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Sorrentino G. Microenvironmental control of the ductular reaction: balancing repair and disease progression. Cell Death Dis 2025; 16:246. [PMID: 40180915 PMCID: PMC11968979 DOI: 10.1038/s41419-025-07590-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.
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Affiliation(s)
- Giovanni Sorrentino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
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Xiao MH, Ma D, Wu S, Huang Z, Liang P, Chen H, Zhong Z, Li W, Wang F, Tang Y, Liu J, Jiang H, Feng X, Luo Z. Integrative single-cell and spatial transcriptomic analyses identify a pathogenic cholangiocyte niche and TNFRSF12A as therapeutic target for biliary atresia. Hepatology 2025; 81:1146-1163. [PMID: 39178365 DOI: 10.1097/hep.0000000000001064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 07/19/2024] [Indexed: 08/25/2024]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA) is a devastating fibroinflammatory biliary disease that is the leading indication for pediatric liver transplants worldwide. Although cholangiocytes are the primary target cells, the pathogenic mechanisms involving cholangiocytes remain elusive. Here, we aimed to characterize the pathogenic role of cholangiocytes in BA. APPROACH AND RESULTS Integration of single-cell RNA sequencing of 12 liver tissues (from 9 BA and 3 controls) and the spatial transcriptome of another four liver sections (from 2 BA and 2 controls) provided a comprehensive spatial liver cell atlas of BA. In particular, we identified a cholangiocyte-enriched spatial niche with infiltration of activated HSCs, activated portal fibroblasts, macrovascular endothelial cells, and TREM2 + macrophages that were elevated in the portal triad of BA. This niche was positively correlated with bile duct profiles, liver fibrosis, and poor survival in 2 independent cohorts of patients with BA. Using integrative bioinformatics analyses to mine the cell-cell communication and regulatory network in BA cholangiocytes, we uncovered the fibroinflammatory phenotype of cholangiocytes with TNFSF12-TNFRSF12A as a significant signal. Genetic ablation or blockade of TNFRSF12A suppresses liver injury, inflammation, and bile duct profiles in a mouse model of disease. Using human biliary organoids, we revealed that BA organoids expressed higher levels of CCL2 in response to TNFSF12 stimulation and promoted monocyte chemotaxis via the CCL2-CCR2 axis. CONCLUSIONS Pathogenic cholangiocytes-enriched niche identifies TNFRSF12A as a potential therapeutic target for BA.
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Affiliation(s)
- Man-Huan Xiao
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dong Ma
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Sihan Wu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zaoli Huang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Peishi Liang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Huadong Chen
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhihai Zhong
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wei Li
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Fen Wang
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yanlai Tang
- Department of Pediatrics, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Juncheng Liu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Hong Jiang
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xuyang Feng
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhenhua Luo
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
- Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
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Liu L, Wu P, Wei Y, Lu M, Ge H, Wang P, Sun J, Horng T, Liu X, Shen X, Sun L, Xi Y. TWEAK-Fn14 signaling protects mice from pulmonary fibrosis by inhibiting fibroblast activation and recruiting pro-regenerative macrophages. Cell Rep 2025; 44:115220. [PMID: 39827460 DOI: 10.1016/j.celrep.2024.115220] [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: 04/08/2024] [Revised: 11/11/2024] [Accepted: 12/26/2024] [Indexed: 01/22/2025] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14 (Fn14), the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is highly induced in myofibroblasts in the lungs of IPF patients and the bleomycin-induced lung fibrosis model. TWEAK-Fn14 signaling inhibits fibroblast activation and ECM synthesis and induces chemokine expression to recruit monocytes/macrophages into the lung. Fn14 deficiency increases ECM production and impairs macrophage infiltration and differentiation, leading to exacerbated lung fibrosis and impaired alveolar regeneration in a bleomycin model. Interestingly, Fn14 deficiency diminishes an injury-induced SiglecF- CD11b- MHCIIlo intermediate macrophage (IntermM) subpopulation, which promotes alveolar type II (AT2) cell proliferation in organoid cultures. These results collectively demonstrate a protective role of TWEAK-Fn14 signaling in lung fibrosis, highlighting the complexities and multilayered regulation of macrophage-fibroblast crosstalk.
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Affiliation(s)
- Li Liu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Pei Wu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Yuqi Wei
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Meng Lu
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Haiyan Ge
- Department of Pulmonary and Critical Care Medicine, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Ping Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Jianlong Sun
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China
| | - Tiffany Horng
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Xiucheng Liu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai 200433, China.
| | - Xiaoyong Shen
- Department of Thoracic Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China.
| | - Lingyun Sun
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210008, China.
| | - Ying Xi
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; State Key Laboratory of Advanced Medical Materials and Devices, ShanghaiTech University, Shanghai 201210, China.
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Bu W, Sun X, Xue X, Geng S, Yang T, Zhang J, Li Y, Feng C, Liu Q, Zhang X, Li P, Liu Z, Shi Y, Shao C. Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment. Hepatology 2025; 81:491-508. [PMID: 38466833 PMCID: PMC11737125 DOI: 10.1097/hep.0000000000000821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 02/06/2024] [Indexed: 03/13/2024]
Abstract
BACKGROUND AND AIMS RAD51 recombinase (RAD51) is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development. APPROACH AND RESULTS RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated a hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( Rad51 -conditional knockout (CKO)) and Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51 -CKO mice is dependent on CRE dosage, with Rad51fl/fl ; Alb -Cre +/+ manifesting a more severe phenotype than the Rad51fl/fl ; Alb -Cre +/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl ; Alb -Cre +/+ mice. While liver regeneration is compromised in Rad51 -CKO mice, they are more tolerant of carbon tetrachloride-induced hepatic injury and resistant to diethylnitrosamine/carbon tetrachloride-induced HCC. A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction the transdifferentiation of cholangiocytes to hepatocytes. The newly derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. CONCLUSIONS Our results demonstrate a novel function of RAD51 in liver development, homeostasis, and tumorigenesis. The Rad51 -CKO mice represent a unique genetic model for premature liver senescence, fibrosis, and hepatocellular carcinogenesis.
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Affiliation(s)
- Wenqing Bu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Xue Sun
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Xiaotong Xue
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Shengmiao Geng
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Tingting Yang
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Jia Zhang
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Yanan Li
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Chao Feng
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Qiao Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Xiyu Zhang
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Peishan Li
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Zhaojian Liu
- Key Laboratory of Experimental Teratology, Ministry of Education, Department of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
| | - Changshun Shao
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Suzhou Medical College, Suzhou, Jiangsu, China
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Tong W, Zhu L, Han P, Bai Y, Wang T, Chen D, Li Z, Chi H, Deng X, Zhang Y, Shen Z. TWEAK is an activator of Hippo-YAP signaling protecting against hepatic Ischemia/ reperfusion injury. Int Immunopharmacol 2024; 143:113567. [PMID: 39500083 DOI: 10.1016/j.intimp.2024.113567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/11/2024] [Accepted: 10/31/2024] [Indexed: 12/08/2024]
Abstract
Hepatic ischemia-reperfusion injury (IRI) represents a formidable complication commonly linked with hemorrhagic shock, liver resection, and transplantation. This study aims to elucidate the role of Tumor Necrosis Factor-like Weak Inducer of Apoptosis (TWEAK) in the pathogenesis of hepatic I/R injury and to delineate the underlying mechanisms involved. Utilizing a hypoxia-reoxygenation model in human liver organoids (HLOs) alongside a murine model of warm ischemia-reperfusion injury, we systematically investigated the interplay between TWEAK, its receptor Fn14, and the HIPPO signaling pathway. Our findings indicate that TWEAK pretreatment significantly mitigates IRI in murine livers as well as hypoxia/reoxygenation injury in HLOs. Notably, administration of adeno-associated virus (AAV) to knock down Fn14 abrogated the protective effects of TWEAK in the murine model. Transcriptome sequencing analysis revealed that the interaction between TWEAK and Fn14 enhances cellular resistance to IRI by activating the HIPPO signaling pathway. Overall, TWEAK emerges as a promising therapeutic target for mitigating hepatic I/R injury, potentially improving outcomes in liver transplantation.
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Affiliation(s)
- Wen Tong
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Liuyang Zhu
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Pinsheng Han
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Yi Bai
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China
| | - Tianze Wang
- School of Medicine, Nankai University, Tianjin 300071, China
| | - Dapeng Chen
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Zhongmin Li
- Department of Hepatobiliary Surgery, Tianjin Nankai Hospital, Tianjin 300100, China
| | - Hao Chi
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Xiyue Deng
- The First Central Clinical School, Tianjin Medical University, Tianjin 300070, China
| | - Yamin Zhang
- Department of Hepatobiliary Surgery, Tianjin First Central Hospital, Tianjin 300192, China.
| | - Zhongyang Shen
- Organ Transplantation Centre, Tianjin First Central Hospital, Tianjin 300192, China.
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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Burvenich IJG, Osellame LD, Rigopoulos A, Huynh N, Cao Z, Hoogenraad NJ, Scott AM. Targeting Fn14 as a therapeutic target for cachexia reprograms the glycolytic pathway in tumour and brain in mice. Eur J Nucl Med Mol Imaging 2024; 51:3854-3862. [PMID: 39060375 PMCID: PMC11527931 DOI: 10.1007/s00259-024-06836-1] [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: 03/16/2024] [Accepted: 07/04/2024] [Indexed: 07/28/2024]
Abstract
PURPOSE Cachexia is a complex syndrome characterized by unintentional weight loss, progressive muscle wasting and loss of appetite. Anti-Fn14 antibody (mAb 002) targets the TWEAK receptor (Fn14) in murine models of cancer cachexia and can extend the lifespan of mice by restoring the body weight of mice. Here, we investigated glucose metabolic changes in murine models of cachexia via [18F]FDG PET imaging, to explore whether Fn14 plays a role in the metabolic changes that occur during cancer cachexia. METHODS [18F]FDG PET/MRI imaging was performed in cachexia-inducing tumour models versus models that do not induce cachexia. SUVaverage was calculated for all tumours via volume of interest (VOI) analysis of PET/MRI overlay images using PMOD software. RESULTS [18F]FDG PET imaging demonstrated increased tumour and brain uptake in cachectic versus non-cachectic tumour-bearing mice. Therapy with mAb 002 was able to reduce [18F]FDG uptake in tumours (P < 0.05, n = 3). Fn14 KO tumours did not induce body weight loss and did not show an increase in [18F]FDG tumour and brain uptake over time. In non-cachectic mice bearing Fn14 KO tumours, [18F]FDG tumour uptake was significantly lower (P < 0.01) than in cachectic mice bearing Fn14 WT counterparts. As a by-product of glucose metabolism, l-lactate production was also increased in cachexia-inducing tumours expressing Fn14. CONCLUSION Our results demonstrate that Fn14 receptor activation is linked to glucose metabolism of cachexia-inducing tumours.
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Affiliation(s)
- Ingrid Julienne Georgette Burvenich
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Laura Danielle Osellame
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3083, Australia
| | - Angela Rigopoulos
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia
| | - Nhi Huynh
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Zhipeng Cao
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, 3083, Australia
| | - Nicholas Johannes Hoogenraad
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3083, Australia
| | - Andrew Mark Scott
- Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, 145 Studley Road, Melbourne, Heidelberg, VIC, 3084, Australia.
- School of Cancer Medicine, La Trobe University, Melbourne, VIC, 3086, Australia.
- Department of Molecular Imaging and Therapy, Austin Health, Melbourne, VIC, 3083, Australia.
- Department of Medicine, University of Melbourne, Melbourne, VIC, 3052, Australia.
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Hazell G, McCallion E, Ahlskog N, Sutton ER, Okoh M, Shaqoura EIH, Hoolachan JM, Scaife T, Iqbal S, Bhomra A, Kordala AJ, Scamps F, Raoul C, Wood MJA, Bowerman M. Exercise, disease state and sex influence the beneficial effects of Fn14-depletion on survival and muscle pathology in the SOD1 G93A amyotrophic lateral sclerosis (ALS) mouse model. Skelet Muscle 2024; 14:23. [PMID: 39396990 PMCID: PMC11472643 DOI: 10.1186/s13395-024-00356-0] [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: 07/05/2024] [Accepted: 10/04/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease. Accumulating evidence strongly suggests that intrinsic muscle defects exist and contribute to disease progression, including imbalances in whole-body metabolic homeostasis. We have previously reported that tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor inducible 14 (Fn14) are significantly upregulated in skeletal muscle of the SOD1G93A ALS mouse model. While antagonising TWEAK did not impact survival, we did observe positive effects in skeletal muscle. Given that Fn14 has been proposed as the main effector of the TWEAK/Fn14 activity and that Fn14 can act independently from TWEAK in muscle, we suggest that manipulating Fn14 instead of TWEAK in the SOD1G93A ALS mice could lead to differential and potentially improved benefits. METHODS We thus investigated the contribution of Fn14 to disease phenotypes in the SOD1G93A ALS mice. To do so, Fn14 knockout mice (Fn14-/-) were crossed onto the SOD1G93A background to generate SOD1G93A;Fn14-/- mice. Investigations were performed on both unexercised and exercised (rotarod and/or grid test) animals (wild type (WT), Fn14-/-, SOD1G93A and SOD1G93A;Fn14-/-). RESULTS Here, we firstly confirm that the TWEAK/Fn14 pathway is dysregulated in skeletal muscle of SOD1G93A mice. We then show that Fn14-depleted SOD1G93A mice display increased lifespan, myofiber size, neuromuscular junction endplate area as well as altered expression of known molecular effectors of the TWEAK/Fn14 pathway, without an impact on motor function. Importantly, we also observe a complex interaction between exercise (rotarod and grid test), genotype, disease state and sex that influences the overall effects of Fn14 deletion on survival, expression of known molecular effectors of the TWEAK/Fn14 pathway, expression of myosin heavy chain isoforms and myofiber size. CONCLUSIONS Our study provides further insights on the different roles of the TWEAK/Fn14 pathway in pathological skeletal muscle and how they can be influenced by age, disease, sex and exercise. This is particularly relevant in the ALS field, where combinatorial therapies that include exercise regimens are currently being explored. As such, a better understanding and consideration of the interactions between treatments, muscle metabolism, sex and exercise will be of importance in future studies.
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Affiliation(s)
- Gareth Hazell
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Eve McCallion
- School of Medicine, Keele University, Staffordshire, UK
| | - Nina Ahlskog
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
| | - Emma R Sutton
- School of Medicine, Keele University, Staffordshire, UK
| | - Magnus Okoh
- School of Medicine, Keele University, Staffordshire, UK
| | | | | | - Taylor Scaife
- School of Life Sciences, Keele University, Staffordshire, UK
| | - Sara Iqbal
- School of Life Sciences, Keele University, Staffordshire, UK
| | - Amarjit Bhomra
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
| | - Anna J Kordala
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
| | | | - Cedric Raoul
- INM, Univ Montpellier, INSERM, Montpellier, France
- ALS Reference Center, Univ Montpellier, CHU Montpellier, Montpellier, France
| | - Matthew J A Wood
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- Department of Paediatrics, University of Oxford, Oxford, UK
| | - Melissa Bowerman
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
- School of Medicine, Keele University, Staffordshire, UK.
- Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK.
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9
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Chen Y, Yan Y, Li Y, Zhang L, Luo T, Zhu X, Qin D, Chen N, Huang W, Chen X, Wang L, Zhu X, Zhang L. Deletion of Tgm2 suppresses BMP-mediated hepatocyte-to-cholangiocyte metaplasia in ductular reaction. Cell Prolif 2024; 57:e13646. [PMID: 38623945 PMCID: PMC11471396 DOI: 10.1111/cpr.13646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/26/2024] [Accepted: 04/03/2024] [Indexed: 04/17/2024] Open
Abstract
Transglutaminase 2 (Tgm2) plays an essential role in hepatic repair following prolonged toxic injury. During cholestatic liver injury, the intrahepatic cholangiocytes undergo dynamic tissue expansion and remodelling, referred to as ductular reaction (DR), which is crucial for liver regeneration. However, the molecular mechanisms governing the dynamics of active cells in DR are still largely unclear. Here, we generated Tgm2-knockout mice (Tgm2-/-) and Tgm2-CreERT2-Rosa26-mTmG flox/flox (Tgm2CreERT2-R26T/Gf/f) mice and performed a three-dimensional (3D) collagen gel culture of mouse hepatocytes to demonstrate how Tgm2 signalling is involved in DR to remodel intrahepatic cholangiocytes. Our results showed that the deletion of Tgm2 adversely affected the functionality and maturity of the proliferative cholangiocytes in DR, thus leading to more severe cholestasis during DDC-induced liver injury. Additionally, Tgm2 hepatocytes played a crucial role in the regulation of DR through metaplasia. We unveiled that Tgm2 regulated H3K4me3Q5ser via serotonin to promote BMP signalling activation to participate in DR. Besides, we revealed that the activation or inhibition of BMP signalling could promote or suppress the development and maturation of cholangiocytes in DDC-induced DR. Furthermore, our 3D collagen gel culture assay indicated that Tgm2 was vital for the development of cholangiocytes in vitro. Our results uncovered a considerable role of BMP signalling in controlling metaplasia of Tgm2 hepatocytes in DR and revealed the phenotypic plasticity of mature hepatocytes.
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Affiliation(s)
- Yaqing Chen
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Yi Yan
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Yujing Li
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Liang Zhang
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Tingting Luo
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Xinlong Zhu
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Dan Qin
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Ning Chen
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
| | - Wendong Huang
- Department of Diabetes Complications and MetabolismDiabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical CenterDuarteCaliforniaUSA
| | - Xiangmei Chen
- Department of Nephrology, First Medical Center of Chinese PLA General HospitalNephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease ResearchBeijingChina
| | - Liqiang Wang
- Department of Nephrology, First Medical Center of Chinese PLA General HospitalNephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease ResearchBeijingChina
| | - Xianmin Zhu
- Department of Hepatobiliary and Pancreatic SurgeryCancer Hospital of Wuhan University (Hubei Cancer Hospital)WuhanChina
| | - Lisheng Zhang
- College of Veterinary Medicine/College of Biomedicine and HealthHuazhong Agricultural UniversityWuhanChina
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10
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Fernández-Tussy P, Cardelo MP, Zhang H, Sun J, Price NL, Boutagy NE, Goedeke L, Cadena-Sandoval M, Xirouchaki CE, Brown W, Yang X, Pastor-Rojo O, Haeusler RA, Bennett AM, Tiganis T, Suárez Y, Fernández-Hernando C. miR-33 deletion in hepatocytes attenuates MASLD-MASH-HCC progression. JCI Insight 2024; 9:e168476. [PMID: 39190492 PMCID: PMC11466198 DOI: 10.1172/jci.insight.168476] [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: 01/04/2023] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
The complexity of the mechanisms underlying metabolic dysfunction-associated steatotic liver disease (MASLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of MASLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 was elevated in the livers of humans and mice with MASLD and that its deletion in hepatocytes (miR-33 HKO) improved multiple aspects of the disease, including steatosis and inflammation, limiting the progression to metabolic dysfunction-associated steatotic hepatitis (MASH), fibrosis, and HCC. Mechanistically, hepatic miR-33 deletion reduced lipid synthesis and promoted mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 altered the expression of several known miR-33 target genes involved in metabolism and resulted in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of MASLD, MASH, and HCC in obesity.
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Affiliation(s)
- Pablo Fernández-Tussy
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
| | - Magdalena P. Cardelo
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
| | - Hanming Zhang
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
| | - Jonathan Sun
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Nathan L. Price
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
- Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA
| | - Nabil E. Boutagy
- Vascular Biology and Therapeutics Program
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Leigh Goedeke
- Cardiovascular Research Institute and Division of Cardiology, Department of Medicine; and
- Diabetes, Obesity and Metabolism Institute and Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Martí Cadena-Sandoval
- Department of Pathology & Cell Biology and Naomi Berrie Diabetes Center, Columbia University, New York, New York, USA
| | - Chrysovalantou E. Xirouchaki
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Surgery, Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | - Wendy Brown
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Xiaoyong Yang
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
- Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Oscar Pastor-Rojo
- Vascular Biology and Therapeutics Program
- Servicio de Bioquímica Clínica, Hospital Universitario Ramón y Cajal IRYCIS, Madrid, Spain
- Departamento de Biología de Sistemas, Universidad de Alcalá de Henares, Madrid, Spain
| | - Rebecca A. Haeusler
- Department of Pathology & Cell Biology and Naomi Berrie Diabetes Center, Columbia University, New York, New York, USA
| | - Anton M. Bennett
- Yale Center for Molecular and System Metabolism, and
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Tony Tiganis
- Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
- Department of Surgery, Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | - Yajaira Suárez
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Carlos Fernández-Hernando
- Vascular Biology and Therapeutics Program
- Department of Comparative Medicine
- Yale Center for Molecular and System Metabolism, and
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
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11
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Xu C, Fang X, Song Y, Xiang Z, Xu X, Wei X. Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates. Int J Biol Sci 2024; 20:3544-3556. [PMID: 38993564 PMCID: PMC11234216 DOI: 10.7150/ijbs.93739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 05/31/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.
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Affiliation(s)
- Chenhao Xu
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xixi Fang
- Hangzhou Normal University, Hangzhou 310006, China
| | - Yisu Song
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
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12
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Gribben C, Galanakis V, Calderwood A, Williams EC, Chazarra-Gil R, Larraz M, Frau C, Puengel T, Guillot A, Rouhani FJ, Mahbubani K, Godfrey E, Davies SE, Athanasiadis E, Saeb-Parsy K, Tacke F, Allison M, Mohorianu I, Vallier L. Acquisition of epithelial plasticity in human chronic liver disease. Nature 2024; 630:166-173. [PMID: 38778114 PMCID: PMC11153150 DOI: 10.1038/s41586-024-07465-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 04/25/2024] [Indexed: 05/25/2024]
Abstract
For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1-4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K-AKT-mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.
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Affiliation(s)
- Christopher Gribben
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Open Targets, Wellcome Genome Campus, Hinxton, UK
| | - Vasileios Galanakis
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Open Targets, Wellcome Genome Campus, Hinxton, UK
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Alexander Calderwood
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Eleanor C Williams
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Ruben Chazarra-Gil
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Miguel Larraz
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Carla Frau
- Berlin Institute of Health Centre for Regenerative Therapies, Berlin, Germany
| | - Tobias Puengel
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | | | - Edmund Godfrey
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Susan E Davies
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Emmanouil Athanasiadis
- Greek Genome Centre, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Medical Image and Signal Processing Laboratory, Department of Biomedical Engineering, University of West Attica, Athens, Greece
| | | | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Allison
- Open Targets, Wellcome Genome Campus, Hinxton, UK.
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Irina Mohorianu
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
| | - Ludovic Vallier
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
- Open Targets, Wellcome Genome Campus, Hinxton, UK.
- Berlin Institute of Health Centre for Regenerative Therapies, Berlin, Germany.
- Max Planck Institute for Molecular Genetics, Berlin, Germany.
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13
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Ferro A, Arshad A, Boyd L, Stanley T, Berisha A, Vrudhula U, Gomez AM, Borniger JC, Cheadle L. The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian function in vivo. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.02.587786. [PMID: 38617238 PMCID: PMC11014623 DOI: 10.1101/2024.04.02.587786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Abstract
To survive, organisms must adapt to a staggering diversity of environmental signals, ranging from sensory information to pathogenic infection, across the lifespan. At the same time, organisms intrinsically generate biological oscillations, such as circadian rhythms, without input from the environment. While the nervous system is well-suited to integrate extrinsic and intrinsic cues, how the brain balances these influences to shape biological function system-wide is not well understood at the molecular level. Here, we demonstrate that the cytokine receptor Fn14, previously identified as a mediator of sensory experience-dependent synaptic refinement during brain development, regulates neuronal activity and function in adult mice in a time-of-day-dependent manner. We show that a subset of excitatory pyramidal (PYR) neurons in the CA1 subregion of the hippocampus increase Fn14 expression when neuronal activity is heightened. Once expressed, Fn14 constrains the activity of these same PYR neurons, suggesting that Fn14 operates as a molecular brake on neuronal activity. Strikingly, differences in PYR neuron activity between mice lacking or expressing Fn14 were most robust at daily transitions between light and dark, and genetic ablation of Fn14 caused aberrations in circadian rhythms, sleep-wake states, and sensory-cued and spatial memory. At the cellular level, microglia contacted fewer, but larger, excitatory synapses in CA1 in the absence of Fn14, suggesting that these brain-resident immune cells may dampen neuronal activity by modifying synaptic inputs onto PYR neurons. Finally, mice lacking Fn14 exhibited heightened susceptibility to chemically induced seizures, implicating Fn14 in disorders characterized by hyperexcitation, such as epilepsy. Altogether, these findings reveal that cytokine receptors that mediates inflammation in the periphery, such as Fn14, can also play major roles in healthy neurological function in the adult brain downstream of both extrinsic and intrinsic cues.
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Affiliation(s)
- Austin Ferro
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | - Anosha Arshad
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
- Department of Neurobiology and Behavior, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA
| | - Leah Boyd
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | - Tess Stanley
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | - Adrian Berisha
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | - Uma Vrudhula
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | - Adrian M. Gomez
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
| | | | - Lucas Cheadle
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 11740, USA
- Howard Hughes Medical Institute, Cold Spring Harbor, NY 11740, USA
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14
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Marakovits C, Francis H. Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights. Am J Physiol Cell Physiol 2024; 326:C698-C706. [PMID: 38105754 PMCID: PMC11193454 DOI: 10.1152/ajpcell.00486.2023] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 12/11/2023] [Accepted: 12/11/2023] [Indexed: 12/19/2023]
Abstract
Ductular reaction and fibrosis are hallmarks of many liver diseases including primary sclerosing cholangitis, primary biliary cholangitis, biliary atresia, alcoholic liver disease, and metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis. Liver fibrosis is the accumulation of extracellular matrix often caused by excess collagen deposition by myofibroblasts. Ductular reaction is the proliferation of bile ducts (which are composed of cholangiocytes) during liver injury. Many other cells including hepatic stellate cells, hepatocytes, hepatic progenitor cells, mesenchymal stem cells, and immune cells contribute to ductular reaction and fibrosis by either directly or indirectly interacting with myofibroblasts and cholangiocytes. This review summarizes the recent findings in cellular links between ductular reaction and fibrosis in numerous liver diseases.
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Affiliation(s)
- Corinn Marakovits
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana, United States
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15
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [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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16
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Li L, He Y, Liu K, Liu L, Shan S, Liu H, Ren J, Sun S, Wang M, Jia J, Wang P. GITRL impairs hepatocyte repopulation by liver progenitor cells to aggravate inflammation and fibrosis by GITR +CD8 + T lymphocytes in CDE Mice. Cell Death Dis 2024; 15:114. [PMID: 38321001 PMCID: PMC10847460 DOI: 10.1038/s41419-024-06506-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/25/2024] [Accepted: 01/26/2024] [Indexed: 02/08/2024]
Abstract
As an alternative pathway for liver regeneration, liver progenitor cells and their derived ductular reaction cells increase during the progression of many chronic liver diseases. However, the mechanism underlying their hepatocyte repopulation after liver injury remains unknown. Here, we conducted progenitor cell lineage tracing in mice and found that fewer than 2% of hepatocytes were derived from liver progenitor cells after 9 weeks of injury with a choline-deficient diet supplemented with ethionine (CDE), and this percentage increased approximately three-fold after 3 weeks of recovery. We also found that the proportion of liver progenitor cells double positive for the ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL, also called Tnfsf18) and SRY-related HMG box transcription 9 (Sox9) among nonparenchymal cells increased time-dependently upon CDE injury and reduced after recovery. When GITRL was conditionally knocked out from hepatic progenitor cells, its expression in nonparenchymal cells was downregulated by approximately fifty percent, and hepatocyte repopulation increased by approximately three folds. Simultaneously, conditional knockout of GITRL reduced the proportion of liver-infiltrating CD8+ T lymphocytes and glucocorticoid-induced tumour necrosis factor receptor (GITR)-positive CD8+ T lymphocytes. Mechanistically, GITRL stimulated cell proliferation but suppressed the differentiation of liver progenitor organoids into hepatocytes, and CD8+ T cells further reduced their hepatocyte differentiation by downregulating the Wnt/β-catenin pathway. Therefore, GITRL expressed by liver progenitor cells impairs hepatocyte differentiation, thus hindering progenitor cell-mediated liver regeneration.
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Affiliation(s)
- Li Li
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Yu He
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Kai Liu
- Beijing Clinical Research Institute, Beijing, 100050, China
| | - Lin Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Shan Shan
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Helin Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Jiangbo Ren
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Shujie Sun
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Min Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China.
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China.
| | - Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
- National Clinical Research Center for Digestive Disease, Beijing, 100069, China.
- Beijing Key Laboratory on Translational Medicine on Cirrhosis, Beijing, 100050, China.
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17
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Chen F, Schönberger K, Tchorz JS. Distinct hepatocyte identities in liver homeostasis and regeneration. JHEP Rep 2023; 5:100779. [PMID: 37456678 PMCID: PMC10339260 DOI: 10.1016/j.jhepr.2023.100779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 07/18/2023] Open
Abstract
The process of metabolic liver zonation is spontaneously established by assigning distributed tasks to hepatocytes along the porto-central blood flow. Hepatocytes fulfil critical metabolic functions, while also maintaining hepatocyte mass by replication when needed. Recent technological advances have enabled us to fine-tune our understanding of hepatocyte identity during homeostasis and regeneration. Subsets of hepatocytes have been identified to be more regenerative and some have even been proposed to function like stem cells, challenging the long-standing view that all hepatocytes are similarly capable of regeneration. The latest data show that hepatocyte renewal during homeostasis and regeneration after liver injury is not limited to rare hepatocytes; however, hepatocytes are not exactly the same. Herein, we review the known differences that give individual hepatocytes distinct identities, recent findings demonstrating how these distinct identities correspond to differences in hepatocyte regenerative capacity, and how the plasticity of hepatocyte identity allows for division of labour among hepatocytes. We further discuss how these distinct hepatocyte identities may play a role during liver disease.
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Affiliation(s)
- Feng Chen
- Novartis Institutes for BioMedical Research, Cambridge, MA, United States
| | | | - Jan S. Tchorz
- Novartis Institutes for BioMedical Research, Basel, Switzerland
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18
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Ma J, Yang Z, Huang Z, Li L, Huang J, Chen J, Ni R, Luo L, He J. Rngtt governs biliary-derived liver regeneration initiation by transcriptional regulation of mTORC1 and Dnmt1 in zebrafish. Hepatology 2023; 78:167-178. [PMID: 36724876 DOI: 10.1097/hep.0000000000000186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 11/23/2022] [Indexed: 02/03/2023]
Abstract
In cases of end-stage liver diseases, the proliferation of existing hepatocytes is compromised, a feature of human chronic liver disease, in which most hepatocytes are dysfunctional. So far, liver transplantation represents the only curative therapeutic solution for advanced liver diseases, and the shortage of donor organs leads to high morbidity and mortality worldwide. The promising treatment is to prompt the biliary epithelial cells (BECs) transdifferentiation. However, the critical factors governing the initiation of BEC-derived liver regeneration are largely unknown. The zebrafish has advantages in large-scale genetic screens to identify the critical factors involved in liver regeneration. Here, we combined N-ethyl-N-nitrosourea screen, positional cloning, transgenic lines, antibody staining, and in situ hybridization methods and identified a liver regeneration defect mutant ( lrd ) using the zebrafish extensive liver injury model. Through positional cloning and genomic sequencing, we mapped the mutation site to rngtt . Loss of rngtt leads to the defects of BEC dedifferentiation, bipotential progenitor cell activation, and cell proliferation in the initiation stage of liver regeneration. The transdifferentiation from BECs to hepatocytes did not occur even at the late stage of liver regeneration. Mechanically, Rngtt transcriptionally regulates the attachment of mRNA cap to mTOR complex 1 (mTORC1) components and dnmt1 to maintain the activation of mTORC1 and DNA methylation in BECs after severe liver injury and prompt BEC to hepatocyte conversion. Furthermore, rptor and dnmt1 mutants displayed the same liver regeneration defects as rngtt mutation. In conclusion, our results suggest Rngtt is a new factor that initiates BEC-derived liver regeneration.
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Affiliation(s)
- Jianlong Ma
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Zhuolin Yang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Zhuofu Huang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Linke Li
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Jingliang Huang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Jingying Chen
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
- University of Chinese Academy of Sciences (Chongqing), Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, Beibei, Chongqing, China
| | - Rui Ni
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
| | - Jianbo He
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing, China
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19
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Bellanti F, Serviddio G, Vendemiale G. Modulation of liver regeneration by the nuclear factor erythroid 2-related factor 2. ADVANCES IN REDOX RESEARCH 2023; 7:100066. [DOI: 10.1016/j.arres.2023.100066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2024]
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20
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TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis. Cancers (Basel) 2023; 15:cancers15061807. [PMID: 36980694 PMCID: PMC10046490 DOI: 10.3390/cancers15061807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/10/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023] Open
Abstract
Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.
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21
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Pu W, Zhu H, Zhang M, Pikiolek M, Ercan C, Li J, Huang X, Han X, Zhang Z, Lv Z, Li Y, Liu K, He L, Liu X, Heim MH, Terracciano LM, Tchorz JS, Zhou B. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet 2023; 55:651-664. [PMID: 36914834 PMCID: PMC10101857 DOI: 10.1038/s41588-023-01335-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/07/2023] [Indexed: 03/16/2023]
Abstract
Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.
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Affiliation(s)
- Wenjuan Pu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Huan Zhu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Mingjun Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Monika Pikiolek
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Caner Ercan
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Jie Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiuzhen Huang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ximeng Han
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zhenqian Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zan Lv
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yan Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Kuo Liu
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Lingjuan He
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Xiuxiu Liu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Markus H Heim
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.,Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Luigi M Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jan S Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. .,Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. .,School of Life Science and Technology, ShanghaiTech University, Shanghai, China. .,New Cornerstone Science Laboratory, Shenzhen, China.
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22
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Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis. Cell Death Dis 2023; 9:26. [PMID: 36690641 PMCID: PMC9871041 DOI: 10.1038/s41420-023-01326-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/25/2023]
Abstract
Tumor necrosis factor receptor superfamily member-12A (TNFRSF12A) plays a critical role in inflammation and cell death. It is expressed in multiple tissues yet extremely low in normal liver. To date, little is known about its role in cholestasis. Therefore, we sought to delineate the role of TNFRSF12A in cholestasis and its underlying mechanisms. Human liver tissues were collected from patients with obstructive cholestasis (OC) or primary biliary cholangitis (PBC). Tnfrsf12a knockout (KO) mice were generated. Cholestasis was induced by bile-duct ligation (BDL) or 0.1% 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding. Human hepatoma PLC/PRF/5-ASBT and THP1 cell lines or primary mouse hepatocytes were used for mechanistic studies. Hepatic TNFRSF12A expression was markedly increased in OC or PBC patients. Genetic ablation of Tnfrsf12a in BDL- and 0.1%DDC-induced cholestatic mice significantly attenuated cholestatic liver injury with remarkable reduction of hepatocyte pyroptosis but without changing scores of necroptosis and apoptosis. Morphological features of hepatocyte pyroptosis and increased levels of pyroptosis-related proteins, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in OC patients and BDL-mice confirmed this observation. Further mechanistic studies revealed that bile acids (BAs) induced TNFRSF12A expression by enhancing the transcription factor c-JUN binding to the TNFRSF12A promoter and subsequently initiated hepatocyte pyroptosis by the NFκB/Caspase-1/GSDMD signaling. Interestingly, TWEAK, a typical ligand of TNFRSF12A, secreted by infiltrated macrophages in cholestatic livers, enhanced TNFRSF12A-induced hepatocyte pyroptosis. Taken together, we report, for the first time, that hepatic TNFRSF12A is dramatically increased in human cholestasis. Deletion of TNFRSF12A inhibits BAs-induced hepatocyte pyroptosis through the NFκB/Caspase-1/GSDMD signaling and thereby ameliorates cholestatic liver injury. As such, targeting TNFRSF12A could be a promising approach to treating cholestasis.
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23
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Short C, Zhong A, Xu J, Mahdi E, Glazier A, Malkoff N, Noriega N, Yeo T, Asahina K, Wang KS. TWEAK/FN14 promotes profibrogenic pathway activation in Prominin-1-expressing hepatic progenitor cells in biliary atresia. Hepatology 2023; 77:1639-1653. [PMID: 36626628 DOI: 10.1097/hep.0000000000000026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 10/01/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Biliary atresia (BA), a congenital cholestatic liver disease, commonly culminates in end-stage liver disease. We previously demonstrated in BA that Prominin-1 ( Prom1 )-expressing hepatic progenitor cells (HPCs) expand within regions of developing fibrosis, giving rise to cholangiocytes within biliary ductular reactions. Null mutation of Prom1 or ablation of cells expressing Prom1 significantly diminishes fibrogenesis. FN14, the receptor for TNF-like weak inducer of apoptosis (TWEAK), is expressed by HPCs. TWEAK/FN14 signaling promotes fibrosis in multiple organ systems. Therefore, we hypothesized that TWEAK/FN14 signaling mediates Prom1 -expressing HPC proliferation leading to profibrogenic ductular reactions in BA. APPROACH AND RESULTS The experimental mouse model of BA mediated by perinatal rhesus rotavirus (RRV) infection resulted in increased co-expression of Fn14 in Prom1 -expressing HPCs within regions of ductular reactions. FN14 antagonist L524-0366 decreased ductular reactions, biliary fibrosis and periportal fibroblast activation in RRV injury. L524-0366 inhibition also demonstrated loss of downstream noncanonical NF-kB signaling expression in RRV injury. Murine HPC organoids demonstrated accelerated organoid growth and proliferation when treated with recombinant TWEAK. Increased organoid proliferation with recombinant TWEAK was lost when also treated with L524-0366. Analysis of a large publicly available RNA sequencing database of BA and normal control patients revealed significant increases in expression of PROM1 , FN14 , and genes downstream of TNF signaling and noncanonical NF-κB signaling pathways in BA infants. Infants who failed to achieve bile drainage after hepatoportoenterostomy had higher relative levels of FN14 expression. CONCLUSION TWEAK/FN14 signaling activation in Prom1 -expressing HPCs contributes to proliferation of profibrogenic ductular reactions in BA.
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Affiliation(s)
- Celia Short
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Allen Zhong
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Jiabo Xu
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Elaa Mahdi
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Alison Glazier
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Nicolas Malkoff
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Nicolas Noriega
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Theresa Yeo
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
| | - Kinji Asahina
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Central Research Laboratory, Shiga University of Medical Science, Ōtsu, Shiga Prefecture, Japan
| | - Kasper S Wang
- Developmental Biology, Regenerative Medicine, and Stem Cell Program, The Saban Research Institute, Children's Hospital of Los Angeles, Los Angeles, California, USA
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24
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Chawla S, Das A. Preclinical-to-clinical innovations in stem cell therapies for liver regeneration. Curr Res Transl Med 2023; 71:103365. [PMID: 36427419 DOI: 10.1016/j.retram.2022.103365] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/03/2022] [Accepted: 09/14/2022] [Indexed: 02/06/2023]
Abstract
Acute and chronic liver diseases are the major cause of high morbidity and mortality globally. Liver transplantation is a widely used therapeutic option for liver failure. However, the shortage of availability of liver donors has encouraged research on the alternative approach to liver regeneration. Cell-based regenerative medicine is the best alternative therapy to cater to this need. To date, advanced preclinical approaches have been undertaken on stem cell differentiation and their use in liver tissue engineering for generating efficacious and promising regenerative therapies. Advancements in the bioengineering of stem cells, and organoid generation are the way forward to efficient therapies against liver injury. This review summarizes the recent approaches for stem cell therapy-based liver regeneration and their proof of concepts for clinical application, bioengineering liver organoids to alleviate the liver failure caused due to chronic liver diseases.
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Affiliation(s)
- Shilpa Chawla
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India
| | - Amitava Das
- Department of Applied Biology, Council of Scientific & Industrial Research-Indian Institute of Chemical Technology (CSIR-IICT), Uppal Road, Tarnaka, Hyderabad, TS 500 007, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, UP 201 002, India.
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25
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Osna NA, Rasineni K, Ganesan M, Donohue TM, Kharbanda KK. Pathogenesis of Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1492-1513. [PMID: 36340300 PMCID: PMC9630031 DOI: 10.1016/j.jceh.2022.05.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 05/25/2022] [Indexed: 12/12/2022] Open
Abstract
Excessive alcohol consumption is a global healthcare problem with enormous social, economic, and clinical consequences. While chronic, heavy alcohol consumption causes structural damage and/or disrupts normal organ function in virtually every tissue of the body, the liver sustains the greatest damage. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. Alcohol-induced damage remains one of the most prevalent disorders of the liver and a leading cause of death or transplantation from liver disease. Despite extensive research on the pathophysiology of this disease, there are still no targeted therapies available. Given the multifactorial mechanisms for alcohol-associated liver disease pathogenesis, it is conceivable that a multitherapeutic regimen is needed to treat different stages in the spectrum of this disease.
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Key Words
- AA, Arachidonic acid
- ADH, Alcohol dehydrogenase
- AH, Alcoholic hepatitis
- ALD, Alcohol-associated liver disease
- ALDH, Aldehyde dehydrogenase
- ALT, Alanine transaminase
- ASH, Alcohol-associated steatohepatitis
- AST, Aspartate transaminase
- AUD, Alcohol use disorder
- BHMT, Betaine-homocysteine-methyltransferase
- CD, Cluster of differentiation
- COX, Cycloxygenase
- CTLs, Cytotoxic T-lymphocytes
- CYP, Cytochrome P450
- CYP2E1, Cytochrome P450 2E1
- Cu/Zn SOD, Copper/zinc superoxide dismutase
- DAMPs, Damage-associated molecular patterns
- DC, Dendritic cells
- EDN1, Endothelin 1
- ER, Endoplasmic reticulum
- ETOH, Ethanol
- EVs, Extracellular vesicles
- FABP4, Fatty acid-binding protein 4
- FAF2, Fas-associated factor family member 2
- FMT, Fecal microbiota transplant
- Fn14, Fibroblast growth factor-inducible 14
- GHS-R1a, Growth hormone secretagogue receptor type 1a
- GI, GOsteopontinastrointestinal tract
- GSH Px, Glutathione peroxidase
- GSSG Rdx, Glutathione reductase
- GST, Glutathione-S-transferase
- GWAS, Genome-wide association studies
- H2O2, Hydrogen peroxide
- HA, Hyaluronan
- HCC, Hepatocellular carcinoma
- HNE, 4-hydroxynonenal
- HPMA, 3-hydroxypropylmercapturic acid
- HSC, Hepatic stellate cells
- HSD17B13, 17 beta hydroxy steroid dehydrogenase 13
- HSP 90, Heat shock protein 90
- IFN, Interferon
- IL, Interleukin
- IRF3, Interferon regulatory factor 3
- JAK, Janus kinase
- KC, Kupffer cells
- LCN2, Lipocalin 2
- M-D, Mallory–Denk
- MAA, Malondialdehyde-acetaldehyde protein adducts
- MAT, Methionine adenosyltransferase
- MCP, Macrophage chemotactic protein
- MDA, Malondialdehyde
- MIF, Macrophage migration inhibitory factor
- Mn SOD, Manganese superoxide dismutase
- Mt, Mitochondrial
- NK, Natural killer
- NKT, Natural killer T-lymphocytes
- OPN, Osteopontin
- PAMP, Pathogen-associated molecular patterns
- PNPLA3, Patatin-like phospholipase domain containing 3
- PUFA, Polyunsaturated fatty acid
- RIG1, Retinoic acid inducible gene 1
- SAH, S-adenosylhomocysteine
- SAM, S-adenosylmethionine
- SCD, Stearoyl-CoA desaturase
- STAT, Signal transduction and activator of transcription
- TIMP1, Tissue inhibitor matrix metalloproteinase 1
- TLR, Toll-like receptor
- TNF, Tumor necrosis factor-α
- alcohol
- alcohol-associated liver disease
- ethanol metabolism
- liver
- miRNA, MicroRNA
- p90RSK, 90 kDa ribosomal S6 kinase
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Affiliation(s)
- Natalia A. Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Karuna Rasineni
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Murali Ganesan
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
| | - Terrence M. Donohue
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Kusum K. Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
- Department of Internal Medicine, Omaha, NE, 68198, USA
- Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
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26
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Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice. Nat Commun 2022; 13:5111. [PMID: 36042192 PMCID: PMC9427946 DOI: 10.1038/s41467-022-32575-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 08/08/2022] [Indexed: 11/21/2022] Open
Abstract
Excessive cholangiocyte expansion (ductular reaction) promotes liver disease progression, but the underlying mechanism is poorly understood. Here we identify biliary NF-κB-inducing kinase (NIK) as a pivotal regulator of ductular reaction. NIK is known to activate the noncanonical IKKα/NF-κB2 pathway and regulate lymphoid tissue development. We find that cholangiocyte NIK is upregulated in mice with cholestasis induced by bile duct ligation (BDL), 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), or α-naphtyl-isothiocyanate (ANIT). DDC, ANIT, or BDL induces ductular reaction, liver injury, inflammation, and fibrosis in mice. Cholangiocyte-specific deletion of NIK, but not IKKα, blunts these pathological alterations. NIK inhibitor treatment similarly ameliorates DDC-induced ductular reaction, liver injury, and fibrosis. Biliary NIK directly increases cholangiocyte proliferation while suppressing cholangiocyte death, and it also promotes secretion of cholangiokines from cholangiocytes. Cholangiokines stimulate liver macrophages and hepatic stellate cells, augmenting liver inflammation and fibrosis. These results unveil a NIK/ductular reaction axis and a NIK/cholangiokine axis that promote liver disease progression. Excessive expansion of cholangiocytes in the liver leads to ductular reaction and liver disease. Here, the authors show that genetic ablation, or pharmacological inhibition, of biliary NIK blocks ductular reaction, liver inflammation, and liver fibrosis in mice by modulating secretion of cholangiokines that mediate liver inflammation and fibrosis.
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27
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Wang W, Chen D, Wang J, Wen L. Cellular Homeostasis and Repair in the Biliary Tree. Semin Liver Dis 2022; 42:271-282. [PMID: 35672015 DOI: 10.1055/a-1869-7714] [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: 02/01/2023]
Abstract
During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In response to various types of biliary injuries, distinct cellular sources, including HPCs, BTSCs, hepatocytes, and BECs, repair or regenerate the injured bile duct. BEC, biliary epithelial cell; BTSC, biliary tree stem/progenitor cell; EHBD, extrahepatic bile ducts; HPC, hepatic progenitor cell.The biliary tree comprises intrahepatic bile ducts and extrahepatic bile ducts lined with epithelial cells known as biliary epithelial cells (BECs). BECs are a common target of various cholangiopathies for which there is an unmet therapeutic need in clinical hepatology. The repair and regeneration of biliary tissue may potentially restore the normal architecture and function of the biliary tree. Hence, the repair and regeneration process in detail, including the replication of existing BECs, expansion and differentiation of the hepatic progenitor cells and biliary tree stem/progenitor cells, and transdifferentiation of the hepatocytes, should be understood. In this paper, we review biliary tree homeostasis, repair, and regeneration and discuss the feasibility of regenerative therapy strategies for cholangiopathy treatment.
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Affiliation(s)
- Wei Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Dongfeng Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jun Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Liangzhi Wen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
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28
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Meijboom KE, Sutton ER, McCallion E, McFall E, Anthony D, Edwards B, Kubinski S, Tapken I, Bünermann I, Hazell G, Ahlskog N, Claus P, Davies KE, Kothary R, Wood MJA, Bowerman M. Dysregulation of Tweak and Fn14 in skeletal muscle of spinal muscular atrophy mice. Skelet Muscle 2022; 12:18. [PMID: 35902978 PMCID: PMC9331072 DOI: 10.1186/s13395-022-00301-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 07/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. METHODS We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-; SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations. RESULTS Here, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-, and Fn14-/- mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models. CONCLUSIONS Our study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.
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Affiliation(s)
- Katharina E Meijboom
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.,Gene Therapy Center, UMass Medical School, Worcester, USA
| | - Emma R Sutton
- School of Medicine, Keele University, Staffordshire, UK
| | - Eve McCallion
- School of Medicine, Keele University, Staffordshire, UK
| | - Emily McFall
- Regenerative Medicine Program and Department of Cellular and Molecular Medicine, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Canada
| | - Daniel Anthony
- Department of Pharmacology, University of Oxford, Oxford, UK
| | - Benjamin Edwards
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Sabrina Kubinski
- Center for Systems Neuroscience and Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany
| | - Ines Tapken
- Center for Systems Neuroscience and Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.,SMATHERIA - Non-Profit Biomedical Research Institute, Hannover, Germany
| | - Ines Bünermann
- SMATHERIA - Non-Profit Biomedical Research Institute, Hannover, Germany
| | - Gareth Hazell
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Nina Ahlskog
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.,Department of Paediatrics, University of Oxford, Oxford, UK
| | - Peter Claus
- Center for Systems Neuroscience and Institute of Neuroanatomy and Cell Biology, Hannover Medical School, Hannover, Germany.,SMATHERIA - Non-Profit Biomedical Research Institute, Hannover, Germany
| | - Kay E Davies
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Rashmi Kothary
- Regenerative Medicine Program and Department of Cellular and Molecular Medicine, Ottawa Hospital Research Institute and University of Ottawa, Ottawa, Canada
| | - Matthew J A Wood
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.,Department of Paediatrics, University of Oxford, Oxford, UK
| | - Melissa Bowerman
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK. .,School of Medicine, Keele University, Staffordshire, UK. .,Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, UK.
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Wang S, Li L, Cook C, Zhang Y, Xia Y, Liu Y. A potential fate decision landscape of the TWEAK/Fn14 axis on stem and progenitor cells: a systematic review. Stem Cell Res Ther 2022; 13:270. [PMID: 35729659 PMCID: PMC9210594 DOI: 10.1186/s13287-022-02930-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/19/2022] [Indexed: 11/21/2022] Open
Abstract
Stem and progenitor cells (SPCs) possess self-remodeling ability and differentiation potential and are responsible for the regeneration and development of organs and tissue systems. However, the precise mechanisms underlying the regulation of SPC biology remain unclear. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) acts on miscellaneous cells via binding to fibroblast growth factor-inducible 14 (Fn14) and exerts pleiotropic functions in the regulation of divergent stem cell fates. TWEAK/Fn14 signaling can regulate the proliferation, differentiation, and migration of multiple SPCs as well as tumorigenesis in certain contexts. Although TWEAK’s roles in modulating multiple SPCs are sparsely reported, the systemic effector functions of this multifaceted protein have not been fully elucidated. In this review, we summarized the fate decisions of TWEAK/Fn14 signaling on multiple stem cells and characterized its potential in stem cell therapy.
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Affiliation(s)
- Sijia Wang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Liang Li
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi, China
| | - Christopher Cook
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Yufei Zhang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
| | - Yale Liu
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, 157 Xiwu Road, Xi'an, 710004, Shaanxi, China.
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Qian Y, Shang Z, Gao Y, Wu H, Kong X. Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells. Cell Mol Gastroenterol Hepatol 2022; 14:971-981. [PMID: 35738473 PMCID: PMC9489753 DOI: 10.1016/j.jcmgh.2022.05.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/28/2022] [Accepted: 07/27/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells. RESULTS Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration. CONCLUSIONS This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi Shang
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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31
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Wang GY, Garcia V, Lee J, Yanum J, Lin J, Jiang H, Dai G. Nrf2 deficiency causes hepatocyte dedifferentiation and reduced albumin production in an experimental extrahepatic cholestasis model. PLoS One 2022; 17:e0269383. [PMID: 35696363 PMCID: PMC9191739 DOI: 10.1371/journal.pone.0269383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/19/2022] [Indexed: 11/18/2022] Open
Abstract
The transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. We evaluated whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. As cholestasis progressed to day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and tumor necrosis factor-like weak induced apoptosis receptor (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. We revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis.
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Affiliation(s)
- Guo-Ying Wang
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- Department of Hepatic Surgery and Liver Transplantation Center, The Third Affiliated Hospital, Sun Yet-Sen University, Guangdong, China
| | - Veronica Garcia
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Joonyong Lee
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Jennifer Yanum
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
| | - Jingmei Lin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Huaizhou Jiang
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
- School of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Anhui, China
| | - Guoli Dai
- Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States of America
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GITR/GITRL reverse signalling modulates the proliferation of hepatic progenitor cells by recruiting ANXA2 to phosphorylate ERK1/2 and Akt. Cell Death Dis 2022; 13:297. [PMID: 35379781 PMCID: PMC8979965 DOI: 10.1038/s41419-022-04759-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 03/02/2022] [Accepted: 03/16/2022] [Indexed: 11/09/2022]
Abstract
AbstractHepatic stem/progenitor cells are the major cell compartment for tissue repair when hepatocyte proliferation is compromised in chronic liver diseases, but the expansion of these cells increases the risk of carcinogenesis. Therefore, it is essential to explore the pathways restricting their expansion and abnormal transformation. The ligand of glucocorticoid-induced tumour necrosis factor receptor (GITRL) showed the most highly increased expression in hepatic progenitor cells treated with transforming growth factor (TGF)-β1. If overexpressed by hepatic progenitor cells, GITRL stimulated cell proliferation by activating the epithelial–mesenchymal transition pathway and enhancing ERK1/2 and Akt phosphorylation via GITRL binding to ANXA2. However, GITR, the specific GITRL receptor, suppressed the epithelial–mesenchymal transition pathway of GITRL-expressing cells and decreased their growth by dissociating ANXA2 from GITRL and reducing downstream ERK1/2 and Akt phosphorylation. This study identifies GITR/GITRL reverse signalling as a cross-interaction pathway between immune cells and hepatic stem/progenitor cells that restricts the expansion of hepatic stem/progenitor cells and reduces the possibility of carcinogenesis.
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Lu MY, Yeh ML, Huang CI, Wang SC, Tsai YS, Tsai PC, Ko YM, Lin CC, Chen KY, Wei YJ, Hsu PY, Hsu CT, Jang TY, Liu TW, Liang PC, Hsieh MY, Lin ZY, Chen SC, Huang CF, Huang JF, Dai CY, Chuang WL, Yu ML. Dynamics of cytokines predicts risk of hepatocellular carcinoma among chronic hepatitis C patients after viral eradication. World J Gastroenterol 2022; 28:140-153. [PMID: 35125824 PMCID: PMC8793012 DOI: 10.3748/wjg.v28.i1.140] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/27/2021] [Accepted: 12/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chronic hepatitis C virus (HCV) infection induces profound alterations in the cytokine and chemokine signatures in peripheral blood. Clearance of HCV by antivirals results in host immune modification, which may interfere with immune-mediated cancer surveillance. Identifying HCV patients who remain at risk of hepatocellular carcinoma (HCC) following HCV eradication remains an unmet need. We hypothesized that antiviral therapy-induced immune reconstruction may be relevant to HCC development.
AIM To investigate the impact of differential dynamics of cytokine expression on the development of HCC following successful antiviral therapy.
METHODS One hundred treatment-naïve HCV patients with advanced fibrosis (F3/4) treated with direct-acting antivirals (DAAs) or peginterferon/ribavirin who achieved sustained virologic response [SVR, defined as undetectable HCV RNA throughout 12 wk (SVR12) for the DAA group or 24 wk (SVR24) for the interferon group after completion of antiviral therapy] were enrolled since 2003. The primary endpoint was the development of new-onset HCC. Standard HCC surveillance (abdominal ultrasound and α-fetoprotein) was performed every six months during the follow-up. Overall, 64 serum cytokines were detected by the multiplex immunoassay at baseline and 24 wk after end-of-treatment.
RESULTS HCC developed in 12 of the 97 patients over 459 person-years after HCV eradication. In univariate analysis, the Fibrosis-4 index (FIB-4), hemoglobin A1c (HbA1c), the dynamics of tumor necrosis factor-α (TNF-α), and TNF-like weak inducer of apoptosis (TWEAK) after antiviral therapy were significant HCC predictors. The multivariate Cox regression model showed that ΔTNF-α (≤ -5.7 pg/mL) was the most important risk factor for HCC (HR = 11.54, 95%CI: 2.27-58.72, P = 0.003 in overall cases; HR = 9.98, 95%CI: 1.88-52.87, P = 0.007 in the interferon group). An HCC predictive model comprising FIB-4, HbA1c, ΔTNF-α, and ΔTWEAK had excellent performance, with 3-, 5-, 10-, and 13-year areas under the curve of 0.882, 0.864, 0.903, and 1.000, respectively. The 5-year accumulative risks of HCC were 0%, 16.9%, and 40.0% in the low-, intermediate-, and high-risk groups, respectively.
CONCLUSION Downregulation of serum TNF-α significantly increases the risk of HCC after HCV eradication. A predictive model consisting of cytokine kinetics could ameliorate personalized HCC surveillance strategies for post-SVR HCV patients.
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Affiliation(s)
- Ming-Ying Lu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Ming-Lun Yeh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ching-I Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shu-Chi Wang
- Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Shan Tsai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Pei-Chien Tsai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Yu-Min Ko
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Ching-Chih Lin
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Kuan-Yu Chen
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Yu-Ju Wei
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Po-Yao Hsu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Cheng-Ting Hsu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Tyng-Yuan Jang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Ta-Wei Liu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Po-Cheng Liang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Ming-Yen Hsieh
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Zu-Yau Lin
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Shinn-Cherng Chen
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chung-Feng Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Jee-Fu Huang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Chia-Yen Dai
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Health Management Center, Department of Community Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Wan-Long Chuang
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Ming-Lung Yu
- Hepatitis Center and Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- School of Medicine and Hepatitis Research Center, College of Medicine, Center for Cancer Research and Center for Liquid Biopsy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 80708, Taiwan
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Alshoubaki YK, Nayer B, Das S, Martino MM. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:248-258. [PMID: 35303109 PMCID: PMC8968657 DOI: 10.1093/stcltm/szab022] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 11/09/2021] [Indexed: 12/04/2022] Open
Abstract
Numerous components of the immune system, including inflammatory mediators, immune cells and cytokines, have a profound modulatory effect on the homeostatic regulation and regenerative activity of endogenous stem cells and progenitor cells. Thus, understanding how the immune system interacts with stem/progenitor cells could build the foundation to design novel and more effective regenerative therapies. Indeed, utilizing and controlling immune system components may be one of the most effective approaches to promote tissue regeneration. In this review, we first summarize the effects of various immune cell types on endogenous stem/progenitor cells, focusing on the tissue healing context. Then, we present interesting regenerative strategies that control or mimic the effect of immune components on stem/progenitor cells, in order to enhance the regenerative capacity of endogenous and transplanted stem cells. We highlight the potential clinical translation of such approaches for multiple tissues and organ systems, as these novel regenerative strategies could considerably improve or eventually substitute stem cell-based therapies. Overall, harnessing the power of the cross-talk between the immune system and stem/progenitor cells holds great potential for the development of novel and effective regenerative therapies.
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Affiliation(s)
- Yasmin K Alshoubaki
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Bhavana Nayer
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Surojeet Das
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
| | - Mikaël M Martino
- European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC, Australia
- Laboratory of Host Defense, World Premier Institute Immunology Frontier Research Center, Osaka University, Osaka, Japan
- Corresponding author: Mikaël M. Martino, Martino Lab, Australian Regenerative Medicine Institute, 15 Innovation Walk, Level 1, Monash University, Victoria 3800, Australia;
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Fatima A, Malick TS, Khan I, Ishaque A, Salim A. Effect of glycyrrhizic acid and 18β-glycyrrhetinic acid on the differentiation of human umbilical cord-mesenchymal stem cells into hepatocytes. World J Stem Cells 2021; 13:1580-1594. [PMID: 34786159 PMCID: PMC8567450 DOI: 10.4252/wjsc.v13.i10.1580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/25/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND End-stage liver disease is a global health complication with high prevalence and limited treatment options. Cell-based therapies using mesenchymal stem cells (MSCs) emerged as an alternative approach to support hepatic regeneration. In vitro preconditioning strategies have been employed to strengthen the regenerative and differentiation potential of MSCs towards hepatic lineage. Chemical compounds of the triterpene class; glycyrrhizic acid (GA) and 18β-glycyrrhetinic acid (GT) possess diverse therapeutic properties including hepato-protection and anti-fibrosis characteristics. They are capable of modulating several signaling pathways that are crucial in hepatic regeneration. Preconditioning with hepato-protective triterpenes may stimulate MSC fate transition towards hepatocytes.
AIM To explore the effect of GA and GT on hepatic differentiation of human umbilical cord-MSCs (hUC-MSCs).
METHODS hUC-MSCs were isolated and characterized phenotypically by flow cytometry and immunocytochemistry for the expression of MSC-associated surface molecules. Isolated cells were treated with GA, GT, and their combination for 24 h and then analyzed at three time points; day 7, 14, and 21. qRT-PCR was performed for the expression of hepatic genes. Expression of hepatic proteins was analyzed by immunocytochemistry at day 21. Periodic acid Schiff staining was performed to determine the functional ability of treated cells.
RESULTS The fusiform-shaped morphology of MSCs in the treatment groups in comparison with the untreated control, eventually progressed towards the polygonal morphology of hepatocytes with the passage of time. The temporal transcriptional profile of preconditioned MSCs displayed significant expression of hepatic genes with increasing time of differentiation. Preconditioned cells showed positive expression of hepatocyte-specific proteins. The results were further corroborated by positive periodic acid Schiff staining, indicating the presence of glycogen in their cytoplasm. Moreover, bi-nucleated cells, which is the typical feature of hepatocytes, were also seen in the preconditioned cells.
CONCLUSION Preconditioning with glycyrrhizic acid, 18β-glycyrrhetinic acid and their combination, successfully differentiates hUC-MSCs into hepatic-like cells. These MSCs may serve as a better therapeutic option for degenerative liver diseases in future.
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Affiliation(s)
- Abiha Fatima
- Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Tuba Shakil Malick
- Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Irfan Khan
- Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Aisha Ishaque
- Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75270, Sindh, Pakistan
| | - Asmat Salim
- Stem Cell Laboratory, Dr. Panjwani Center for Molecular Medicine and Drug Research, ICCBS, University of Karachi, Karachi 75270, Sindh, Pakistan
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Sánchez PS, Rigual MDM, Djouder N. Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development. Cancers (Basel) 2021; 13:cancers13205045. [PMID: 34680192 PMCID: PMC8534267 DOI: 10.3390/cancers13205045] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary The liver is continuously exposed to several harmful factors, subsequently activating sophisticated mechanisms set-up in order to repair and regenerate the damaged liver and hence to prevent its failure. When the injury becomes chronic, the regenerative response becomes perpetual and goes awry, leading to cirrhosis with a fatal liver dysfunction. Cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC), the most common, usually lethal, human primary liver neoplasm with very limited therapeutic options. Considering the pivotal role of immune factors in the development of cirrhosis, here we review and discuss the inflammatory pathways and components implicated in the development of cirrhosis. A better understanding of these circuits would help the design of novel strategies to prevent and treat cirrhosis and HCC, two lethal diseases. Abstract Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.
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Affiliation(s)
| | | | - Nabil Djouder
- Correspondence: ; Tel.: +34-3-491-732-8000 (ext. 3830); Fax: +34-3-491-224-6914
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Tezuka Y, Eguchi-Ishimae M, Ozaki E, Ito T, Ishii E, Eguchi M. Activation of fibroblast growth factor-inducible 14 in the early phase of childhood IgA nephropathy. PLoS One 2021; 16:e0258090. [PMID: 34597335 PMCID: PMC8486145 DOI: 10.1371/journal.pone.0258090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Accepted: 09/17/2021] [Indexed: 11/23/2022] Open
Abstract
IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Pediatric patients in Japan are diagnosed with IgAN at an early stage of the disease through annual urinary examinations. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible 14 (Fn14) have various roles, including proinflammatory effects, and modulation of several kidney diseases; however, no reports have described their roles in pediatric IgAN. In this study, we performed pathological and immunohistochemical analyses of samples from 14 pediatric IgAN patients. Additionally, gene expression arrays of glomeruli by laser-captured microdissection were performed in hemi-nephrectomized high serum IgA (HIGA) mice, a model of IgA nephropathy, to determine the role of Fn14. Glomeruli with intense Fn14 deposition were observed in 80% of mild IgAN cases; however, most severe cases showed glomeruli with little or no Fn14 deposition. Fn14 deposition was not observed in obvious mesangial proliferation or the crescent region of glomeruli, but was detected strongly in the glomerular tuft, with an intact appearance. In HIGA mice, Fn14 deposition was observed mildly beginning at 11 weeks of age, and stronger Fn14 deposition was detected at 14 weeks of age. Expression array analysis indicated that Fn14 expression was higher in HIGA mice at 6 weeks of age, increased slightly at 11 weeks, and then decreased at 26 weeks when compared with controls at equivalent ages. These findings suggest that Fn14 signaling affects early lesions but not advanced lesions in patients with IgAN. Further study of the TWEAK/Fn14 pathway will contribute to our understanding of the progression of IgAN.
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Affiliation(s)
- Yuko Tezuka
- Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | | | - Erina Ozaki
- Department of Total Medical Support Center, Ehime University Hospital, Toon, Ehime, Japan
| | - Toshiyuki Ito
- Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
| | - Mariko Eguchi
- Department of Pediatrics, Takamatsu Red Cross Hospital, Takamatsu, Kagawa, Japan
- Division of Medical Genetics, Ehime University Hospital, Toon, Ehime, Japan
- * E-mail:
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Wu H, Chen C, Ziani S, Nelson LJ, Ávila MA, Nevzorova YA, Cubero FJ. Fibrotic Events in the Progression of Cholestatic Liver Disease. Cells 2021; 10:cells10051107. [PMID: 34062960 PMCID: PMC8147992 DOI: 10.3390/cells10051107] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 04/28/2021] [Accepted: 04/30/2021] [Indexed: 02/07/2023] Open
Abstract
Cholestatic liver diseases including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are associated with active hepatic fibrogenesis, which can ultimately lead to the development of cirrhosis. However, the exact relationship between the development of liver fibrosis and the progression of cholestatic liver disease remains elusive. Periductular fibroblasts located around the bile ducts seem biologically different from hepatic stellate cells (HSCs). The fibrotic events in these clinical conditions appear to be related to complex crosstalk between immune/inflammatory mechanisms, cytokine signalling, and perturbed homeostasis between cholangiocytes and mesenchymal cells. Several animal models including bile duct ligation (BDL) and the Mdr2-knockout mice have improved our understanding of mechanisms underlying chronic cholestasis. In the present review, we aim to elucidate the mechanisms of fibrosis in order to help to identify potential diagnostic and therapeutic targets.
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Affiliation(s)
- Hanghang Wu
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Chaobo Chen
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Department of General Surgery, Wuxi Xishan People’s Hospital, Wuxi 214000, China
| | - Siham Ziani
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
| | - Leonard J. Nelson
- Institute for Bioengineering (IBioE), School of Engineering, Faraday Building, The University of Edinburgh, Edinburgh EH9 3 JL, Scotland, UK;
- Institute of Biological Chemistry, Biophysics and Bioengineering (IB3), School of Engineering and Physical Sciences (EPS), Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK
| | - Matías A. Ávila
- Hepatology Program, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain;
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, 31008 Pamplona, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (C.C.); (S.Z.); (Y.A.N.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centro de Investigacion Biomedica en Red, Enfermedades Hepáticas y Digestivas (CIBERehd), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-91-394-1385; Fax: +34-91-394-1641
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Guillot A, Guerri L, Feng D, Kim SJ, Ahmed YA, Paloczi J, He Y, Schuebel K, Dai S, Liu F, Pacher P, Kisseleva T, Qin X, Goldman D, Tacke F, Gao B. Bile acid-activated macrophages promote biliary epithelial cell proliferation through integrin αvβ6 upregulation following liver injury. J Clin Invest 2021; 131:132305. [PMID: 33724957 DOI: 10.1172/jci132305] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 03/11/2021] [Indexed: 01/18/2023] Open
Abstract
Cholangiopathies caused by biliary epithelial cell (BEC) injury represent a leading cause of liver failure. No effective pharmacologic therapies exist, and the underlying mechanisms remain obscure. We aimed to explore the mechanisms of bile duct repair after targeted BEC injury. Injection of intermedilysin into BEC-specific human CD59 (hCD59) transgenic mice induced acute and specific BEC death, representing a model to study the early signals that drive bile duct repair. Acute BEC injury induced cholestasis followed by CCR2+ monocyte recruitment and BEC proliferation. Using microdissection and next-generation RNA-Seq, we identified 5 genes, including Mapk8ip2, Cdkn1a, Itgb6, Rgs4, and Ccl2, that were most upregulated in proliferating BECs after acute injury. Immunohistochemical analyses confirmed robust upregulation of integrin αvβ6 (ITGβ6) expression in this BEC injury model, after bile duct ligation, and in patients with chronic cholangiopathies. Deletion of the Itgb6 gene attenuated BEC proliferation after acute bile duct injury. Macrophage depletion or Ccr2 deficiency impaired ITGβ6 expression and BEC proliferation. In vitro experiments revealed that bile acid-activated monocytes promoted BEC proliferation through ITGβ6. Our data suggest that BEC injury induces cholestasis, monocyte recruitment, and induction of ITGβ6, which work together to promote BEC proliferation and therefore represent potential therapeutic targets for cholangiopathies.
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Affiliation(s)
- Adrien Guillot
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA.,Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | | | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA
| | - Seung-Jin Kim
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA
| | - Yeni Ait Ahmed
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA
| | - Janos Paloczi
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, Maryland, USA
| | - Yong He
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA
| | | | - Shen Dai
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA
| | - Fengming Liu
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA
| | - Pal Pacher
- Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, Maryland, USA
| | | | - Xuebin Qin
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, Louisiana, USA
| | | | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism (NIAAA), NIH, Bethesda, Maryland, USA
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Dwyer BJ, Jarman EJ, Gogoi-Tiwari J, Ferreira-Gonzalez S, Boulter L, Guest RV, Kendall TJ, Kurian D, Kilpatrick AM, Robson AJ, O'Duibhir E, Man TY, Campana L, Starkey Lewis PJ, Wigmore SJ, Olynyk JK, Ramm GA, Tirnitz-Parker JEE, Forbes SJ. TWEAK/Fn14 signalling promotes cholangiocarcinoma niche formation and progression. J Hepatol 2021; 74:860-872. [PMID: 33221352 DOI: 10.1016/j.jhep.2020.11.018] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 10/26/2020] [Accepted: 11/09/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Cholangiocarcinoma (CCA) is a cancer of the hepatic bile ducts that is rarely resectable and is associated with poor prognosis. Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is known to signal via its receptor fibroblast growth factor-inducible 14 (Fn14) and induce cholangiocyte and myofibroblast proliferation in liver injury. We aimed to characterise its role in CCA. METHODS The expression of the TWEAK ligand and Fn14 receptor was assessed immunohistochemically and by bulk RNA and single cell transcriptomics of human liver tissue. Spatiotemporal dynamics of pathway regulation were comprehensively analysed in rat and mouse models of thioacetamide (TAA)-mediated CCA. Flow cytometry, qPCR and proteomic analyses of CCA cell lines and conditioned medium experiments with primary macrophages were performed to evaluate the downstream functions of TWEAK/Fn14. In vivo pathway manipulation was assessed via TWEAK overexpression in NICD/AKT-induced CCA or genetic Fn14 knockout during TAA-mediated carcinogenesis. RESULTS Our data reveal TWEAK and Fn14 overexpression in multiple human CCA cohorts, and Fn14 upregulation in early TAA-induced carcinogenesis. TWEAK regulated the secretion of factors from CC-SW-1 and SNU-1079 CCA cells, inducing polarisation of proinflammatory CD206+ macrophages. Pharmacological blocking of the TWEAK downstream target chemokine monocyte chemoattractant protein 1 (MCP-1 or CCL2) significantly reduced CCA xenograft growth, while TWEAK overexpression drove cancer-associated fibroblast proliferation and collagen deposition in the tumour niche. Genetic Fn14 ablation significantly reduced inflammatory, fibrogenic and ductular responses during carcinogenic TAA-mediated injury. CONCLUSION These novel data provide evidence for the action of TWEAK/Fn14 on macrophage recruitment and phenotype, and cancer-associated fibroblast proliferation in CCA. Targeting TWEAK/Fn14 and its downstream signals may provide a means to inhibit CCA niche development and tumour growth. LAY SUMMARY Cholangiocarcinoma is an aggressive, chemotherapy-resistant liver cancer. Interactions between tumour cells and cells that form a supportive environment for the tumour to grow are a source of this aggressiveness and resistance to chemotherapy. Herein, we describe interactions between tumour cells and their supportive environment via a chemical messenger, TWEAK and its receptor Fn14. TWEAK/Fn14 alters the recruitment and type of immune cells in tumours, increases the growth of cancer-associated fibroblasts in the tumour environment, and is a potential target to reduce tumour formation.
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Affiliation(s)
- Benjamin J Dwyer
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
| | - Edward J Jarman
- MRC Human Genetics Unit, Western General Hospital Campus, Edinburgh, UK
| | - Jully Gogoi-Tiwari
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia
| | - Sofia Ferreira-Gonzalez
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Luke Boulter
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; MRC Human Genetics Unit, Western General Hospital Campus, Edinburgh, UK
| | - Rachel V Guest
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK; Department of Clinical Surgery, University of Edinburgh, Edinburgh, EH16 4SA, UK
| | - Timothy J Kendall
- University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom
| | - Dominic Kurian
- The Roslin Institute & Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, United Kingdom
| | - Alastair M Kilpatrick
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Andrew J Robson
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Eoghan O'Duibhir
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Tak Yung Man
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Lara Campana
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Philip J Starkey Lewis
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Stephen J Wigmore
- University of Edinburgh Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, United Kingdom; Department of Surgery, Royal Infirmary of Edinburgh, Edinburgh EH16 4SA, United Kingdom
| | - John K Olynyk
- Department of Gastroenterology, Fiona Stanley Fremantle Hospital Group, Murdoch, WA, Australia; School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Grant A Ramm
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Janina E E Tirnitz-Parker
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, WA, Australia; Centre for Cell Therapy and Regenerative Medicine, and School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Scottish Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
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Poveda J, Vázquez-Sánchez S, Sanz AB, Ortiz A, Ruilope LM, Ruiz-Hurtado G. TWEAK-Fn14 as a common pathway in the heart and the kidneys in cardiorenal syndrome. J Pathol 2021; 254:5-19. [PMID: 33512736 DOI: 10.1002/path.5631] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 12/23/2020] [Accepted: 01/12/2021] [Indexed: 12/19/2022]
Abstract
There is a complex relationship between cardiac and renal disease, often referred to as the cardiorenal syndrome. Heart failure adversely affects kidney function, and both acute and chronic kidney disease are associated with structural and functional changes to the myocardium. The pathological mechanisms and contributing interactions that surround this relationship remain poorly understood, limiting the opportunities for therapeutic intervention. The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor, fibroblast growth factor-inducible 14 (Fn14), are abundantly expressed in injured kidneys and heart. The TWEAK-Fn14 axis promotes responses that drive tissue injury such as inflammation, proliferation, fibrosis, and apoptosis, while restraining the expression of tissue protective factors such as the anti-aging factor Klotho and the master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). High levels of TWEAK induce cardiac remodeling, and promote inflammation, tubular and podocyte injury and death, fibroblast proliferation, and, ultimately, renal fibrosis. Accordingly, targeting the TWEAK-Fn14 axis is protective in experimental kidney and heart disease. TWEAK has also emerged as a biomarker of kidney damage and cardiovascular outcomes and has been successfully targeted in clinical trials. In this review, we update our current knowledge of the roles of the TWEAK-Fn14 axis in cardiovascular and kidney disease and its potential contribution to the cardiorenal syndrome. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Jonay Poveda
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Sara Vázquez-Sánchez
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Ana B Sanz
- Research Institute - Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Alberto Ortiz
- Research Institute - Fundacion Jimenez Diaz, Autonoma University, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Luis M Ruilope
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.,School of Doctoral Studies and Research, European University of Madrid, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Gema Ruiz-Hurtado
- Cardiorenal Translational Laboratory, Institute of Research i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.,CIBER-CV, Hospital Universitario 12 de Octubre, Madrid, Spain
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Chen T, Oh S, Gregory S, Shen X, Diehl AM. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration. JCI Insight 2020. [DOI: 10.1172/jci.insight.141024 33208554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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43
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Chen T, Oh S, Gregory S, Shen X, Diehl AM. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration. JCI Insight 2020; 5:141024. [PMID: 33208554 PMCID: PMC7710279 DOI: 10.1172/jci.insight.141024] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/08/2020] [Indexed: 01/07/2023] Open
Abstract
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
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Affiliation(s)
- Tianyi Chen
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Simon Gregory
- Department of Neurology, Duke University, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Xiling Shen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, USA
| | - Anna Mae Diehl
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Medicine and
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Zhang Y, Zeng W, Xia Y. TWEAK/Fn14 axis is an important player in fibrosis. J Cell Physiol 2020; 236:3304-3316. [PMID: 33000480 DOI: 10.1002/jcp.30089] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 12/15/2022]
Abstract
Fibrosis is a common pathological condition associated with abnormal repair after tissue injury. However, the etiology and molecular mechanisms of fibrosis are still not well-understood. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) belongs to the TNF superfamily and acts by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14), thereby activating a variety of intracellular signal transduction pathways in various types of cells. Besides promoting the expression of growth factors, activation of TWEAK/Fn14 signaling after tissue injury can promote the expression of pro-inflammatory cytokines, which trigger the immune response, thereby exacerbating the injury. Severe or repetitive injury leads to a dysregulated tissue repair process, in which the TWEAK/Fn14 axis promotes the activation and proliferation of myofibroblasts, induces the secretion of the extracellular matrix, and regulates profibrotic mediators to further perpetuate and sustain the fibrotic process. In this review, we summarize the available experimental evidence on the underlying molecular mechanisms by which the TWEAK/Fn14 pathway mediates the development and progression of fibrosis. In addition, we discuss the therapeutic potential of the TWEAK/Fn14 pathway in fibrosis-associated diseases based on evidence derived from multiple models and cells from injured tissue and fibrotic tissue.
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Affiliation(s)
- Yitian Zhang
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Weihui Zeng
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yumin Xia
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Cheadle L, Rivera SA, Phelps JS, Ennis KA, Stevens B, Burkly LC, Lee WCA, Greenberg ME. Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism. Neuron 2020; 108:451-468.e9. [PMID: 32931754 DOI: 10.1016/j.neuron.2020.08.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 05/10/2020] [Accepted: 08/05/2020] [Indexed: 12/21/2022]
Abstract
Sensory experience remodels neural circuits in the early postnatal brain through mechanisms that remain to be elucidated. Applying a new method of ultrastructural analysis to the retinogeniculate circuit, we find that visual experience alters the number and structure of synapses between the retina and the thalamus. These changes require vision-dependent transcription of the receptor Fn14 in thalamic relay neurons and the induction of its ligand TWEAK in microglia. Fn14 functions to increase the number of bulbous spine-associated synapses at retinogeniculate connections, likely contributing to the strengthening of the circuit that occurs in response to visual experience. However, at retinogeniculate connections near TWEAK-expressing microglia, TWEAK signals via Fn14 to restrict the number of bulbous spines on relay neurons, leading to the elimination of a subset of connections. Thus, TWEAK and Fn14 represent an intercellular signaling axis through which microglia shape retinogeniculate connectivity in response to sensory experience.
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Affiliation(s)
- Lucas Cheadle
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
| | - Samuel A Rivera
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
| | - Jasper S Phelps
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA
| | - Katelin A Ennis
- Research and Early Development, Biogen, 115 Broadway, Cambridge, MA 04142, USA
| | - Beth Stevens
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Linda C Burkly
- Research and Early Development, Biogen, 115 Broadway, Cambridge, MA 04142, USA
| | - Wei-Chung Allen Lee
- Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Michael E Greenberg
- Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
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Garrido A, Djouder N. Cirrhosis: A Questioned Risk Factor for Hepatocellular Carcinoma. Trends Cancer 2020; 7:29-36. [PMID: 32917550 DOI: 10.1016/j.trecan.2020.08.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/30/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023]
Abstract
The liver is one of the major metabolic organs in the body, susceptible to injury caused by various factors. In response to injury, sophisticated mechanisms are engaged to repair and regenerate the damaged liver, preventing its failure. When the damage is chronic, regeneration goes awry, impairing liver function and causing cirrhosis. Hence, cirrhosis may rather be a protective response to injury, where wound-healing processes are set to primarily repair the damaged liver. Although cirrhosis is clinically considered a risk factor for hepatocellular carcinoma (HCC), comprehensive population-based studies demonstrate a very modest incidence, refuting the idea that cirrhosis progresses to HCC. Here, we discuss and shed light on the provocative question of whether cirrhosis predisposes to HCC.
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Affiliation(s)
- Amanda Garrido
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
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Pascoe AL, Johnston AJ, Murphy RM. Controversies in TWEAK-Fn14 signaling in skeletal muscle atrophy and regeneration. Cell Mol Life Sci 2020; 77:3369-3381. [PMID: 32200423 PMCID: PMC11104974 DOI: 10.1007/s00018-020-03495-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/27/2020] [Accepted: 02/24/2020] [Indexed: 12/13/2022]
Abstract
Skeletal muscle is one of the largest functional tissues in the human body; it is highly plastic and responds dramatically to anabolic and catabolic stimuli, including weight training and malnutrition, respectively. Excessive loss of muscle mass, or atrophy, is a common symptom of many disease states with severe impacts on prognosis and quality of life. TNF-like weak inducer of apoptosis (TWEAK) and its cognate receptor, fibroblast growth factor-inducible 14 (Fn14) are an emerging cytokine signaling pathway in the pathogenesis of muscle atrophy. Upregulation of TWEAK and Fn14 has been described in a number of atrophic and injured muscle states; however, it remains unclear whether they are contributing to the degenerative or regenerative aspect of muscle insults. The current review focuses on the expression and apparent downstream outcomes of both TWEAK and Fn14 in a range of catabolic and anabolic muscle models. Apparent changes in the signaling outcomes of TWEAK-Fn14 activation dependent on the relative expression of both the ligand and the receptor are discussed as a potential source of divergent TWEAK-Fn14 downstream effects. This review proposes both a physiological and pathological model of TWEAK-Fn14 signaling. Further research is needed on the switch between these states to develop therapeutic interventions for this pathway.
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Affiliation(s)
- Amy L Pascoe
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Amelia J Johnston
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia
| | - Robyn M Murphy
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, 3086, Australia.
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Kiliç F, Işik Ü, Usta A, Demirdaş A. Serum tumor necrosis factor-like weak inducer of apoptosis levels are elevated in schizophrenia. ACTA ACUST UNITED AC 2020; 43:242-246. [PMID: 32785454 PMCID: PMC8136394 DOI: 10.1590/1516-4446-2020-0950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 04/02/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE The purpose of this study was to assess serum Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) concentrations to determine whether changes in patients with schizophrenia could have etiopathogenetic importance. Since very little research has addressed the connection between the inflammatory marker TWEAK and schizophrenia, we wanted to examine alterations of TWEAK and investigate the possible correlation between clinical symptomatology and serum concentrations. METHODS A total of 45 schizophrenia patients and 40 healthy controls were included in this study. The Positive Symptom Assessment scale and the Negative Symptom Assessment scale were administered to determine symptom severity. Venous blood samples were collected and serum TWEAK levels were measured. RESULTS Serum TWEAK levels were significantly higher in the schizophrenia group than the control group, independently of potential confounders, including sex, age, body mass index and smoking status. CONCLUSION The results indicate that TWEAK is elevated in schizophrenia patients, which could deepen our understanding of the role of inflammation in the pathogenesis of schizophrenia.
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Affiliation(s)
- Faruk Kiliç
- Department of Psychiatry, Süleyman Demirel University Medicine Faculty, Isparta, Turkey
| | - Ümit Işik
- Department of Child and Adolescent Psychiatry, Süleyman Demirel University Medicine Faculty, Isparta, Turkey
| | - Ayşe Usta
- Department of Psychiatry, Süleyman Demirel University Medicine Faculty, Isparta, Turkey
| | - Arif Demirdaş
- Department of Psychiatry, Süleyman Demirel University Medicine Faculty, Isparta, Turkey
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So J, Kim A, Lee SH, Shin D. Liver progenitor cell-driven liver regeneration. Exp Mol Med 2020; 52:1230-1238. [PMID: 32796957 PMCID: PMC8080804 DOI: 10.1038/s12276-020-0483-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/08/2020] [Accepted: 06/17/2020] [Indexed: 12/28/2022] Open
Abstract
The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Angie Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Yin Y, Kong D, He K, Xia Q. Regeneration and activation of liver progenitor cells in liver cirrhosis. Genes Dis 2020; 8:623-628. [PMID: 34291133 PMCID: PMC8278536 DOI: 10.1016/j.gendis.2020.07.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/20/2020] [Accepted: 07/31/2020] [Indexed: 12/27/2022] Open
Abstract
Cirrhosis is characterized as the progress of regenerative nodules surrounded by fibrous bands in response to chronic hepatic injury and causes portal hypertension and end-stage hepatic disease. Following liver injury, liver progenitor cells (LPCs) can be activated and differentiate into hepatocytes in order to awaken liver regeneration and reach homeostasis. Recent research has uncovered some new sources of LPCs. Here, we update the mechanisms of LPCs-mediated liver regeneration in cirrhosis by introducing the origin of LPCs and LPCs’ niche with a discussion of the influence of LPC-related cells. This article analyzes the mechanism of regeneration and activation of LPCs in cirrhosis in recent years aiming to provide help for clinical application.
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Affiliation(s)
- Yanze Yin
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Defu Kong
- Department of Hepatology & Gastroenterology, University Medical Center Groningen, Groningen, 9713, the Netherlands
| | - Kang He
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200240, PR China
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