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Gad El-Hak HN, Kishk SM, Abdelrazek HMA. Evening primrose oil enriched with gamma linolenic acid and D/L-alpha tocopherol acetate attenuated carbon tetrachloride-induced hepatic injury model in male rats via TNF-α, IL-1β, and IL-6 pathway. Toxicol Mech Methods 2024; 34:469-483. [PMID: 38166523 DOI: 10.1080/15376516.2023.2301357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 12/28/2023] [Indexed: 01/04/2024]
Abstract
The modulatory role of primrose oil (PO) supplementation enriched with γ-linolenic acid and D/L-alpha tocopherol acetate against a carbon tetrachloride (CCl4)-induced liver damage model was assessed in this study. Twenty male Albino rats were divided into four groups. The control group received corn oil orally. The PO group received 10 mg/kg P O orally. The CCl4 group received 2 mL/kg CCl4 orally and PO/CCl4 group; received PO and 2 mL/kg CCl4 orally. The relative liver weight was recorded. Serum liver enzymes, hepatic malondialdehyde (MDA), hepatic reduced glutathione (GSH) and the expression of hepatic tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) were assessed. The binding affinities of γ-linolenic acid and D/L-alpha tocopherol constituents with IL-1β, IL-6 and TNF-α were investigated using molecular docking simulations. Histopathological and electron microscopic examinations of the liver were performed. The results indicated that CCl4 elevated serum liver enzyme and hepatic MDA levels, whereas GSH levels were diminished. The upregulation of IL-1β, IL-6, and TNF-α gene expressions were induced by CCl4 treatment. The PO/CCl4-treated group showed amelioration of hepatic injury biomarkers and oxidative stress. Restoration of histopathological and ultrastructural alterations while downregulations the gene expressions of TNF-α, IL1-β and IL-6 were observed. In conclusion, evening primrose oil enriched with γ-linolenic acid and D/L-alpha tocopherol acetate elicited a potential amelioration of CCl4-induced hepatic toxicity.
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Affiliation(s)
| | - Safaa M Kishk
- Department of Medicinal Chemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Heba M A Abdelrazek
- Department of Physiology, Faculty of Veterinary Medicine, Suez Canal University, Ismailia, Egypt
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Liu Q, Lei X, Cao Z, Zhang J, Yan L, Fu J, Tong Q, Qin W, Shao Y, Liu C, Liu Z, Wang Z, Chu Y, Xu G, Liu S, Wen X, Yamamoto H, Mori M, Liang XM, Xu X. TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling. Cell Biosci 2022; 12:58. [PMID: 35525986 PMCID: PMC9080211 DOI: 10.1186/s13578-022-00789-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 04/18/2022] [Indexed: 12/03/2022] Open
Abstract
Background Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect of TRPM8 in liver fibrosis. Methods The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8−/− (KO) fibrotic mice after carbon tetrachloride (CCl4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments. Results Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4α expressions were observed in liver of CCl4- and BDL- treated TRPM8−/− mice. A strong regulatory linkage between S100A9 and HNF4α was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo. Conclusions These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s13578-022-00789-4.
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An CZ, Li CQ, Song LB, He YF, Chen W, Liu B, Zhao YD. A simple fluorescent strategy for liver capillary labeling with carbon quantum dot-lectin nanoprobe. Analyst 2022; 147:1952-1960. [DOI: 10.1039/d1an02364k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Based on lycopersicon esculentum lectin that can target vascular endothelial cells and carbon quantum dots, we designed a carbon-based probe for the fluorescence labeling and imaging of hepatic blood vessels of liver tissue sections.
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Affiliation(s)
- Chang-Zhi An
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Chao-Qing Li
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Lai-Bo Song
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Yan-Fei He
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Wei Chen
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Bo Liu
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
| | - Yuan-Di Zhao
- Britton Chance Center for Biomedical Photonics at Wuhan National Laboratory for Optoelectronics-Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
- Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, Hubei, P. R. China
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Kanikarla Marie P, Fowlkes NW, Afshar-Kharghan V, Martch SL, Sorokin A, Shen JP, Morris VK, Dasari A, You N, Sood AK, Overman MJ, Kopetz S, Menter DG. The Provocative Roles of Platelets in Liver Disease and Cancer. Front Oncol 2021; 11:643815. [PMID: 34367949 PMCID: PMC8335590 DOI: 10.3389/fonc.2021.643815] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Both platelets and the liver play important roles in the processes of coagulation and innate immunity. Platelet responses at the site of an injury are rapid; their immediate activation and structural changes minimize the loss of blood. The majority of coagulation proteins are produced by the liver—a multifunctional organ that also plays a critical role in many processes: removal of toxins and metabolism of fats, proteins, carbohydrates, and drugs. Chronic inflammation, trauma, or other causes of irreversible damage to the liver can dysregulate these pathways leading to organ and systemic abnormalities. In some cases, platelet-to-lymphocyte ratios can also be a predictor of disease outcome. An example is cirrhosis, which increases the risk of bleeding and prothrombotic events followed by activation of platelets. Along with a triggered coagulation cascade, the platelets increase the risk of pro-thrombotic events and contribute to cancer progression and metastasis. This progression and the resulting tissue destruction is physiologically comparable to a persistent, chronic wound. Various cancers, including colorectal cancer, have been associated with increased thrombocytosis, platelet activation, platelet-storage granule release, and thrombosis; anti-platelet agents can reduce cancer risk and progression. However, in cancer patients with pre-existing liver disease who are undergoing chemotherapy, the risk of thrombotic events becomes challenging to manage due to their inherent risk for bleeding. Chemotherapy, also known to induce damage to the liver, further increases the frequency of thrombotic events. Depending on individual patient risks, these factors acting together can disrupt the fragile balance between pro- and anti-coagulant processes, heightening liver thrombogenesis, and possibly providing a niche for circulating tumor cells to adhere to—thus promoting both liver metastasis and cancer-cell survival following treatment (that is, with minimal residual disease in the liver).
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Affiliation(s)
- Preeti Kanikarla Marie
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Natalie W Fowlkes
- Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Vahid Afshar-Kharghan
- Division of Internal Medicine, Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Stephanie L Martch
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Nancy You
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - David George Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Jo HS, Han JH, Choi YY, Seok JI, Yoon YI, Kim DS. The beneficial impacts of splanchnic vasoactive agents on hepatic functional recovery in massive hepatectomy porcine model. Hepatobiliary Surg Nutr 2021; 10:325-336. [PMID: 34159160 DOI: 10.21037/hbsn.2019.11.31] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Background Excessive portal pressure after massive hepatectomy can cause hepatic sinusoidal injury and have deleterious impacts on hepatic functional recovery, contributing to developing post-hepatectomy liver failure. This study aimed to assess the effects of splanchnic vasoactive agents on hepatic functional recovery and regeneration while clarifying the underlying mechanism, using a 70% hepatectomy porcine model. Methods Eighteen pigs undergoing 70% hepatectomy were involved in this study and divided into three groups: control (n=6), terlipressin (n=6), and octreotide (n=6). Terlipressin (0.5 mg) and octreotide (0.2 mg) were administered 3 times a day for each group with the first dose starting just before surgery until the 7th postoperative day, at which time the surviving pigs were sacrificed. During the period, portal pressure, liver weight, biochemical analysis, histological injury score, and molecular markers were evaluated and compared between groups. Results The 7-day survival rates in the octreotide, terlipressin, and control groups were 100%, 83.3%, and 66.7%, respectively. The portal pressures decreased in both terlipressin and octreotide groups than the control group at 30 minutes, 1 hour and 6 hours after hepatectomy. The amount of regeneration measured by liver weight to body weight ratio at the time of sacrifice in the terlipressin group was smaller than that in the control group (117% vs. 129%, P=0.03). Serum aspartate aminotransferase (AST) and total bilirubin levels at 1 and 6 hours after hepatectomy and prothrombin time/international normalized ratio (PT/INR) at 6 hours after hepatectomy were significantly improved in the terlipressin and octreotide groups compared to the control group. Serum endothelin-1 (ET-1) was significantly lower in the terlipressin group than that in the control group 6 hours after hepatectomy (P<0.01). The histological injury score in the control group was significantly higher than that in the terlipressin group on the 7th postoperative day (P<0.01). Conclusions Splanchnic vasoactive agents, such as terlipressin and octreotide, could effectively decrease portal pressure and attenuate liver injury after massive hepatectomy.
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Affiliation(s)
- Hye-Sung Jo
- Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Jae Hyun Han
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yoon Young Choi
- Department of Biomedical Science, Korea University College of Medicine Graduate School, Seoul, Republic of Korea
| | - Jin-I Seok
- Department of Biomedical Science, Korea University College of Medicine Graduate School, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Dong-Sik Kim
- Division of HBP Surgery and Liver Transplantation, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
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Ishikawa J, Takeo M, Iwadate A, Koya J, Kihira M, Oshima M, Suzuki Y, Taniguchi K, Kobayashi A, Tsuji T. Mechanical homeostasis of liver sinusoid is involved in the initiation and termination of liver regeneration. Commun Biol 2021; 4:409. [PMID: 33828226 PMCID: PMC8027462 DOI: 10.1038/s42003-021-01936-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 02/23/2021] [Indexed: 12/12/2022] Open
Abstract
Organogenesis and regeneration are fundamental for developmental progress and are associated with morphogenesis, size control and functional properties for whole-body homeostasis. The liver plays an essential role in maintaining homeostasis of the entire body through various functions, including metabolic functions, detoxification, and production of bile, via the three-dimensional spatial arrangement of hepatic lobules and has high regenerative capacity. The regeneration occurs as hypertrophy, which strictly controls the size and lobule structure. In this study, we established a three-dimensional sinusoidal network analysis method and determined valuable parameters after partial hepatectomy by comparison to the static phase of the liver. We found that mechanical homeostasis, which is crucial for organ morphogenesis and functions in various phenomena, plays essential roles in liver regeneration for both initiation and termination of liver regeneration, which is regulated by cytokine networks. Mechanical homeostasis plays critical roles in the initiation and termination of organogenesis, tissue repair and organ regeneration in coordination with cytokine networks.
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Affiliation(s)
- Jun Ishikawa
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Hyogo, Japan
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Makoto Takeo
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Hyogo, Japan
| | - Ayako Iwadate
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Junko Koya
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Miho Kihira
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Masamitsu Oshima
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Hyogo, Japan
- Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Yuki Suzuki
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Kazushi Taniguchi
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Ayaka Kobayashi
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan
| | - Takashi Tsuji
- Laboratory for Organ Regeneration, RIKEN Center for Developmental Biology (CDB) and RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Hyogo, Japan.
- Department of Biological Science and Technology, Graduate School of Industrial Science and Technology, Tokyo University of Science, Noda, Chiba, Japan.
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Kitto LJ, Henderson NC. Hepatic Stellate Cell Regulation of Liver Regeneration and Repair. Hepatol Commun 2021; 5:358-370. [PMID: 33681672 PMCID: PMC7917274 DOI: 10.1002/hep4.1628] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/22/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver regeneration. As our knowledge of the cellular and molecular mechanisms driving hepatic regeneration deepens, the key role of the mesenchymal compartment during the regenerative response has been increasingly appreciated. Single-cell genomics approaches have recently uncovered both spatial and functional zonation of the hepatic mesenchyme in homeostasis and following liver injury. Here we discuss how the use of preclinical models, from in vivo mouse models to organoid-based systems, are helping to shape our understanding of the role of the mesenchyme during liver regeneration, and how these approaches should facilitate the precise identification of highly targeted, pro-regenerative therapies for patients with liver disease.
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Affiliation(s)
- Laura J. Kitto
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUnited Kingdom
| | - Neil C. Henderson
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUnited Kingdom
- MRC Human Genetics UnitInstitute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
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Lu J, Zhao YL, Zhang XQ, Li LJ. The vascular endothelial growth factor signaling pathway regulates liver sinusoidal endothelial cells during liver regeneration after partial hepatectomy. Expert Rev Gastroenterol Hepatol 2021; 15:139-147. [PMID: 32902336 DOI: 10.1080/17474124.2020.1815532] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver regeneration after partial hepatectomy is a very complex and well-regulated procedure. It utilizes all liver cell types, which are associated with signaling pathways involving growth factors, cytokines, and stimulatory and inhibitory feedback of several growth-related signals. Liver sinusoidal endothelial cells (LSECs) contribute to liver regeneration after partial hepatectomy. Vascular endothelial growth factor (VEGF) has various functions in LSECs. In this review, we summarize the relationship between VEGF and LSECs involving VEGF regulatory activity in the vascular endothelium. AREAS COVERED Maintenance of the fenestrated LSEC phenotype requires two VEGF pathways: VEGF stimulated-NO acting through the cGMP pathway and VEGF independent of nitric oxide (NO). The results suggest that VEGF is a key regenerating mediator of LSECs in the partial hepatectomy model. NO-independent pathway was also essential to the maintenance of the LSEC in liver regeneration. EXPERT OPINION Liver regeneration remains a fascinating and significative research field in recent years. The liver involved of molecular pathways except for LSEC-VEGF pathways that make the field of liver further depth studies should be put into effect to elaborate the undetermined confusions, which will be better to understand liver regeneration.
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Affiliation(s)
- Juan Lu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Ya-Lei Zhao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Xiao-Qian Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
| | - Lan-Juan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital of Medicine School, Zhejiang University , Hangzhou, China
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Mak KM, Shin DW. Hepatic sinusoids versus central veins: Structures, markers, angiocrines, and roles in liver regeneration and homeostasis. Anat Rec (Hoboken) 2020; 304:1661-1691. [PMID: 33135318 DOI: 10.1002/ar.24560] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 10/14/2020] [Accepted: 10/22/2020] [Indexed: 01/20/2023]
Abstract
The blood circulates through the hepatic sinusoids delivering nutrients and oxygen to the liver parenchyma and drains into the hepatic central vein, yet the structures and phenotypes of these vessels are distinctively different. Sinusoidal endothelial cells are uniquely fenestrated, lack basal lamina and possess organelles involved in endocytosis, pinocytosis, degradation, synthesis and secretion. Hepatic central veins are nonfenestrated but are also active in synthesis and secretion. Endothelial cells of sinusoids and central veins secrete angiocrines that play respective roles in hepatic regeneration and metabolic homeostasis. The list of markers for identifying sinusoidal endothelial cells is long and their terminologies are complex. Further, their uses vary in different investigations and, in some instances, could be confusing. Central vein markers are fewer but more distinctive. Here we analyze and categorize the molecular pathways/modules associated with the sinusoid-mediated liver regeneration in response to partial hepatectomy and chemical-induced acute or chronic injury. Similarly, we highlight the findings that central vein-derived angiocrines interact with Wnt/β-catenin in perivenous hepatocytes to direct gene expression and maintain pericentral metabolic zonation. The proposal that perivenous hepatocytes behave as stem/progenitor cells to provoke hepatic homeostatic cell renewal is reevaluated and newer concepts of broad zonal distribution of hepatocyte proliferation in liver homeostasis and regeneration are updated. Thus, this review integrates the structures, biology and physiology of liver sinusoids and central veins in mediating hepatic regeneration and metabolic homeostasis.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Da Wi Shin
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Tsomaia K, Patarashvili L, Karumidze N, Bebiashvili I, Azmaipharashvili E, Modebadze I, Dzidziguri D, Sareli M, Gusev S, Kordzaia D. Liver structural transformation after partial hepatectomy and repeated partial hepatectomy in rats: A renewed view on liver regeneration. World J Gastroenterol 2020; 26:3899-3916. [PMID: 32774065 PMCID: PMC7385567 DOI: 10.3748/wjg.v26.i27.3899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 05/12/2020] [Accepted: 06/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The phenomenon of liver regeneration after partial hepatectomy (PH) is still a subject of considerable interest due to the increasing frequency of half liver transplantation on the one hand, and on the other hand, new surgical approaches which allow removal of massive space-occupying hepatic tumors, which earlier was considered as inoperable. Interestingly, the mechanisms of liver regeneration are extensively studied after PH but less attention is paid to the architectonics of the regenerated organ. Because of this, the question "How does the structure of regenerated liver differ from normal, regular liver?" has not been fully answered yet. Furthermore, almost without any attention is left the liver's structural transformation after repeated hepatectomy (of the re-regenereted liver). AIM To compare the architectonics of the lobules and circulatory bed of normal, re-generated and re-regenerated livers. METHODS The livers of 40 adult, male, albino Wistar rats were studied. 14 rats were subjected to PH - the 1st study group (SG1); 10 rats underwent repeated PH - the 2nd study group (SG2); 16 rats were subjected to sham operation - control group (CG); The livers were studied after 9 months from PH, and after 6 months from repeated PH. Cytological (Schiff reaction for the determination of DNA concen-tration), histological (H&E, Masson trichrome, CK8 Immunohistochemical marker, transparent slides after Indian Ink injection, ), morphometrical (hepatocytes areas, perimeters and ploidy) and Electron Microscopical (Scanning Electron Microscopy of corrosion casts) methods were used. RESULTS In the SG1 and SG2, the area of hepatocytes and their perimeter are increased compared to the CG (P < 0.05). However, the areas and perimeters of the hepatocytes of the SG1 and SG2 groups reveal a lesser difference. In regenerated (SG1) and re-regenerated (SG2) livers, the hepatocytes form the remodeled lobules, which size (300-1200 µm) exceeds the sizes of the lobules from CG (300-600 µm). The remodeled lobules (especially the "mega-lobules" with the sizes 1000-1200 µm) contain the transformed meshworks of the sinusoids, the part of which is dilated asymmetrically. This meshwork might have originated from the several portal venules (interlobular and/or inlet). The boundaries between the adjacent lobules (including mega-lobules) are widened and filled by connective tissue fibers, which gives the liver parenchyma a nodular look. In SG2 the unevenness of sinusoid diameters, as well as the boundaries between the lobules (including the mega-lobules) are more vividly expressed in comparison with SG1. The liver tissue of both SG1 and SG2 is featured by the slightly expressed ductular reaction. CONCLUSION Regenerated and re-regenerated livers in comparison with normal liver contain hypertrophied hepatocytes with increased ploidy which together with transformed sinusoidal and biliary meshworks form the remodeled lobulli.
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Affiliation(s)
- Keti Tsomaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Leila Patarashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Nino Karumidze
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irakli Bebiashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Elza Azmaipharashvili
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
| | - Irina Modebadze
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Diana Dzidziguri
- Faculty of Exact and Natural Sciences, Ivane Javakhishvili Tbilisi State University, Tbilisi 0179, Georgia
| | - Marom Sareli
- Department of Surgical Oncology (Surgery C), Chaim Sheba Medical Center at HaShomer, Tel Aviv 52621, Israel
| | - Sergey Gusev
- Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow 119435, Russia
| | - Dimitri Kordzaia
- Faculty of Medicine, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
- Clinical Anatomy and Operative Surgery, Ivane Javakhishvili Tbilisi State University, Tbilisi 0159, Georgia
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12
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13
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Wu Y, Feng W, Liu R, Xia T, Liu S. Graphene Oxide Causes Disordered Zonation Due to Differential Intralobular Localization in the Liver. ACS NANO 2020; 14:877-890. [PMID: 31891481 DOI: 10.1021/acsnano.9b08127] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
The liver is the primary organ to sequester nanodrugs, representing a substantial hurdle for drug delivery and raising toxicity concerns. However, the mechanistic details underlying the liver sequestration and effects on the liver are still elusive. The difficulty in studying the liver lies in its complexity, which is structured with stringently organized anatomical units called lobules. Graphene oxide (GO) has attracted attention for its applications in biomedicine, especially as a nanocarrier; however, its sequestration and effects in the liver, the major enrichment and metabolic organ, are less understood. Herein, we unveiled the differential distribution of GO in lobules in the liver, with a higher amount surrounding portal triad zones than the central vein zones. Strikingly, liver zonation patterns also changed, as reflected by changes in vital zonated genes involved in hepatocyte integrity and metabolism, leading to compromised hepatic functions. RNA-Seq and DNA methylation sequencing analyses unraveled that GO-induced changes in liver functional zonation could be ascribed to dysregulation of key signaling pathways governing liver zonation at not only mRNA transcriptions but also DNA methylation imprinting patterns, partially through TET-dependent signaling. Together, this study reveals the differential GO distribution pattern in liver lobules and pinpoints the genetic and epigenetic mechanisms in GO-induced liver zonation alterations.
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Affiliation(s)
- Yakun Wu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology , Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Wenya Feng
- State Key Laboratory of Environmental Chemistry and Ecotoxicology , Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Rui Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology , Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
| | - Tian Xia
- Division of Nanomedicine, Department of Medicine, California NanoSystems Institute , University of California , Los Angeles , California 90095 , United States
| | - Sijin Liu
- State Key Laboratory of Environmental Chemistry and Ecotoxicology , Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences , Beijing 100085 , China
- University of Chinese Academy of Sciences , Beijing 100049 , China
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14
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Tan RJ, Li Y, Rush BM, Cerqueira DM, Zhou D, Fu H, Ho J, Beer Stolz D, Liu Y. Tubular injury triggers podocyte dysfunction by β-catenin-driven release of MMP-7. JCI Insight 2019; 4:e122399. [PMID: 31743113 PMCID: PMC6975262 DOI: 10.1172/jci.insight.122399] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 11/14/2019] [Indexed: 01/19/2023] Open
Abstract
Proteinuric chronic kidney disease (CKD) remains a major health problem worldwide. While it is well established that the progression of primary glomerular disease induces tubulointerstitial lesions, how tubular injury triggers glomerular damage is poorly understood. We hypothesized that injured tubules secrete mediators that adversely affect glomerular health. To test this, we used conditional knockout mice with tubule-specific ablation of β-catenin (Ksp-β-cat-/-) and subjected them to chronic angiotensin II (Ang II) infusion or Adriamycin. Compared with control mice, Ksp-β-cat-/- mice were dramatically protected from proteinuria and glomerular damage. MMP-7, a downstream target of β-catenin, was upregulated in treated control mice, but this induction was blunted in the Ksp-β-cat-/- littermates. Incubation of isolated glomeruli with MMP-7 ex vivo led to nephrin depletion and impaired glomerular permeability. Furthermore, MMP-7 specifically and directly degraded nephrin in cultured glomeruli or cell-free systems, and this effect was dependent on its proteolytic activity. In vivo, expression or infusion of exogenous MMP-7 caused proteinuria, and genetic ablation of MMP-7 protected mice from Ang II-induced proteinuria and glomerular injury. Collectively, these results demonstrate that β-catenin-driven MMP-7 release from renal tubules promotes glomerular injury via direct degradation of the key slit diaphragm protein nephrin.
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Affiliation(s)
| | | | | | - Débora Malta Cerqueira
- Division of Pediatric Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | | | - Haiyan Fu
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jacqueline Ho
- Division of Pediatric Nephrology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Donna Beer Stolz
- Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Youhua Liu
- Department of Pathology, and
- Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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15
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Xie C, Liu G, Li M, Fang Y, Qian K, Tang Y, Wu X, Lei X, Li X, Liu Q, Liu G, Liu J, Zhang Y, Huang Z, Hu Z, Cao Z, Hu J, Huang S, Zhong D, Huang J, Wu F, Wang J, Mori M, Yamamoto H, Wang J, Xu X. Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma. Biomed Pharmacother 2019; 118:109270. [PMID: 31401394 DOI: 10.1016/j.biopha.2019.109270] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 07/15/2019] [Accepted: 07/25/2019] [Indexed: 11/16/2022] Open
Abstract
The landscape of cellular plasticity and sources with relevant niche signals in hepatocellular carcinoma is still obscure. Transient receptor potential vanilloid 1 (TRPV1), a non-selective cation channel, is involved in a variety of malignancies and overexpressed in hepatocellular carcinoma (HCC). We have investigated the role of TRPV1 in HCC from different angles by various experimental techniques, such as in vivo and in vitro experiments, and by bioinformatics analysis of data from genetic models induced by diethylnitrosamine (DEN), mice samples and human HCC samples. We find that TRPV1 knockout promotes to hepatocarcinogenesis and deconstructs the portal triad adjacent to tumor border that is contributed by originations of tumor initiating cells and biliary cells. Epithelial to mesenchymal transition (EMT) is involved and transcription factors Ovol2 and Zeb1 coordinated with Sox 10 drive gene expression in the event which is also confirmed by the expression of these proteins in human HCC samples. Treatment with TRPV1 agonist Capsaicin inhibits the growth of HCC cells in xenograft models. Our findings demonstrate that TRPV1 is a potential therapeutic target in human HCC and exerts effects on cellular plasticity with modulation of Ovol2, Zeb1 and Sox10.
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Affiliation(s)
- Chengzhi Xie
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China; Department of General Surgery, The Second Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan Province, 410005, China.
| | - Guoxing Liu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Min Li
- Department of computer science and technology, School of Information Science and Engineering, Central South University, Changsha, Hunan Province, 410083, China.
| | - Yu Fang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Ke Qian
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Yu Tang
- Department of computer science and technology, School of Information Science and Engineering, Central South University, Changsha, Hunan Province, 410083, China.
| | - Xiaolong Wu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Xiaohua Lei
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Xiaocheng Li
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Qiang Liu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Gao Liu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Jiefeng Liu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Yueming Zhang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Zhao Huang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Zecheng Hu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Zhenyu Cao
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Jixiong Hu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Shengfu Huang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Dewu Zhong
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Jiangsheng Huang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
| | - Fangxiang Wu
- Department of computer science and technology, School of Information Science and Engineering, Central South University, Changsha, Hunan Province, 410083, China; Division of Biomedical Engineering, Department of Mechanical Engineering, College of Engineering, University of Saskatchewan, 57 Campus Dr., Saskatoon, SK Canada, Canada.
| | - Jun Wang
- Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, 77030, USA.
| | - Masaki Mori
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China; Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, 565-0871, Japan.
| | - Hirofumi Yamamoto
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China; Department of Surgery, Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2, Suita City, Osaka, 565-0871, Japan.
| | - Jianxin Wang
- Department of computer science and technology, School of Information Science and Engineering, Central South University, Changsha, Hunan Province, 410083, China.
| | - Xundi Xu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The 2ndXiangya Hospital, Central South University, Changsha, Hunan Province, 410011, China.
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16
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Wang X, Maretti-Mira AC, Wang L, DeLeve LD. Liver-Selective MMP-9 Inhibition in the Rat Eliminates Ischemia-Reperfusion Injury and Accelerates Liver Regeneration. Hepatology 2019; 69:314-328. [PMID: 30019419 PMCID: PMC6325019 DOI: 10.1002/hep.30169] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 07/03/2018] [Indexed: 12/22/2022]
Abstract
Recruitment of liver sinusoidal endothelial cell progenitor cells (sprocs) from the bone marrow by vascular endothelial growth factor-stromal cell-derived factor-1 (VEGF-sdf-1) signaling promotes recovery from injury and drives liver regeneration. Matrix metalloproteinases (MMPs) can proteolytically cleave VEGF, which might inhibit progenitor cell recruitment, but systemic matrix metalloproteinase inhibition might prevent efflux of progenitors from the bone marrow. The hypothesis for this study was that liver-selective MMP-9 inhibition would protect the hepatic VEGF-sdf-1 signaling pathway, enhance bone marrow sproc recruitment, and thereby ameliorate liver injury and accelerate liver regeneration, whereas systemic MMP inhibition would impair bone marrow sproc mobilization and therefore have less benefit or be detrimental. We found that liver-selective MMP-9 inhibition accelerated liver regeneration after partial hepatectomy by 40%, whereas systemic MMP inhibition impaired liver regeneration. Liver-selective MMP-9 inhibition largely abolished warm ischemia-reperfusion injury. In the extended hepatectomy model, liver-selective MMP-9 inhibition restored liver sinusoidal endothelial cell integrity, enhanced liver regeneration, and reduced ascites. Liver-selective MMP-9 inhibition markedly increased recruitment and engraftment of bone marrow sprocs, whereas systemic MMP inhibition impaired mobilization of bone marrow sprocs and their hepatic engraftment. Hepatic MMP-9 proteolytically cleaved VEGF after partial hepatectomy. Liver-selective MMP-9 inhibition prevented VEGF cleavage and doubled protein expression of VEGF and its downstream signaling partner sdf-1. In contrast, systemic MMP inhibition enhanced recruitment and engraftment of infused allogeneic progenitors. Conclusion: Liver-selective MMP inhibition prevents proteolytic cleavage of hepatic VEGF, which enhances recruitment and engraftment of bone marrow sprocs after liver injury. This ameliorates injury and accelerates liver regeneration. Liver-selective MMP-9 inhibition may be a therapeutic tool for liver injury that damages the vasculature, whereas systemic MMP inhibition can enhance the benefit of stem cell therapy with endothelial progenitor cells.
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Affiliation(s)
| | | | - Lei Wang
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
| | - Laurie D. DeLeve
- USC Division of Gastrointestinal and Liver Disease and the USC Research Center for Liver Disease, Keck Medicine of USC Los Angeles CA
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17
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Elevated ADAMTS13 Activity is Associated with Poor Postoperative Outcome in Patients Undergoing Liver Resection. Sci Rep 2018; 8:16823. [PMID: 30429491 PMCID: PMC6235878 DOI: 10.1038/s41598-018-34794-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 10/19/2018] [Indexed: 02/08/2023] Open
Abstract
Recently, von-Willebrand-Factor (vWF) has been shown to correlate with postoperative liver dysfunction (LD). Accordingly, “disintegrin-like metalloprotease with thrombospondin type1 motif” (ADAMTS13) is known to cleave vWF in less active fragments. Thus, we aimed to evaluate the diagnostic potential of ADAMTS13-activity (ADAMTS13-AC) to identify patients with postoperative LD after hepatectomy. Accordingly 37 patients undergoing hepatectomy for different neoplastic entities were included in this study. Plasma ADAMTS13-AC and vWF-Ag were measured 1 day prior to (preOP), 1 and 5 days (POD1/5) after hepatectomy. In accordance to the ISGLS-criteria LD was prospectively recorded. In this context, perioperative ADAMTS13-AC- and vWF-Ag/ADAMTS13-AC-ratio- levels revealed a significant increase after hepatectomy. Accordingly, elevated vWF-Ag/ADAMTS13-AC-ratio significantly predicted LD (preOP AUC: 0.75, p = 0.02; POD1 AUC: 0.80, p = 0.03). Patients who fulfilled our perioperative vWF-Ag/ADAMTS13-AC-ratio cut-off-levels (preOP: ≥116, POD1: ≥165) suffered from significantly higher incidences of LD (preOP: 70% vs. 30%, p = 0.01; POD1: 83% vs. 17%, p = 0.001). In conclusion, perioperative ADAMTS13-AC measurement may serve as a useful parameter to early detect high-risk patients developing postoperative LD prior to liver resection in patients suffering from hepatic malignancies. Indeed, further investigations have to be performed to consolidate its role as a predictive marker for LD.
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18
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Ray S, Mehta N, Golhar A, Nundy S. Post hepatectomy liver failure - A comprehensive review of current concepts and controversies. Ann Med Surg (Lond) 2018; 34:4-10. [PMID: 30181871 PMCID: PMC6120608 DOI: 10.1016/j.amsu.2018.08.012] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 07/24/2018] [Accepted: 08/14/2018] [Indexed: 02/06/2023] Open
Abstract
Post hepatectomy liver failure (PHLF) comprises of a conundrum of symptoms and signs following major hepatic resections. The pathophysiology essentially revolves around disruption of the normal hepatocyte regeneration and disturbed liver homeostasis. Prompt identification of the pre-operative predictors of PHLF in the form of biochemical parameters and imaging features are of paramount importance for any hepatic surgeon and forms the cornerstone of its management. Treatment revolves around a goal-directed resuscitation of the systemic organ failure. Auxiliary support systems such as liver dialysis devices and stem cell therapy are still under investigational trials for treatment of the same. Orthotopic liver transplantation (OLT) is the last resort in most cases not responding to other measures.
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Affiliation(s)
- S. Ray
- Department of Surgical Gastroenterology and Liver Transplantation, Sir Ganga Ram Hospital, New Delhi, India
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19
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Li W, Zhang G, Guan T, Zhang X, Khosrozadeh A, Xing M, Kong J. Manipulable Permeability of Nanogel Encapsulation on Cells Exerts Protective Effect against TNF-α-Induced Apoptosis. ACS Biomater Sci Eng 2018; 4:2825-2835. [DOI: 10.1021/acsbiomaterials.8b00654] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
| | - Guohui Zhang
- Department of Forensic Medicine, Hebei North University, Zhangjiakou 075000, China
| | | | | | | | | | - Jiming Kong
- Department of Forensic Medicine, Hebei North University, Zhangjiakou 075000, China
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20
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de Lazari MGT, Pereira LX, Viana CTR, Orellano LAA, de Almeida SA, Vasconcelos AC, Ribeiro GB, Couto LC, Andrade SP, Campos PP. Induction of liver proliferation using a polymeric platform in mice. Life Sci 2018; 193:226-233. [PMID: 29097158 DOI: 10.1016/j.lfs.2017.10.040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/17/2017] [Accepted: 10/29/2017] [Indexed: 11/25/2022]
Abstract
AIMS Currently, animal models of liver regeneration are based on extensive lesions of the native organ and on cellular approaches using biomaterials to host growth factors and extracellular components to create artificial liver systems. We report a polymeric biological platform, minimally invasive, that induced sequential proliferation of liver parenchyma inside the scaffold in mice. MAIN METHODS Porous discs of polyether-polyurethane were surgically placed under the left liver lobe and removed at days 4, 8, 12 and 25 after implantation. No exogenous growth factors or extracellular matrix components were added to the scaffold. Histological analysis of the implants was performed to identify hepatocytes, liver vascular structures and bile ducts in the newly formed tissue. In addition, systemic markers for hepatic function were determined. KEY FINDINGS This biohybrid device provided a scaffold that was gradually filled with parenchymal and non-parenchymal liver tissue as detected by histological analysis. At day 4, the pores of the scaffold were filled with inflammatory cells and spindled-shaped like fibroblasts, and extracellular matrix components. At day 8, hepatocytes clusters, central lobular hepatic veins, portal space containing arteries, veins and biliary ducts were detected. By days 12 and 25 a liver-like structure filled 2/3 of the scaffold. Its organization resembled that of a mature liver. Serum concentration of ALT increased three-fold initially after implantation, returning gradually to control levels. SIGNIFICANCE The plain synthetic scaffold (without addition of exogenous molecules) placed under the intact left liver lobe exhibits the potential to investigate physiological mechanisms that regulate liver parenchyma proliferation.
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Affiliation(s)
| | - Luciana Xavier Pereira
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Celso Tarso Rodrigues Viana
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Laura Alejandra Ariza Orellano
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Simone Aparecida de Almeida
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anilton Cesar Vasconcelos
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Giani Barbosa Ribeiro
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Leticia Chinait Couto
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Silvia Passos Andrade
- Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Paula Peixoto Campos
- Department of General Pathology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
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21
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Marlini M, Mabuchi A, Mallard BL, Hairulhisyam N, Akashi-Takamura S, Harper JL, Wheatley AM. Delayed liver regeneration in C3H/HeJ mice: possible involvement of haemodynamic and structural changes in the hepatic microcirculation. Exp Physiol 2018; 101:1492-1505. [PMID: 27634415 DOI: 10.1113/ep085727] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 09/09/2016] [Indexed: 12/16/2022]
Abstract
NEW FINDINGS What is the central question of this study? The liver regenerative process is complex and involves a sequence of signalling events, but the possible involvement of structural and haemodynamic changes in vivo during this process has never been explored. What is the main finding and its importance? Normal sinusoidal blood flow and velocity are crucial for a normal regenerative response, and delays in these haemodynamic events resulted in impaired liver regeneration in lipopolysaccharide-insensitive, C3H/HeJ mice. Toll-like receptor 4 signalling is required for restoration of normal liver architecture during the liver regenerative process. Liver regeneration is delayed in mice with a defective Toll-like receptor 4 (TLR4; C3H/HeJ mice) but is normal in TLR4 knockouts (TLR4-/- ). Here, we investigated the possible involvement of structural and haemodynamic changes in vivo in the underlying mechanism. In lipopolysaccharide-sensitive (C3H/HeN and C57BL/6) and lipopolysaccharide-insensitive (C3H/HeJ and TLR4-/- ) mice, a 70% partial hepatectomy (PH) was performed under inhalational anaesthesia. At days 3 and 7 after PH, the hepatic microcirculation was interrogated using intravital microscopy. Delayed liver regeneration was confirmed in C3H/HeJ, but not in C3H/HeN, C57BL/6 (WT) or TLR4-/- mice by liver weight-to-body-weight ratio, the percentage of proliferating cell nuclear antigen (PCNA)-positive cells and mitotic index data. At day 3 after PH, sinusoidal red blood cell velocity increased by 100% in C3H/HeN mice, but by only 40% in C3H/HeJ mice. Estimated sinusoidal blood flow was significantly higher at day 7 after PH in C3H/HeN than in C3H/HeJ mice. The hepatic cord width was significantly larger in C3H/HeN than in C3H/HeJ mice at day 3 and it was significantly larger in TLR4-/- than in C57BL/6 WT mice at day 7 after PH. Hepatocyte nucleus density and functional sinusoidal density was significantly reduced at days 3 and 7 after PH in all mouse strains compared with their zero-time controls. Functional sinusoidal density was significantly lower in C3H/HeJ compared with C3H/HeN mice at day 7 after PH. The present study indicates that altered sinusoidal blood flow and velocity in C3H/HeJ mice may contribute to the observed delay in the regenerative response in these mice. In addition, restoration of normal liver architecture may be delayed in TLR4-/- mice.
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Affiliation(s)
- Muhamad Marlini
- Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.,Department of Physiology, University of Otago, Dunedin, New Zealand.,Medical Faculty, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia
| | - Ayako Mabuchi
- Department of Physiology, University of Otago, Dunedin, New Zealand
| | - Beth L Mallard
- Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.,Department of Physiology, University of Otago, Dunedin, New Zealand
| | - Ngatiman Hairulhisyam
- Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.,Medical Faculty, Universiti Sains Islam Malaysia, Kuala Lumpur, Malaysia
| | | | | | - Antony M Wheatley
- Physiology, School of Medicine, National University of Ireland Galway, Galway, Ireland.,Department of Physiology, University of Otago, Dunedin, New Zealand
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22
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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23
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Liu G, Xie C, Fang Y, Qian K, Liu Q, Liu G, Cao Z, Du H, Fu J, Xu X. Splenectomy after partial hepatectomy accelerates liver regeneration in mice by promoting tight junction formation via polarity protein Par 3-aPKC. Life Sci 2017; 192:91-98. [PMID: 29166570 DOI: 10.1016/j.lfs.2017.11.032] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/28/2017] [Accepted: 11/18/2017] [Indexed: 12/26/2022]
Abstract
AIMS Several experimental studies have demonstrated that removal of the spleen accelerates liver regeneration after partial hepatectomy. While the mechanism of splenectomy promotes liver regeneration by the improvement of the formation of tight junction and the establishment of hepatocyte polarity is still unknown. MAIN METHODS We analyzed the cytokines, genes and proteins expression between 70% partial hepatectomy mice (PHx) and simultaneous 70% partial hepatectomy and splenectomy mice (PHs) at predetermined timed points. KEY FINDINGS Compared with the PHx group mice, splenectomy accelerated hepatocyte proliferation in PHs group. The expression of Zonula occludens-1 (ZO-1) indicated that splenectomy promotes the formation of tight junction during liver regeneration. TNF-α, IL-6, HGF, TSP-1 and TGF-β1 were essential factors for the formation of tight junction and the establishment of hepatocytes polarity in liver regeneration. After splenectomy, Partitioning defective 3 homolog (Par 3) and atypical protein kinase C (aPKC) regulate hepatocyte localization and junctional structures in regeneration liver. SIGNIFICANCE Our data suggest that the time course expression of TNF-α, IL-6, HGF, TSP-1, and TGF-β1 and the change of platelets take part in liver regeneration. Combination with splenectomy accelerates liver regeneration by improvement of the tight junction formation which may help to establish hepatocyte polarity via Par 3-aPKC. This may provide a clue for us that splenectomy could accelerate liver regeneration after partial hepatectomy of hepatocellular carcinoma and living donor liver transplantation.
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Affiliation(s)
- Guoxing Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Chengzhi Xie
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yu Fang
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Ke Qian
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qiang Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Gao Liu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Zhenyu Cao
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Huihui Du
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Jie Fu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Xundi Xu
- Division of Hepato-Biliary-Pancreatic Surgery, Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
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Abstract
This update focuses on two main topics. First, recent developments in our understanding of liver sinusoidal endothelial cell (LSEC) function will be reviewed, specifically elimination of blood-borne waste, immunological function of LSECs, interaction of LSECs with liver metastases, LSECs and liver regeneration, and LSECs and hepatic fibrosis. Second, given the current emphasis on rigor and transparency in biomedical research, the update discusses the need for standardization of methods to demonstrate identity and purity of isolated LSECs, pitfalls in methods that might lead to a selection bias in the types of LSECs isolated, and questions about long-term culture of LSECs. Various surface markers used for immunomagnetic selection are reviewed.
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Affiliation(s)
- Laurie D. DeLeve
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Ana C. Maretti-Mira
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California
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25
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Alizai PH, Bertram L, Kroy D, Kummer J, Andert A, Neumann UP, Ulmer TF, Fragoulis A. Expression of VEGFR-2 during Liver Regeneration after Partial Hepatectomy in a Bioluminescence Mouse Model. Eur Surg Res 2017; 58:330-340. [PMID: 29073598 DOI: 10.1159/000479628] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Accepted: 07/19/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Liver regeneration requires the formation of new blood vessels. Endothelial cell proliferation is stimulated by vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR-2. The aim of this study was to investigate VEGFR-2 expression in vivo during liver regeneration after partial hepatectomy (PHx). METHODS Transgenic VEGFR-2-luc mice were used in which the luciferase reporter gene was under control of the VEGFR-2 promoter. Following 2/3 PHx, the mice underwent in vivo bioluminescence imaging until the 14th postoperative day. Additionally, liver tissue was analyzed by immunohistochemistry, in vitro luminescence assays, and quantitative RT-PCR. RESULTS In vivo bioluminescence imaging showed a significant increase in VEGFR-2 promoter activity after PHx. Maximum signal was recorded on the 3rd day; 8 days postoperatively the signal intensity decreased significantly. On the 14th day, bioluminescence signal reached almost baseline levels. Immunohistochemistry, quantitative RT-PCR, and in vitro luminescence confirmed a significant increase on the 3rd day following resection. The mRNA expression of VEGFR-2 was significantly higher on day 3 than preoperatively as well as on day 8. CONCLUSION In vivo bioluminescence imaging with transgenic VEGFR-2-luc mice is feasible and provides a convenient model for noninvasively studying VEGFR-2 expression during liver regeneration. This may facilitate further experiments with modulation of angiogenesis by different substances.
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Affiliation(s)
- Patrick Hamid Alizai
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Lea Bertram
- Department of Surgery, Luisenhospital Aachen, Aachen, Germany.,Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, Aachen, Germany
| | - Daniela Kroy
- Department of Gastroenterology and Metabolic Disorders, RWTH Aachen University Hospital, Aachen, Germany
| | - Julia Kummer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.,Department of Gynaecology and Obstetrics, Vivantes Clinic Berlin, Berlin, Germany
| | - Anne Andert
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany
| | - Athanassious Fragoulis
- Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Aachen, Germany.,Department of Anatomy and Cell Biology, RWTH Aachen University Hospital, Aachen, Germany
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26
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Du Y, Li N, Yang H, Luo C, Gong Y, Tong C, Gao Y, Lü S, Long M. Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip. LAB ON A CHIP 2017; 17:782-794. [PMID: 28112323 DOI: 10.1039/c6lc01374k] [Citation(s) in RCA: 159] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/18/2023]
Abstract
Physiologically, four major types of hepatic cells - the liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and hepatocytes - reside inside liver sinusoids and interact with flowing peripheral cells under blood flow. It is hard to mimic an in vivo liver sinusoid due to its complex multiple cell-cell interactions, spatiotemporal construction, and mechanical microenvironment. Here we developed an in vitro liver sinusoid chip by integrating the four types of primary murine hepatic cells into two adjacent fluid channels separated by a porous permeable membrane, replicating liver's key structures and configurations. Each type of cells was identified with its respective markers, and the assembled chip presented the liver-specific unique morphology of fenestration. The flow field in the liver chip was quantitatively analyzed by computational fluid dynamics simulations and particle tracking visualization tests. Intriguingly, co-culture and shear flow enhance albumin secretion independently or cooperatively, while shear flow alone enhances HGF production and CYP450 metabolism. Under lipopolysaccharide (LPS) stimulations, the hepatic cell co-culture facilitated neutrophil recruitment in the liver chip. Thus, this 3D-configured in vitro liver chip integrates the two key factors of shear flow and the four types of primary hepatic cells to replicate key structures, hepatic functions, and primary immune responses and provides a new in vitro model to investigate the short-duration hepatic cellular interactions under a microenvironment mimicking the physiology of a liver.
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Affiliation(s)
- Yu Du
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ning Li
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hao Yang
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunhua Luo
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yixin Gong
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chunfang Tong
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuxin Gao
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Shouqin Lü
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Mian Long
- Key Laboratory of Microgravity (National Microgravity Laboratory), Center of Biomechanics and Bioengineering, and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing 100190, China. and School of Engineering Sciences, University of Chinese Academy of Sciences, Beijing 100049, China
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Taira Z, Ueda Y, Monmasu H, Yamase D, Miyake S, Shiraishi M. Characteristics of intracellular Ca 2+ signals consisting of two successive peaks in hepatocytes during liver regeneration after 70% partial hepatectomy in rats. J Exp Pharmacol 2016; 8:21-33. [PMID: 27757054 PMCID: PMC5055106 DOI: 10.2147/jep.s106084] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Two specific signals for regulating liver regeneration were found after 70% partial hepatectomy (PH) in rats. The first finding was a sustained increasing signal of intracellular Ca2+ ([Ca2+]i) in hepatocytes, consisting of two successive peaks with the first narrow peak at 1 hour and the second broad peak increasing by day 3 and then returning to normal by day 4. The second finding was an abnormal peak in the restoring ratio (Rr) curve of liver regeneration after 70% PH at day 4, where the Rr exceeded 100% temporarily, returned to a lower level, and then proceeded to a termination phase of liver regeneration. For 4 days around the two successive [Ca2+]i peaks and abnormal peak, various physiological activities were induced to promote liver regeneration after 70% PH. mRNA expression of genes encoding Ca2+-binding proteins S100A4 and calpain was induced between the two Ca2+ peaks. Hepatocytes underwent synchronous cell proliferation as the liver was restored from 30% to 70% at day 4, and significant expression of VEGF mRNA at around day 4 promoted angiogenesis to remodel the sinusoidal system. Cytochrome P450 activity levels in microsomes and alanine aminotransferase values at 24 hours after CCl4 administration were decreased after 70% PH, which recovered transiently to the control level at day 4, returned to the decreased level, and then slowly recovered by day 10. Thus, these results indicate that day 4 is important during liver regeneration after 70% PH.
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Affiliation(s)
- Zenei Taira
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Yukari Ueda
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Hiroshi Monmasu
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Daisuke Yamase
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Sayaka Miyake
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
| | - Maya Shiraishi
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan
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Kostallari E, Shah VH. Angiocrine signaling in the hepatic sinusoids in health and disease. Am J Physiol Gastrointest Liver Physiol 2016; 311:G246-51. [PMID: 27288423 PMCID: PMC5007289 DOI: 10.1152/ajpgi.00118.2016] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 06/06/2016] [Indexed: 02/08/2023]
Abstract
The capillary network irrigating the liver is important not only for nutrient and oxygen delivery, but also for the signals distributed to other hepatic cell types necessary to maintain liver homeostasis. During development, endothelial cells are a key component in liver zonation. In adulthood, they maintain hepatic stellate cells and hepatocytes in quiescence. Their importance in pathobiology is highlighted in liver regeneration and chronic liver diseases, where they coordinate paracrine cell behavior. During regeneration, liver sinusoidal endothelial cells induce hepatocyte proliferation and angiogenesis. During fibrogenesis, they undergo morphological and functional changes, which are reflected by their role in hepatic stellate cell activation, inflammation, and distorted sinusoidal structure. Therapeutic strategies to target angiocrine signaling are in progress but are in the early stages. Here, we offer a short synthesis of recent studies on angiocrine signaling in liver homeostasis, regeneration, and fibrogenesis.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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29
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Encapsulated Whole Bone Marrow Cells Improve Survival in Wistar Rats after 90% Partial Hepatectomy. Stem Cells Int 2015; 2016:4831524. [PMID: 26649048 PMCID: PMC4663362 DOI: 10.1155/2016/4831524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 01/18/2015] [Accepted: 01/28/2015] [Indexed: 12/16/2022] Open
Abstract
Background and Aims. The use of bone marrow cells has been suggested as an alternative treatment for acute liver failure. In this study, we investigate the effect of encapsulated whole bone marrow cells in a liver failure model. Methods. Encapsulated cells or empty capsules were implanted in rats submitted to 90% partial hepatectomy. The survival rate was assessed. Another group was euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy to study expression of cytokines and growth factors. Results. Whole bone marrow group showed a higher than 10 days survival rate compared to empty capsules group. Gene expression related to early phase of liver regeneration at 6 hours after hepatectomy was decreased in encapsulated cells group, whereas genes related to regeneration were increased at 12, 24, and 48 hours. Whole bone marrow group showed lower regeneration rate at 72 hours and higher expression and activity of caspase 3. In contrast, lysosomal-β-glucuronidase activity was elevated in empty capsules group. Conclusions. The results show that encapsulated whole bone marrow cells reduce the expression of genes involved in liver regeneration and increase those responsible for ending hepatocyte division. In addition, these cells favor apoptotic cell death and decrease necrosis, thus increasing survival.
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Meyer J, Lejmi E, Fontana P, Morel P, Gonelle-Gispert C, Bühler L. A focus on the role of platelets in liver regeneration: Do platelet-endothelial cell interactions initiate the regenerative process? J Hepatol 2015; 63:1263-1271. [PMID: 26169159 DOI: 10.1016/j.jhep.2015.07.002] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 06/05/2015] [Accepted: 07/02/2015] [Indexed: 12/13/2022]
Abstract
Platelets are involved in the early phases of liver regeneration. Moreover, platelet transfusion and thrombocytosis were recently shown to enhance hepatocyte proliferation. However, the precise mechanisms remain elusive. This review discusses the latest updates regarding the mechanisms by which platelets stimulate liver regeneration, focusing on their interactions with liver sinusoidal endothelial cells and on their fate within the liver. Following liver injury, platelets are recruited to and trapped within the liver, where they adhere to the endothelium. Subsequent platelet activation results in the release of platelet granules, which stimulate hepatocyte proliferation through activation of the Akt and ERK1/2 signalling pathways. Platelets activate liver sinusoidal endothelial cells, leading to the secretion of growth factors, such as interleukin-6. Finally, liver sinusoidal cells and hepatocytes can also internalize platelets, but the effects of this alternate process on liver regeneration remain to be explored. A better understanding of the mechanisms by which platelets stimulate liver regeneration could lead to improvement in post-operative organ function and allow hepatectomies of a greater extent to be performed.
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Affiliation(s)
- Jeremy Meyer
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland.
| | - Esma Lejmi
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Pierre Fontana
- Division of Angiology and Haemostasis, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Geneva Platelet Group, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Philippe Morel
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Carmen Gonelle-Gispert
- Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
| | - Léo Bühler
- Division of Visceral and Transplantation Surgery, University Hospitals of Geneva, Rue Gabrielle-Perret-Gentil 4, 1211 Genève 14, Switzerland; Unit of Surgical Research, University of Geneva, Rue Michel-Servet 1, 1206 Genève, Switzerland
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31
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Defining Post Hepatectomy Liver Insufficiency: Where do We stand? J Gastrointest Surg 2015; 19:2079-92. [PMID: 26063080 DOI: 10.1007/s11605-015-2872-6] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Accepted: 06/02/2015] [Indexed: 01/31/2023]
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a major source of morbidity and mortality in patients undergoing liver resection. The aim of this review is to summarize the recent literature available on PHLF including its definition, predictive factors, preoperative risk assessment, severity grading, preventative measures, and management strategies. METHODS A systematic literature search was carried out with the search engines PubMed, Medline, and Cochrane Database using the keywords related to "liver failure", "posthepatectomy", and "hepatic resection". RESULTS Liver resection is a curative treatment of liver tumors. However, it leads to concurrent death and regeneration of the remaining hepatocytes. Factors related to the patient, liver parenchyma and the extent of surgery can inhibit regeneration leading to PHLF. CONCLUSION Given its resistance to treatment and the high postoperative mortality associated with PHLF, great effort has been put in to both accurately identify patients at high risk and to develop strategies that can help prevent its occurrence.
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Zhou L, Pradhan-Sundd T, Poddar M, Singh S, Kikuchi A, Stolz DB, Shou W, Li Z, Nejak-Bowen KN, Monga SP. Mice with Hepatic Loss of the Desmosomal Protein γ-Catenin Are Prone to Cholestatic Injury and Chemical Carcinogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:3274-89. [PMID: 26485505 DOI: 10.1016/j.ajpath.2015.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2015] [Revised: 07/22/2015] [Accepted: 08/10/2015] [Indexed: 12/11/2022]
Abstract
γ-Catenin, an important component of desmosomes, may also participate in Wnt signaling. Herein, we dissect the role of γ-catenin in liver by generating conditional γ-catenin knockout (KO) mice and assessing their phenotype after bile duct ligation (BDL) and diethylnitrosamine-induced chemical carcinogenesis. At baseline, KO and wild-type littermates showed comparable serum biochemistry, liver histology, and global gene expression. β-Catenin protein was modestly increased without any change in Wnt signaling. Desmosomes were maintained in KO, and despite no noticeable changes in gene expression, differential detergent fractionation revealed quantitative and qualitative changes in desmosomal cadherins, plaque proteins, and β-catenin. Enhanced association of β-catenin to desmoglein-2 and plakophilin-3 was observed in KO. When subjected to BDL, wild-type littermates showed specific changes in desmosomal protein expression. In KO, BDL deteriorated baseline compensatory changes, which manifested as enhanced injury and fibrosis. KO also showed enhanced tumorigenesis to diethylnitrosamine treatment because of Wnt activation, as also verified in vitro. γ-Catenin overexpression in hepatoma cells increased its binding to T-cell factor 4 at the expense of β-catenin-T-cell factor 4 association, induced unique target genes, affected Wnt targets, and reduced cell proliferation and viability. Thus, γ-catenin loss in liver is basally well tolerated. However, after insults like BDL, these compensations at desmosomes fail, and KO show enhanced injury. Also, γ-catenin negatively regulates tumor growth by affecting Wnt signaling.
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Affiliation(s)
- Lili Zhou
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China; Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | | | - Minakshi Poddar
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Sucha Singh
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Alex Kikuchi
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Donna B Stolz
- Department of Cell Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Weinian Shou
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zongfang Li
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Kari N Nejak-Bowen
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
| | - Satdarshan P Monga
- Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania.
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33
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Starlinger P, Assinger A, Gruenberger T, Brostjan C. The role of platelets and portal venous pressure fluctuations in postoperative liver regeneration. Eur Surg 2015. [DOI: 10.1007/s10353-015-0352-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Cogger VC, O'Reilly JN, Warren A, Le Couteur DG. A standardized method for the analysis of liver sinusoidal endothelial cells and their fenestrations by scanning electron microscopy. J Vis Exp 2015:e52698. [PMID: 25993325 PMCID: PMC4650683 DOI: 10.3791/52698] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Liver sinusoidal endothelial cells are the gateway to the liver, their transcellular fenestrations allow the unimpeded transfer of small and dissolved substances from the blood into the liver parenchyma for metabolism and processing. Fenestrations are dynamic structures--both their size and/or number can be altered in response to various physiological states, drugs, and disease, making them an important target for modulation. An understanding of how LSEC morphology is influenced by various disease, toxic, and physiological states and how these changes impact on liver function requires accurate measurement of the size and number of fenestrations. In this paper, we describe scanning electron microscopy fixation and processing techniques used in our laboratory to ensure reproducible specimen preparation and accurate interpretation. The methods include perfusion fixation, secondary fixation and dehydration, preparation for the scanning electron microscope and analysis. Finally, we provide a step by step method for standardized image analysis which will benefit all researchers in the field.
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Affiliation(s)
- Victoria C Cogger
- Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital; Ageing and Alzheimers Institute, Concord Hospital; Charles Perkins Centre, University of Sydney;
| | - Jennifer N O'Reilly
- Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital; Ageing and Alzheimers Institute, Concord Hospital
| | - Alessandra Warren
- Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital; Ageing and Alzheimers Institute, Concord Hospital; Charles Perkins Centre, University of Sydney
| | - David G Le Couteur
- Centre for Education and Research on Ageing & ANZAC Research Institute, University of Sydney and Concord Hospital; Ageing and Alzheimers Institute, Concord Hospital; Charles Perkins Centre, University of Sydney
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Li W, Guan T, Zhang X, Wang Z, Wang M, Zhong W, Feng H, Xing M, Kong J. The Effect of Layer-by-Layer Assembly Coating on the Proliferation and Differentiation of Neural Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2015; 7:3018-3029. [PMID: 25347385 DOI: 10.1021/am504456t] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Nanocoating of a single-cell with biocompatible materials creates a defined microenvironment for cell differentiation and proliferation, as well as a model for studies in cell biology. In addition, the acidic environment in the tissue of stroke victims necessitates drug release upon pH stimuli. Here, we report the encapsulation of single neural stem cells (NSCs) using a layer-by-layer (LbL) self-assembly technique with polyelectrolytes gelatin and alginate. Analysis of the NSCs showed that the LbL encapsulation would not affect the viability, proliferation, or differentiation of the cells. When insulin-like growth factor-1 (IGF-1) was loaded on the coating material alginate, its release from alginate into the medium presented in a time-dependent and pH-dependent way. IGF-1 significantly enhanced the proliferation of the encapsulated NSCs, demonstrating a drug-carrier function of the LbL single-cell nanocoating. It provided a potential treatment strategy for nervous system disorders such as stroke.
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Affiliation(s)
- Wenyan Li
- Department of Neurosurgery, Southwest Hospital, Third Military Medical University , 30 Gaotanyan Street, Chongqing 400038, China
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Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 2014; 61:912-24. [PMID: 24911462 PMCID: PMC4346093 DOI: 10.1016/j.jhep.2014.05.047] [Citation(s) in RCA: 229] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 05/26/2014] [Accepted: 05/28/2014] [Indexed: 12/12/2022]
Abstract
Chronic liver disease is associated with remarkable alterations in the intra- and extrahepatic vasculature. Because of these changes, the fields of liver vasculature and portal hypertension have recently become closely integrated within the broader vascular biology discipline. As developments in vascular biology have evolved, a deeper understanding of vascular processes has led to a better understanding of the mechanisms of the dynamic vascular changes associated with portal hypertension and chronic liver disease. In this context, hepatic vascular cells, such as sinusoidal endothelial cells and pericyte-like hepatic stellate cells, are closely associated with one another, where they have paracrine and autocrine effects on each other and themselves. These cells play important roles in the pathogenesis of liver fibrosis/cirrhosis and portal hypertension. Further, a variety of signaling pathways have recently come to light. These include growth factor pathways involving cytokines such as transforming growth factor β, platelet derived growth factor, and others as well as a variety of vasoactive peptides and other molecules. An early and consistent feature of liver injury is the development of an increase in intra-hepatic resistance; this is associated with changes in hepatic vascular cells and their signaling pathway that cause portal hypertension. A critical concept is that this process aggregates signals to the extrahepatic circulation, causing derangement in this system's cells and signaling pathways, which ultimately leads to the collateral vessel formation and arterial vasodilation in the splanchnic and systemic circulation, which by virtue of the hydraulic derivation of Ohm's law (pressure = resistance × flow), worsens portal hypertension. This review provides a detailed review of the current status and future direction of the basic biology of portal hypertension with a focus on the physiology, pathophysiology, and signaling of cells within the liver, as well as those in the mesenteric vascular circulation. Translational implications of recent research and the future directions that it points to are also highlighted.
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Affiliation(s)
- Yasuko Iwakiri
- The Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States
| | - Vijay Shah
- The Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Don C Rockey
- The Department of Medicine, Medical University of South Carolina, Charleston, SC, United States.
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Hessheimer AJ, Escobar B, Muñoz J, Flores E, Gracia-Sancho J, Taurá P, Fuster J, Rimola A, García-Valdecasas JC, Fondevila C. Somatostatin therapy protects porcine livers in small-for-size liver transplantation. Am J Transplant 2014; 14:1806-16. [PMID: 24935350 DOI: 10.1111/ajt.12758] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Revised: 03/17/2014] [Accepted: 03/25/2014] [Indexed: 01/25/2023]
Abstract
Small-for-size (SFS) injury occurs in partial liver transplantation due to several factors, including excessive portal inflow and insufficient intragraft responses. We aim to determine the role somatostatin plays in reducing portal hyperperfusion and preventing the cascade of deleterious events produced in small grafts. A porcine model of 20% liver transplantation is performed. Perioperatively treated recipients receive somatostatin and untreated controls standard intravenous fluids. Recipients are followed for up to 5 days. In vitro studies are also performed to determine direct protective effects of somatostatin on hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). At reperfusion, portal vein flow (PVF) per gram of tissue increased fourfold in untreated animals versus approximately threefold among treated recipients (p = 0.033). Postoperatively, markers of hepatocellular, SEC and HSC injury were improved among treated animals. Hepatic regeneration occurred in a slower but more orderly fashion among treated grafts; functional recovery was also significantly better. In vitro studies revealed that somatostatin directly reduces HSC activation, though no direct effect on SEC was found. In SFS transplantation, somatostatin reduces PVF and protects SEC in the critical postreperfusion period. Somatostatin also exerts a direct cytoprotective effect on HSC, independent of changes in PVF.
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Affiliation(s)
- A J Hessheimer
- Department of Surgery, Institut de Malalties Digestives I Metabòliques (IMDiM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, Barcelona, Spain
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Zhang LJ, Sun MY, Ning BB, Zhang WM, Chen GF, Mu YP, Zhang H, Liu J, Bian YQ, Liu P. Xiayuxue Decoction ([symbols; see text]) attenuates hepatic stellate cell activation and sinusoidal endothelium defenestration in CCl4-induced fibrotic liver of mice. Chin J Integr Med 2014; 20:516-23. [PMID: 24972579 DOI: 10.1007/s11655-014-1862-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To investigate the effects of ancient Chinese medical formula Xiayuxue Decoction ([symbols; see text], XYXD) on activation of hepatic stellate cells (HSCs) and defenestration of sinusoidal endothelial cells (SECs) in CCl4-induced fibrotic liver of mice. METHODS High performance liquid chromatography was used to identify the main components of XYXD and control the quality of extraction. C57BL/6 mice were induced liver fibrosis by CCl4 exposure and administered with XYXD for 6 weeks simultaneously. Liver tissue was investigated by hematoxylin-eosin and Sirius-red staining. Sinusoidal fenestrations were observed by scanning electronic microscopy and fluorescent immunohistochemistry of PECAM-1 (CD31). Whole liver lysates were detected of α-smooth muscle actin (α-SMA) and type-I collagen by Western blot. Primary rat HSCs-T6 cells were analyzed by detecting α-SMA, F-actin, DNA fragmentation through confocal microscopy, Western blot, terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay and cellomics arrayscan, respectively. RESULTS Amygdalin and emodin in XYXD were identified. XYXD (993 mg/kg) inhibited Sirius red positive area up to 70.1% (P<0.01), as well as protein levels of α-SMA and type-I collagen by 42.0% and 18.5% (P<0.05) respectively. In vitro, XYXD (12.5 μg/mL, 50 μg/mL) suppressed the activation of HSCs and reversed the myofibroblastic HSCs into quiescent, demonstrated as inhibition of fluorescent F-actin by 32.3% and 46.6% (P<0.05). Besides, XYXD induced the apoptosis of HSC-T6 cells by 20.0% (P<0.05) and 49.5% (P<0.01), evidenced by enhanced TUNEL positivity. Moreover, ultrastructural observation suggested XYXD inhibited defenestration of SECs, which was confirmed by 31.1% reduction of protein level of CD31 (P<0.05). CONCLUSIONS XYXD inhibited both HSCs activation and SECs defenestration which accompany chronic liver injuries. These data may help to understand the underlying mechanisms of XYXD for prevetion of chronic liver diseases.
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Affiliation(s)
- Li-jun Zhang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
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Ebrahimkhani MR, Neiman JAS, Raredon MSB, Hughes DJ, Griffith LG. Bioreactor technologies to support liver function in vitro. Adv Drug Deliv Rev 2014; 69-70:132-57. [PMID: 24607703 PMCID: PMC4144187 DOI: 10.1016/j.addr.2014.02.011] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2014] [Revised: 02/18/2014] [Accepted: 02/24/2014] [Indexed: 02/08/2023]
Abstract
Liver is a central nexus integrating metabolic and immunologic homeostasis in the human body, and the direct or indirect target of most molecular therapeutics. A wide spectrum of therapeutic and technological needs drives efforts to capture liver physiology and pathophysiology in vitro, ranging from prediction of metabolism and toxicity of small molecule drugs, to understanding off-target effects of proteins, nucleic acid therapies, and targeted therapeutics, to serving as disease models for drug development. Here we provide perspective on the evolving landscape of bioreactor-based models to meet old and new challenges in drug discovery and development, emphasizing design challenges in maintaining long-term liver-specific function and how emerging technologies in biomaterials and microdevices are providing new experimental models.
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Affiliation(s)
- Mohammad R Ebrahimkhani
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Jaclyn A Shepard Neiman
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Micha Sam B Raredon
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Linda G Griffith
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Center for Gynepathology Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
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Murata S, Maruyama T, Nowatari T, Takahashi K, Ohkohchi N. Signal transduction of platelet-induced liver regeneration and decrease of liver fibrosis. Int J Mol Sci 2014; 15:5412-5425. [PMID: 24686514 PMCID: PMC4013572 DOI: 10.3390/ijms15045412] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 03/16/2014] [Accepted: 03/20/2014] [Indexed: 12/16/2022] Open
Abstract
Platelets contain three types of granules: alpha granules, dense granules, and lysosomal granules. Each granule contains various growth factors, cytokines, and other physiological substances. Platelets trigger many kinds of biological responses, such as hemostasis, wound healing, and tissue regeneration. This review presents experimental evidence of platelets in accelerating liver regeneration and improving liver fibrosis. The regenerative effect of liver by platelets consists of three mechanisms; i.e., the direct effect on hepatocytes, the cooperative effect with liver sinusoidal endothelial cells, and the collaborative effect with Kupffer cells. Many signal transduction pathways are involved in hepatocyte proliferation. One is activation of Akt and extracellular signal-regulated kinase (ERK)1/2, which are derived from direct stimulation from growth factors in platelets. The other is signal transducer and activator of transcription-3 (STAT3) activation by interleukin (IL)-6 derived from liver sinusoidal endothelial cells and Kupffer cells, which are stimulated by contact with platelets during liver regeneration. Platelets also improve liver fibrosis in rodent models by inactivating hepatic stellate cells to decrease collagen production. The level of intracellular cyclic adenosine monophosphate (cyclic AMP) is increased by adenosine through its receptors on hepatic stellate cells, resulting in inactivation of these cells. Adenosine is produced by the degradation of adenine nucleotides such as adenosine diphosphate (ADP) and adenosine tri-phosphate (ATP), which are stored in abundance within the dense granules of platelets.
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Affiliation(s)
- Soichiro Murata
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Takehito Maruyama
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Takeshi Nowatari
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Kazuhiro Takahashi
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
| | - Nobuhiro Ohkohchi
- Department of Surgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan.
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Peng Y, Chen Q, Yang T, Tao Y, Lu X, Liu C. Cultured mycelium Cordyceps sinensis protects liver sinusoidal endothelial cells in acute liver injured mice. Mol Biol Rep 2014; 41:1815-27. [PMID: 24442316 PMCID: PMC3933741 DOI: 10.1007/s11033-014-3031-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2013] [Accepted: 01/03/2014] [Indexed: 11/26/2022]
Abstract
Cultured mycelium Cordyceps sinensis (CMCS) was widely used for a variety of diseases including liver injury, the current study aims to investigate the protective effects of CMCS on liver sinusoidal endothelial cells (LSECs) in acute injury liver and related action mechanisms. The mice were injected intraperitoneally with lipopolysaccharide (LPS) and D-galactosamine (D-GalN). 39 male BABL/c mice were randomly divided into four groups: normal control, model control, CMCS treatment and 1,10-phenanthroline treatment groups. The Serum liver function parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were assayed with the commercial kit. The inflammation and scaffold structure in liver were stained with hematoxylin and eosin and silver staining respectively. The LSECs and sub-endothelial basement membrane were observed with the scanning and transmission electronic microscope. The protein expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in liver were analyzed with Western blotting. Expression of von Willebrand factor (vWF) was investigated with immunofluorescence staining. The lipid peroxidation indicators including antisuperoxideanion (ASAFR), hydroxyl free radical (·OH), superoxide dismutase (SOD), malondialdehyde and glutathione S-transferase (GST) were determined with kits, and matrix metalloproteinase-2 and 9 (MMP-2/9) activities in liver were analyzed with gelatin zymography and in situ fluorescent zymography respectively. The model mice had much higher serum levels of ALT and AST than the normal mice. Compared to that in the normal control, more severe liver inflammation and hepatocyte apoptosis, worse hepatic lipid peroxidation demonstrated by the increased ASAFR, ·OH and MDA, but decreased SOD and GST, increased MMP-2/9 activities and VCAM-1, ICAM-1 and vWF expressions, which revealed obvious LSEC injury and scaffold structure broken, were shown in the model control. Compared with the model group, CMCS and 1,10-phenanthroline significantly improved serum ALT/AST, attenuated hepatic inflammation and improved peroxidative injury in liver, decreased MMP-2/9 activities in liver tissue, improved integration of scaffold structure, and decreased protein expression of VCAM-1 and ICAM-1. CMCS could protect LSECs from injury and maintain the microvasculature integration in acute injured liver of mice induced by LPS/D-GalN. Its action mechanism was associated with the down-regulation of MMP-2/9 activities and inhibition of peroxidation in injured liver.
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Affiliation(s)
- Yuan Peng
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203 China
| | - Qian Chen
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203 China
- Central Laboratory, Shanghai Xuhui Central Hospital, Shanghai, 200031 China
| | - Tao Yang
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203 China
| | - Yanyan Tao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203 China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203 China
| | - Xiong Lu
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203 China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203 China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, 201203 China
- E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, Shanghai, 201203 China
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Early Graft Dysfunction in Living Donor Liver Transplantation and the Small for Size Syndrome. CURRENT TRANSPLANTATION REPORTS 2014; 1:43-52. [PMID: 27280080 DOI: 10.1007/s40472-013-0006-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
LDLT has arisen as a viable means to reduce waitlist mortality. However, its widespread embrace by the liver transplant community has been met with frustration centered on donor morbidity and small-for-size-syndrome. Focusing on the later entity, we describe the initial recognition of this early graft dysfunction, the theorized pathophysiology and solutions to remedy its emergence.
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43
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Liu S, Ko ACT, Li W, Zhong W, Xing M. NIR initiated and pH sensitive single-wall carbon nanotubes for doxorubicin intracellular delivery. J Mater Chem B 2014; 2:1125-1135. [DOI: 10.1039/c3tb21362e] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Ji J, Hu S, Zheng M, Du W, Shang Q, Li W. Bacillus amyloliquefaciens SC06 inhibits ETEC-induced pro-inflammatory responses by suppression of MAPK signaling pathways in IPEC-1 cells and diarrhea in weaned piglets. Livest Sci 2013. [DOI: 10.1016/j.livsci.2013.09.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Petrovai G, Truant S, Langlois C, Bouras AF, Lemaire S, Buob D, Leteurtre E, Boleslawski E, Pruvot FR. Mechanisms of splenic hypertrophy following hepatic resection. HPB (Oxford) 2013; 15:919-27. [PMID: 23458075 PMCID: PMC3843609 DOI: 10.1111/hpb.12056] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Following hepatic resection, liver regeneration has been associated with concurrent splenic hypertrophy. The mechanisms of this phenomenon are unknown, may be multiple and include: splanchnic sequestration caused by a reduction in the hepatic mass; hepatic growth factors that may indirectly act on the spleen, and the redistribution of the total reticuloendothelial system. METHODS Seventy-five patients (40 males; median age: 60 years) who underwent minor (16%) or major (84%) hepatectomy between September 2004 and October 2009 were included. Prospective measurements of liver and spleen volumes were obtained preoperatively and postoperatively 1 month after hepatectomy using computed tomography (CT). The future remnant liver volume (RLV) was calculated on preoperative CT and the extent of resection was expressed as the RLV divided by total liver volume (TLV). Liver and spleen hypertrophy were expressed according to the absolute gain or relative increase in the initial volumes (%).The presence of fibrosis >F1, associated extrahepatic resection (except minor resections), and previous hepatectomy (major or minor) within 3 months represented exclusion criteria. RESULTS Mean ± standard deviation (SD) liver volume at 1 month was higher than RLV (1187 ± 286 cm(3) versus 764 ± 421 cm(3) ; P < 0.001). Mean ± SD splenic volume increased from 252 ± 100 cm(3) preoperatively to 300 ± 111 cm(3) at 1 month (P < 0.001). Liver and splenic hypertrophy were significant after major hepatectomies (+100% and +26%, respectively; P < 0.001), but not after minor hepatectomies. Liver hypertrophy was inversely correlated to RLV/TLV (r = -0.687, P < 0.001). Splenic hypertrophy was not correlated to RLV/TLV. Liver and splenic hypertrophy were linearly correlated (r = 0.495, P < 0.001). Neoadjuvant chemotherapy (n = 37), preoperative portal vein embolization (n = 10) and postoperative complications (overall: n = 25; major: n = 10; infectious: n = 6) had no impact on hepatic or splenic hypertrophy. CONCLUSIONS Splenic hypertrophy occurred after major hepatectomy, but was not correlated to the extent of resection, by contrast with liver hypertrophy. Nevertheless, there was a linear correlation between splenic and liver hypertrophy. This correlation suggests the hypothesis of a splenic action of hepatic growth factors or a redistribution of the total reticuloendothelial system rather than an effect of reduction of the portal bed or hepatic outflow.
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Affiliation(s)
- Gheorghe Petrovai
- Department of Digestive Surgery and Transplantation, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Stéphanie Truant
- Department of Digestive Surgery and Transplantation, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Carole Langlois
- Department of Biostatistics, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Ahmed F Bouras
- Department of Digestive Surgery and Transplantation, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Stéphanie Lemaire
- Department of Digestive Radiology, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - David Buob
- Department of Pathology, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Emmanuelle Leteurtre
- Department of Pathology, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - Emmanuel Boleslawski
- Department of Digestive Surgery and Transplantation, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
| | - François-René Pruvot
- Department of Digestive Surgery and Transplantation, University Hospital Centre [Centre Hospitalier Universitaire (CHU)], University of Lille Nord de FranceLille, France
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Mihara K, Sugiura T, Okamura Y, Kanemoto H, Mizuno T, Moriguchi M, Aramaki T, Uesaka K. A predictive factor of insufficient liver regeneration after preoperative portal vein embolization. ACTA ACUST UNITED AC 2013; 51:118-28. [PMID: 24247292 DOI: 10.1159/000356368] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2013] [Accepted: 10/14/2013] [Indexed: 01/10/2023]
Abstract
BACKGROUND Preoperative portal vein embolization (PVE) is performed to enhance the future remnant liver function (FRLF) and volume (FRLV). However, the volume of the nonembolized liver does not increase enough in some patients, which results in an insufficient FRLF. The aim of this study was to evaluate the predictors of insufficient FRLF after PVE for extended hepatectomy. METHODS This retrospective study included 172 patients (107 patients with cholangiocarcinoma, 40 patients with metastatic liver cancer and 25 patients with hepatocellular carcinoma) who underwent PVE before extended hepatectomy. The total liver function was evaluated by measuring the indocyanine green plasma clearance rate (KICG). Computed tomography volumetry was conducted to evaluate the total liver volume and FRLV. The KICG of the future remnant liver (remK) was calculated using the following formula: KICG × FRLV/total liver volume. The safety margin for hepatectomy was set at remK after PVE (post-PVE remK) ≥ 0.05. RESULTS One hundred and twenty-three patients with a post-PVE remK level of >0.05 underwent hepatectomy without postoperative liver failure [sufficient liver regeneration (SLR) group], and 9 patients with a post-PVE remK level of <0.05 did not due to insufficient FRLF [insufficient liver regeneration (ILR) group]. In the SLR group, the KICG values did not change after PVE (median, 0.144-0.146, p = 0.523); however, the %FRLV and remK increased significantly (35.0-44.3%, p < 0.001 and 0.0488-0.0610, p < 0001, respectively). In contrast, in the ILR group, the KICG values decreased significantly (0.128-0.108, p = 0.021) and the %FRLV increased marginally (27.4-32.6%, p = 0.051). As a result, the remK did not increase significantly (0.0351-0.0365, p = 0.213). A receiver operating characteristic curve demonstrated an remK value of 0.04 obtained before PVE (pre-PVE remK) to be the optimal cutoff point for defective liver regeneration. The univariate and multivariate analyses revealed that a pre-PVE remK value of <0.04 was a factor for ILR. It was also correlated with postoperative liver failure in the analysis of the patients who underwent hepatectomy. CONCLUSIONS The patients in the ILR group did not achieve SLR after PVE due to a significant decrease in the KICG and an insufficient increase in %FRLV. A pre-PVE remK value of <0.04 is a useful predictor of insufficient regeneration of the nonembolized liver, even after PVE.
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Affiliation(s)
- K Mihara
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center Hospital, Shizuoka, Japan
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Abstract
Angiogenesis, defined as the formation of new microvasculature from preexisting blood vessels and mature endothelial cells, plays a major role in wound healing and scar formation, and it is associated with inflammatory responses. Angiogenesis can occur in physiological conditions, such as during liver regeneration, and in pathological situations, such as during the progression of fibrosis to cirrhosis and also during tumor angiogenesis. Cellular cross-talk among liver sinusoidal endothelial cells (LSECs), hepatic stellate cells and hepatocytes is believed to play an important role in the angiogenesis process during both liver regeneration and development of cirrhosis. In addition to mature endothelial cells, bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) have been recently identified for their contribution to post-natal vasculogenesis/angiogenesis. In vivo, EPCs are mobilized into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to the sites of injured endothelium and differentiate into mature endothelial cells. In our recent studies, we have explored the role of EPC-mediated angiogenesis in liver regeneration and/or cirrhosis. Results have demonstrated significantly increased endogenous levels of circulating EPCs in cirrhotic patients in comparison to the controls. Also, EPCs from cirrhotic patients have been observed to stimulate substantial angiogenesis by resident LSECs in vitro via paracrine factors such as vascular endothelial growth factor and platelet-derived growth factor. This review gives an overview of the angiogenesis process in liver regeneration and disease and discusses a new mechanism for intrahepatic angiogenesis mediated by BM-derived EPCs.
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Affiliation(s)
- Savneet Kaur
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201312, UP, India.
| | - K Anita
- School of Biotechnology, Gautam Buddha University, Greater Noida, 201312, UP, India
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γ-Catenin at adherens junctions: mechanism and biologic implications in hepatocellular cancer after β-catenin knockdown. Neoplasia 2013; 15:421-34. [PMID: 23555187 DOI: 10.1593/neo.122098] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 01/29/2013] [Accepted: 01/30/2013] [Indexed: 12/22/2022] Open
Abstract
β-Catenin is important in liver homeostasis as a part of Wnt signaling and adherens junctions (AJs), while its aberrant activation is observed in hepatocellular carcinoma (HCC). We have reported hepatocyte-specific β-catenin knockout (KO) mice to lack adhesive defects as γ-catenin compensated at AJ. Because γ-catenin is a desmosomal protein, we asked if its increase in KO might deregulate desmosomes. No changes in desmosomal proteins or ultrastructure other than increased plakophilin-3 were observed. To further elucidate the role and regulation of γ-catenin, we contemplate an in vitro model and show γ-catenin increase in HCC cells upon β-catenin knockdown (KD). Here, γ-catenin is unable to rescue β-catenin/T cell factor (TCF) reporter activity; however, it sufficiently compensates at AJs as assessed by scratch wound assay, centrifugal assay for cell adhesion (CAFCA), and hanging drop assays. γ-Catenin increase is observed only after β-catenin protein decrease and not after blockade of its transactivation. γ-Catenin increase is associated with enhanced serine/threonine phosphorylation and abrogated by protein kinase A (PKA) inhibition. In fact, several PKA-binding sites were detected in γ-catenin by in silico analysis. Intriguingly γ-catenin KD led to increased β-catenin levels and transactivation. Thus, γ-catenin compensates for β-catenin loss at AJ without affecting desmosomes but is unable to fulfill functions in Wnt signaling. γ-Catenin stabilization after β-catenin loss is brought about by PKA. Catenin-sensing mechanism may depend on absolute β-catenin levels and not its activity. Anti-β-catenin therapies for HCC affecting total β-catenin may target aberrant Wnt signaling without negatively impacting intercellular adhesion, provided mechanisms leading to γ-catenin stabilization are spared.
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Abstract
Liver sinusoidal endothelial cells (LSECs) have long been noted to contribute to liver regeneration after liver injury. In normal liver, the major cellular source of HGF is the hepatic stellate cell, but after liver injury, HGF expression has been thought to increase markedly in proliferating LSECs. However, emerging data suggest that even after injury, LSEC expression of HGF does not increase greatly. In contrast, bone marrow progenitor cells of LSECs (BM SPCs), which are rich in HGF, are recruited to the liver after injury. This Review examines liver regeneration from the perspective that BM SPCs that have been recruited to the liver, rather than mature LSECs, drive liver regeneration.
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Affiliation(s)
- Laurie D DeLeve
- Division of Gastrointestinal and Liver Diseases and USC Research Center for Liver Disease, Keck School of the University of Southern California, Los Angeles, California 90033, USA.
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Golse N, Bucur PO, Adam R, Castaing D, Sa Cunha A, Vibert E. New paradigms in post-hepatectomy liver failure. J Gastrointest Surg 2013; 17:593-605. [PMID: 23161285 DOI: 10.1007/s11605-012-2048-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 10/04/2012] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Liver failure after hepatectomy remains the most feared postoperative complication. Many risk factors are already known, related to patient's comorbidities, underlying liver disease, received treatments and type of resection. Preoperative assessment of functional liver reserve must be a priority for the surgeon. METHODS Physiopathology of post-hepatectomy liver failure is not comparable to fulminant liver failure. Liver regeneration is an early phenomenon whose cellular mechanisms are beginning to be elucidated and allowing most of the time to quickly recover a functional organ. In some cases, microscopic and macroscopic disorganization appears. The hepatocyte hyperproliferation and the asynchronism between hepatocytes and non-hepatocyte cells mitosis probably play a major role in this pathogenesis. RESULTS Many peri- or intra-operative techniques try to prevent the occurrence of this potentially lethal complication, but a better understanding of involved mechanisms might help to completely avoid it, or even to extend the possibilities of resection. CONCLUSION Future prevention and management may include pharmacological slowing of proliferation, drug or physical modulation of portal flow to reduce shear-stress, stem cells or immortalized hepatocytes injection, and liver bioreactors. Everything must be done to avoid the need for transplantation, which remains today the most efficient treatment of liver failure.
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Affiliation(s)
- Nicolas Golse
- Centre Hépatobiliaire, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris, Université Paris XI, Paris, France.
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