiliation(s)
- Jorge López-Gutierrez
- Faculty of Biology, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Rosalío Ramos-Payán
- Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Jose Geovanni Romero-Quintana
- Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Alfredo Ayala-Ham
- Faculty of Odontology, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Yolanda Castro-Salazar
- Faculty of Odontology, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Hipolito Castillo-Ureta
- Faculty of Biology, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - German Jiménez-Gastélum
- Faculty of Biology, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
| | - Mercedes Bermúdez
- Faculty of Odontology, Autonomous University of Chihuahua, Circuito Universitario Campus I, Chihuahua, Chihuahua, México
| | - Maribel Aguilar-Medina
- Faculty of Biological and Chemical Sciences, Autonomous University of Sinaloa, Josefa Ortiz de Domínguez s/n y Avenida de las Américas, Culiacan, Sinaloa, México
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Lisman T. Bleeding and thrombosis in cirrhosis. CARDIO-HEPATOLOGY 2023:165-202. [DOI: 10.1016/b978-0-12-817394-7.00010-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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García-Berumen CI, Vargas-Vargas MA, Ortiz-Avila O, Piña–Zentella RM, Ramos-Gómez M, Figueroa–García MDC, Mejía-Zepeda R, Rodríguez–Orozco AR, Saavedra–Molina A, Cortés-Rojo C. Avocado oil alleviates non-alcoholic fatty liver disease by improving mitochondrial function, oxidative stress and inflammation in rats fed a high fat-High fructose diet. Front Pharmacol 2022; 13:1089130. [PMID: 36601051 PMCID: PMC9807168 DOI: 10.3389/fphar.2022.1089130] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 12/07/2022] [Indexed: 12/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in hepatocytes, and in advanced stages, by inflammation and fibrosis. Excessive ROS production due to mitochondrial dysfunction contributes to NAFLD development, making the decrease in mitochondrial ROS production an emerging target to alleviate NAFLD. Previously, we have shown that avocado oil, a source of several bioactive compounds with antioxidant effects, decreases oxidative stress by improving the function of the mitochondrial electron transport chain (ETC) and decreasing ROS levels in mitochondria of diabetic and hypertensive rats. Therefore, we tested in this work whether avocado oil alleviates NAFLD by attenuating mitochondrial dysfunction, oxidative stress and inflammation. NAFLD was induced in rats by a high fat-high fructose (HF) diet administered for six (HF6) or twelve (HF12) weeks. Hepatic steatosis, hypertrophy and inflammation were detected in both the HF6 and HF12 groups. Hyperglycemia was observed only in the HF12 group. The HF6 and HF12 groups displayed dyslipidemia, impairments in mitochondrial respiration, complex III activity, and electron transfer in cytochromes in the complex III. This led to an increase in the levels of ROS and lipid peroxidation. The substitution of the HF6 diet by standard chow and avocado oil for 6 weeks (HF6+AVO + D), or supplementation of the HF12 diet with avocado oil (HF12 + AVO), ameliorated NAFLD, hyperglycemia, dyslipidemia, and counteracted mitochondrial dysfunctions and oxidative stress. The substitution of the HF6 diet by standard chow without avocado oil did not correct many of these abnormalities, confirming that the removal of the HF diet is not enough to counteract NAFLD and mitochondrial dysfunction. In summary, avocado oil decreases NAFLD by improving mitochondrial function, oxidative stress, and inflammation.
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Affiliation(s)
| | | | - Omar Ortiz-Avila
- Facultad de Enfermería, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México
| | | | | | | | - Ricardo Mejía-Zepeda
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla de Baz, México
| | - Alain Raimundo Rodríguez–Orozco
- Facultad de Ciencias Médicas y Biológicas “Dr. Ignacio Chávez”, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México
| | - Alfredo Saavedra–Molina
- Instituto de Investigaciones Químico–Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México
| | - Christian Cortés-Rojo
- Instituto de Investigaciones Químico–Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Morelia, México
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Brandel V, Schimek V, Göber S, Hammond T, Brunnthaler L, Schrottmaier WC, Mussbacher M, Sachet M, Liang YY, Reipert S, Ortmayr G, Pereyra D, Santol J, Rainer M, Walterskirchen N, Ramos C, Gerakopoulos V, Rainer C, Spittler A, Weiss T, Kain R, Messner B, Gruenberger T, Assinger A, Oehler R, Starlinger P. Hepatectomy-induced apoptotic extracellular vesicles stimulate neutrophils to secrete regenerative growth factors. J Hepatol 2022; 77:1619-1630. [PMID: 35985549 DOI: 10.1016/j.jhep.2022.07.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 06/30/2022] [Accepted: 07/25/2022] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Surgical resection of the cancerous tissue represents one of the few curative treatment options for neoplastic liver disease. Such partial hepatectomy (PHx) induces hepatocyte hyperplasia, which restores liver function. PHx is associated with bacterial translocation, leading to an immediate immune response involving neutrophils and macrophages, which are indispensable for the priming phase of liver regeneration. Additionally, PHx induces longer-lasting intrahepatic apoptosis. Herein, we investigated the effect of apoptotic extracellular vesicles (aEVs) on neutrophil function and their role in this later phase of liver regeneration. METHODS A total of 124 patients undergoing PHx were included in this study. Blood levels of the apoptosis marker caspase-cleaved cytokeratin-18 (M30) and circulating aEVs were analyzed preoperatively and on the first and fifth postoperative days. Additionally, the in vitro effects of aEVs on the secretome, phenotype and functions of neutrophils were investigated. RESULTS Circulating aEVs increased at the first postoperative day and were associated with higher concentrations of M30, which was only observed in patients with complete liver recovery. Efferocytosis of aEVs by neutrophils induced an activated phenotype (CD11bhighCD16highCD66bhighCD62Llow); however, classical inflammatory responses such as NETosis, respiratory burst, degranulation, or secretion of pro-inflammatory cytokines were not observed. Instead, efferocytosing neutrophils released various growth factors including fibroblast growth factor-2 and hepatocyte growth factor (HGF). Accordingly, we observed an increase of HGF-positive neutrophils after PHx and a correlation of plasma HGF with M30 levels. CONCLUSIONS These data suggest that the clearance of PHx-induced aEVs leads to a population of non-inflammatory but regenerative neutrophils, which may support human liver regeneration. LAY SUMMARY In this study, we show that the surgical removal of a diseased part of the liver triggers a specific type of programmed cell death in the residual liver tissue. This results in the release of vesicles from dying cells into the blood, where they are cleared by circulating immune cells. These respond by secreting hepatocyte growth factors that could potentially support the regeneration of the liver remnant.
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Affiliation(s)
- Victoria Brandel
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria; Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Vanessa Schimek
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Samantha Göber
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Hammond
- Division of Molecular & Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; Clinical Pharmacology and Safety Sciences, AstraZeneca, Cambridge, UK
| | - Laura Brunnthaler
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Waltraud Cornelia Schrottmaier
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Marion Mussbacher
- Department of Pharmacology and Toxicology, University of Graz, Graz, Austria
| | - Monika Sachet
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Ying Yu Liang
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Siegfried Reipert
- Core Facility Cell Imaging and Ultrastructure Research, University of Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - David Pereyra
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria; Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jonas Santol
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria; Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Marlene Rainer
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Natalie Walterskirchen
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Cristiano Ramos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Vasileios Gerakopoulos
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Carina Rainer
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Andreas Spittler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Tamara Weiss
- Department of Plastic, Reconstructive and Aesthetic Surgery, Medical University of Vienna, Vienna, Austria
| | - Renate Kain
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Barbara Messner
- Cardiac Surgery Research Laboratory, Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - Thomas Gruenberger
- Department of Surgery, HPB Center, Viennese Health Network, Clinic Favoriten and Sigmund Freud Private University, Vienna, Austria
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Rudolf Oehler
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria.
| | - Patrick Starlinger
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria; Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
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Premature Macrophage Activation by Stored Red Blood Cell Transfusion Halts Liver Regeneration Post-Partial Hepatectomy in Rats. Cells 2022; 11:cells11213522. [DOI: 10.3390/cells11213522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 11/03/2022] [Accepted: 11/03/2022] [Indexed: 11/09/2022] Open
Abstract
Liver resection is a common treatment for various conditions and often requires blood transfusions to compensate for operative blood loss. As partial hepatectomy (PHx) is frequently performed in patients with a pre-damaged liver, avoiding further injury is of paramount clinical importance. Our aim was to study the impact of red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% PHx in rats and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion. The liver was successfully regenerated after PHx when rats were transfused with fresh RBCs (F-RBCs). However, in rats resuscitated with stored RBCs (S-RBCs), the regeneration process was disrupted, as detected by delayed hepatocyte proliferation and lack of hypertrophy. The delayed regeneration was associated with elevated numbers of hemorrhage-activated liver macrophages (Mhem) secreting HO-1. Depletion of macrophages prior to PHx and transfusion improved the regeneration process. Gene expression profiling revealed alterations in numerous genes belonging to critical pathways, including cell cycle and DNA replication, and genes associated with immune cell activation, such as chemokine signaling and platelet activation and adhesion. Our results implicate activated macrophages in delayed liver regeneration following S-RBC transfusion via HO-1 and PAI-1 overexpression.
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Dong Y, Zhang Y, Feng Y, An W. The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease. Front Pharmacol 2022; 13:928606. [PMID: 36304168 PMCID: PMC9592723 DOI: 10.3389/fphar.2022.928606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) occurs in 25% of the global population and manifests as lipid deposition, hepatocyte injury, activation of Kupffer and stellate cells, and steatohepatitis. Predominantly expressed in hepatocytes, the augmenter of liver regeneration (ALR) is a key factor in liver regulation that can alleviate fatty liver disease and protect the liver from abnormal liver lipid metabolism. ALR has three isoforms (15-, 21-, and 23-kDa), amongst which 23-kDa ALR is the most extensively studied. The 23-kDa ALR isoform is a sulfhydryl oxidase that resides primarily in the mitochondrial intermembrane space (IMS), whereby it protects the liver against various types of injury. In this review, we describe the role of ALR in regulating hepatocytes in the context of NAFLD. We also discuss questions about ALR that remain to be explored in the future. In conclusion, ALR appears to be a promising therapeutic target for treating NAFLD.
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Affiliation(s)
- Yuan Dong
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yuejie Zhang
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yingmei Feng
- Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- *Correspondence: Yingmei Feng, ; Wei An,
| | - Wei An
- Department of Cell Biology, Capital Medical University and the Municipal Key Laboratory for Liver Protection and Regulation of Regeneration, Beijing, China
- *Correspondence: Yingmei Feng, ; Wei An,
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New Properties of a Well-Known Antioxidant: Pleiotropic Effects of Human Lactoferrin in Mice Exposed to Gamma Irradiation in a Sublethal Dose. Antioxidants (Basel) 2022; 11:antiox11091833. [PMID: 36139907 PMCID: PMC9495689 DOI: 10.3390/antiox11091833] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/12/2022] [Accepted: 09/15/2022] [Indexed: 11/28/2022] Open
Abstract
We studied the effects of human lactoferrin (hLf), a multifunctional protein from the transferrin family, on integral (survival, lifespan during the experiment, body weight, behavior, subfractional compositions of blood serum) and systemic (hemoglobin level, leukocyte number, differential leukocyte count, histological structure of the liver and spleen) parameters of the body in mice after acute gamma irradiation in a sublethal dose. The experiments were performed on male C57BL/6 mice. The mice in the experimental groups were exposed to whole-body gamma radiation in a dose of 7.5 Gy from a 60Co source. Immediately after irradiation and 24 h after it, some animals received an intraperitoneal injection of hLf (4 mg/mouse). Single or repeated administration of hLf had a positive pleiotropic effect on irradiated animals: animal survival increased from 28% to 78%, and the mean life expectancy during the experiment (30 days) increased from 16 to 26 days. A compensatory effect of hLf on radiation-induced body weight loss, changes in homeostasis parameters, and a protective effect on the structural organization of the spleen were demonstrated. These data indicate that Lf has potential as a means of early therapy after radiation exposure.
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Shu W, Yang M, Yang J, Lin S, Wei X, Xu X. Cellular crosstalk during liver regeneration: unity in diversity. Cell Commun Signal 2022; 20:117. [PMID: 35941604 PMCID: PMC9358812 DOI: 10.1186/s12964-022-00918-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/08/2022] [Indexed: 11/27/2022] Open
Abstract
The liver is unique in its ability to regenerate from a wide range of injuries and diseases. Liver regeneration centers around hepatocyte proliferation and requires the coordinated actions of nonparenchymal cells, including biliary epithelial cells, liver sinusoidal endothelial cells, hepatic stellate cells and kupffer cells. Interactions among various hepatocyte and nonparenchymal cells populations constitute a sophisticated regulatory network that restores liver mass and function. In addition, there are two different ways of liver regeneration, self-replication of liver epithelial cells and transdifferentiation between liver epithelial cells. The interactions among cell populations and regenerative microenvironment in the two modes are distinct. Herein, we first review recent advances in the interactions between hepatocytes and surrounding cells and among nonparenchymal cells in the context of liver epithelial cell self-replication. Next, we discuss the crosstalk of several cell types in the context of liver epithelial transdifferentiation, which is also crucial for liver regeneration.
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