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Schonfeld M, Nataraj K, Mah S, Weinman S, Tikhanovich I. Continuous Activation of C/EBPβ Transcription Factor Prevents Fibrosis Resolution After Alcohol Cessation. Cell Mol Gastroenterol Hepatol 2025; 19:101525. [PMID: 40288442 DOI: 10.1016/j.jcmgh.2025.101525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Revised: 04/18/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
BACKGROUND & AIMS Abstinence is an important therapeutic intervention for patients with alcohol-associated liver disease (ALD). However, fibrosis improvement after cessation is not uniform and some patients do not improve. METHODS Mice were fed high-fat diet with 20% alcohol in the drinking water for 20 weeks (ALD) followed by 4 weeks of chow diet with plain water (resolution). scATAC-seq dataset was analyzed using Signac R package. Cebpb floxed mice received AAV-TBG-Cre or AAV-control at the time of alcohol cessation. Hepatocyte-macrophage and endothelial cell-hepatocytes crosstalk was investigated using a Transwell coculture system. To test the role of angiopoietin mice were treated with recombinant angiopoietin-1, 1 week after alcohol cessation. RESULTS We analyzed differentially accessible regions in hepatocytes from control, ALD, or 4 weeks post alcohol cessation mice and identified transcription factors activated in ALD that remained activated after alcohol withdrawal. The top hit was CCAAT enhancer binding protein beta (C/EBPβ). We found that hepatocyte-specific Cebpb knockout at the time of alcohol cessation promoted fibrosis resolution. The resolution was mediated by altered hepatocyte-macrophage crosstalk. C/EBPβ suppressed the expression of CYP3A family of enzymes in hepatocytes and downstream macrophage collagen degradation ability. Cebpb knockout in hepatocytes promoted a proresolving phenotype in liver macrophages. We further identified upstream events leading to persistent C/EBPβ activation. C/EBPβ was induced by alcohol-mediated endothelial changes during ALD development and resolution. Restoring endothelial cell function with angiopoietin-1 supplementation reduced C/EBPβ and promoted fibrosis resolution. CONCLUSIONS Taken together, alcohol-induced C/EBPβ activation is a key driver of poor disease resolution in ALD and a promising target for patients who fail to recover after alcohol abstinence.
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Affiliation(s)
- Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Kruti Nataraj
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Samson Mah
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas
| | - Steven Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas; Kansas City VA Medical Center, Kansas City, Missouri
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Imamura H, Tomimaru Y, Kobayashi S, Harada A, Kita S, Sasaki K, Iwagami Y, Yamada D, Noda T, Takahashi H, Hokkoku D, Kado T, Toya K, Kodama T, Saito S, Shimomura I, Miyagawa S, Doki Y, Eguchi H. Adipose-derived stem cells using fibrin gel as a scaffold enhances post-hepatectomy liver regeneration. Sci Rep 2025; 15:6334. [PMID: 39984656 PMCID: PMC11845764 DOI: 10.1038/s41598-025-90805-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 02/17/2025] [Indexed: 02/23/2025] Open
Abstract
We investigated the potential of adipose-derived stem cells (ADSCs) in preventing post-hepatectomy liver failure, emphasizing the necessity of direct administration using a scaffold. A fibrin gel scaffold was employed for ADSCs (gelADSC) to assess their therapeutic impact on liver regeneration in both in vitro and in vivo settings. Experiments were conducted on C57BL/6 mice with normal livers and those with chronic hepatitis. We also explored the role of extracellular vesicles (EVs) secreted by ADSCs in conjunction with fibrin gel. GelADSC showed sustained release of hepatocyte growth factor, vascular endothelial growth factor, and stromal cell-derived factor 1 for at least 7 days in vitro. In vivo, gelADSC significantly enhanced postoperative liver regeneration by upregulating the cell cycle and fatty acid oxidation in both normal and chronically hepatitis-affected mice. The therapeutic effects of gelADSC were potentially favorable over those of intravenously administered ADSCs, especially in mice with chronic hepatitis. Increased EV secretion associated with fibrin gel use was significantly linked to enhanced liver regeneration post-surgery through the promotion of fatty acid oxidation. The findings underscore the enhanced therapeutic potential of gelADSC, particularly in the context of chronic hepatitis, possibly compared to intravenous administration.
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Affiliation(s)
- Hiroki Imamura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan.
| | - Akima Harada
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Daiki Hokkoku
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Takeshi Kado
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Keisuke Toya
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shigeyoshi Saito
- Department of Medical Physics and Engineering, Division of Health Sciences, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, 565-0871, Osaka, Japan
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Eyraud D, Philippe A, Guerin C, Sarmiento I, Suner L, Puybasset L, Bertil S, Vaillant JC, Helley D, Granger B, Smadja DM, Gaussem P. Cirrhotic Patients Exhibit Remarkable Vascular Regenerative Profile One Month after Liver Transplantation. Stem Cell Rev Rep 2025; 21:276-279. [PMID: 39377987 DOI: 10.1007/s12015-024-10796-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/24/2024] [Indexed: 01/26/2025]
Affiliation(s)
- Daniel Eyraud
- Université Pierre et Marie Curie, Paris, France, Department of Anesthesiology and Reanimation, AP-HP, Pitié-Salpêtrière University Hospital, Paris, F-75013, France
| | - Aurélien Philippe
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France
- Université de Paris Cité, Innovative Therapies in Haemostasis, INSERM, Paris, F-75006, France
| | - Coralie Guerin
- Université de Paris Cité, Innovative Therapies in Haemostasis, INSERM, Paris, F-75006, France
- Cytometry Platform, Curie CoreTech, Institut Curie, Paris, F-75005, France
| | - Ignacio Sarmiento
- Université Pierre et Marie Curie, Paris, France, Department of Anesthesiology and Reanimation, AP-HP, Pitié-Salpêtrière University Hospital, Paris, F-75013, France
| | - Ludovic Suner
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France
| | - Louis Puybasset
- Université Pierre et Marie Curie, Paris, France, Department of Anesthesiology and Reanimation, AP-HP, Pitié-Salpêtrière University Hospital, Paris, F-75013, France
| | - Sébastien Bertil
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France
| | - Jean-Christophe Vaillant
- Université Pierre et Marie Curie, Paris, France, Department of Digestive, HPB Surgery, and Liver Transplantation, AP-HP, Pitié-Salpêtrière University Hospital, Paris, F-75013, France
| | - Dominique Helley
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France
- Université de Paris Cité, Paris Cardiovascular Research Center, Paris, F-75015, France
| | - Benjamin Granger
- Université Pierre et Marie Curie, Paris, France, Department of statistics, Clinical Research Unit, AP-HP, Pitié-Salpêtrière University Hospital, Paris, F-75013, France
| | - David M Smadja
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France.
- Université de Paris Cité, Innovative Therapies in Haemostasis, INSERM, Paris, F-75006, France.
| | - Pascale Gaussem
- Service d'hématologie biologique, AP-HP, Université de Paris Cité, Hôpital Européen Georges Pompidou, Paris, F-75015, France
- Université de Paris Cité, Innovative Therapies in Haemostasis, INSERM, Paris, F-75006, France
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Nacif LS, Galvão F, Kubrusly MS, Zanini LYK, Espinoza P, Waisberg DR, Pinheiro RSN, da Silva AB, Rocha-Santos V, Alves VAF, Carneiro-D’Albuquerque L, Andraus W. Nuclear factor kappa-light-chain-enhancer of activated B cells gene expression involvement in porcine liver transplant experimental model. Acta Cir Bras 2024; 39:e392724. [PMID: 38958304 PMCID: PMC11216529 DOI: 10.1590/acb392724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 04/02/2024] [Indexed: 07/04/2024] Open
Abstract
PURPOSE Gene expressions of vascular Endothelial Growth Factor Alpha (VEGFa), Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B cells (NFkB) and cytokines could be useful for identifying potential therapeutic targets to alleviate ischemia-reperfusion injury after liver transplantation. Cytokine gene expressions, VEGFa and NFkB were investigated in a preclinical swine model of liver transplantation. METHODS A total of 12 pigs were used as donors and recipients in liver transplantation without venovenous bypass or aortic clamping. NFkB, IL-6, IL-10, VEGFa and Notch1 gene expression were assessed. These samples were collected in two specific times: group 1 (n= 6) - control, samples were collected before recipient's total hepatectomy and group 2 - liver transplantation group (n=6), where the samples were collected one hour after graft reperfusion. RESULTS Liver transplantation was successfully performed in all recipients. Liver enzymes were elevated in the transplantation group. NFkB gene expression was significantly decreased in the transplantation group in comparison with the control group (0.62±0.19 versus 0.39±0.08; p= 0.016). No difference was observed between groups Interleucine 6 (IL-6), interleucine 10 (IL-10), VEGFa and Notch homolog 1 (Notch1). CONCLUSIONS In this survey a decreased NFkB gene expression in a porcine model of liver transplantation was observed.
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Affiliation(s)
- Lucas Souto Nacif
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Flávio Galvão
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Márcia Saldanha Kubrusly
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Leonardo Yuri Kasputis Zanini
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Paola Espinoza
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Daniel Reis Waisberg
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Rafael Soares Nunes Pinheiro
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Amadeo Batista da Silva
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Vinicius Rocha-Santos
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | | | - Luiz Carneiro-D’Albuquerque
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
| | - Wellington Andraus
- Universidade de São Paulo – School of Medicine – Liver and Gastrointestinal Transplant Division – São Paulo (SP), Brazil
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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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Hu Y, Wang R, An N, Li C, Wang Q, Cao Y, Li C, Liu J, Wang Y. Unveiling the power of microenvironment in liver regeneration: an in-depth overview. Front Genet 2023; 14:1332190. [PMID: 38152656 PMCID: PMC10751322 DOI: 10.3389/fgene.2023.1332190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 11/29/2023] [Indexed: 12/29/2023] Open
Abstract
The liver serves as a vital regulatory hub for various physiological processes, including sugar, protein, and fat metabolism, coagulation regulation, immune system maintenance, hormone inactivation, urea metabolism, and water-electrolyte acid-base balance control. These functions rely on coordinated communication among different liver cell types, particularly within the liver's fundamental hepatic lobular structure. In the early stages of liver development, diverse liver cells differentiate from stem cells in a carefully orchestrated manner. Despite its susceptibility to damage, the liver possesses a remarkable regenerative capacity, with the hepatic lobule serving as a secure environment for cell division and proliferation during liver regeneration. This regenerative process depends on a complex microenvironment, involving liver resident cells, circulating cells, secreted cytokines, extracellular matrix, and biological forces. While hepatocytes proliferate under varying injury conditions, their sources may vary. It is well-established that hepatocytes with regenerative potential are distributed throughout the hepatic lobules. However, a comprehensive spatiotemporal model of liver regeneration remains elusive, despite recent advancements in genomics, lineage tracing, and microscopic imaging. This review summarizes the spatial distribution of cell gene expression within the regenerative microenvironment and its impact on liver regeneration patterns. It offers valuable insights into understanding the complex process of liver regeneration.
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Affiliation(s)
- Yuelei Hu
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Ruilin Wang
- Department of Cadre’s Wards Ultrasound Diagnostics, Ultrasound Diagnostic Center, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Ni An
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Chen Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- College of Life Science and Bioengineering, Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing, China
| | - Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yannan Cao
- Department of Hepatobiliary and Pancreatic Surgery, The First Hospital of Jilin University, Jilin University, Changchun, China
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Chao Li
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Juan Liu
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yunfang Wang
- Hepato-Pancreato-Biliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
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Elias G, Schonfeld M, Saleh S, Parrish M, Barmanova M, Weinman SA, Tikhanovich I. Sepsis-induced endothelial dysfunction drives acute-on-chronic liver failure through Angiopoietin-2-HGF-C/EBPβ pathway. Hepatology 2023; 78:803-819. [PMID: 36943063 PMCID: PMC10440279 DOI: 10.1097/hep.0000000000000354] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AND AIMS Acute-on-chronic liver failure (ACLF) is an acute liver and multisystem failure in patients with previously stable cirrhosis. A common cause of ACLF is sepsis secondary to bacterial infection. Sepsis-associated ACLF involves a loss of differentiated liver function in the absence of direct liver injury, and its mechanism is unknown. We aimed to study the mechanism of sepsis-associated ACLF using a novel mouse model. APPROACH AND RESULTS Sepsis-associated ACLF was induced by cecal ligation and puncture procedure (CLP) in mice treated with thioacetamide (TAA). The combination of TAA and CLP resulted in a significant decrease in liver synthetic function and high mortality. These changes were associated with reduced metabolic gene expression and increased CCAAT enhancer binding protein beta (C/EBPβ) transcriptional activity. We found that C/EBPβ binding to its target gene promoters was increased. In humans, C/EBPβ chromatin binding was similarly increased in the ACLF group compared with control cirrhosis. Hepatocyte-specific Cebpb knockout mice had reduced mortality and increased gene expression of hepatocyte differentiation markers in TAA/CLP mice, suggesting that C/EBPβ promotes liver failure in these mice. C/EBPβ activation was associated with endothelial dysfunction, characterized by reduced Angiopoietin-1/Angiopoietin-2 ratio and increased endothelial production of HGF. Angiopoietin-1 supplementation or Hgf knockdown reduced hepatocyte C/EBPβ accumulation, restored liver function, and reduced mortality, suggesting that endothelial dysfunction induced by sepsis drives ACLF through HGF-C/EBPβ pathway. CONCLUSIONS The transcription factor C/EBPβ is activated in both mouse and human ACLF and is a potential therapeutic target to prevent liver failure in patients with sepsis and cirrhosis.
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Affiliation(s)
- Grant Elias
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Michael Schonfeld
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Sara Saleh
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Mark Parrish
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Marina Barmanova
- Liver Center, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
| | - Steven A Weinman
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
- Kansas City VA Medical Center, Kansas City, MO, USA
| | - Irina Tikhanovich
- Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS 66160, U.S.A
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Ribatti D. Liver angiocrine factors. Tissue Cell 2023; 81:102027. [PMID: 36657255 DOI: 10.1016/j.tice.2023.102027] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/15/2023]
Abstract
Endothelial cells secrete growth factors, chemokines, and extracellular matrix components, including angiocrine factors or angiokines, involved in the regulation of organ morphogenesis, homeostasis, and regeneration. The concepts of angiocrine signaling have been demonstrated in the liver, pancreas, brain, lung, heart, kidney, skin, bone marrow, as well as in pathological conditions, including cancer. The aim of this review article is to analyze the role of angiocrine factors in the liver in physiological as well as in pathological conditions.
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Affiliation(s)
- Domenico Ribatti
- Department of Translational Biomedicine and Neurosciences,University of Bari Medical School, Piazza Giulio Cesare, 11, Policlinico, 70124 Bari, Italy.
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A new hemostatic agent composed of Zn2+-enriched Ca2+ alginate activates vascular endothelial cells in vitro and promotes tissue repair in vivo. Bioact Mater 2022; 18:368-382. [PMID: 35415309 PMCID: PMC8965972 DOI: 10.1016/j.bioactmat.2022.01.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/28/2022] [Accepted: 01/28/2022] [Indexed: 12/28/2022] Open
Abstract
To control capillary bleeding, surgeons may use absorbable hemostatic agents, such as Surgicel® and TachoSil®. Due to their slow resorption, their persistence in situ can have a negative impact on tissue repair in the resected organ. To avoid complications and obtain a hemostatic agent that promotes tissue repair, a zinc-supplemented calcium alginate compress was developed: HEMO-IONIC®. This compress is non-absorbable and is therefore removed once hemostasis has been achieved. After demonstrating the hemostatic efficacy and stability of the blood clot obtained with HEMO-IONIC, the impact of Surgicel, TachoSil, and HEMO-IONIC on cell activation and tissue repair were compared (i) in vitro on endothelial cells, which are essential to tissue repair, and (ii) in vivo in a mouse skin excision model. In vitro, only HEMO-IONIC maintained the phenotypic and functional properties of endothelial cells and induced their migration. In comparison, Surgicel was found to be highly cytotoxic, and TachoSil inhibited endothelial cell migration. In vivo, only HEMO-IONIC increased angiogenesis, the recruitment of cells essential to tissue repair (macrophages, fibroblasts, and epithelial cells), and accelerated maturation of the extracellular matrix. These results demonstrate that a zinc-supplemented calcium alginate, HEMO-IONIC, applied for 10 min at the end of surgery and then removed has a long-term positive effect on all phases of tissue repair.
A new Zn2+ enriched Ca2+ alginate hemostatic agent, HEMO-IONIC, has been developed. Non-absorbable, it achieves hemostasis with no foreign bodies left in the wound. HEMO-IONIC stimulates endothelial cell migration in vitro and angiogenesis in vivo. HEMO-IONIC, removed 10 min after application, promotes all stages of tissue repair.
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United 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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12
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Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021; 18:40-55. [PMID: 32764740 DOI: 10.1038/s41575-020-0342-4] [Citation(s) in RCA: 556] [Impact Index Per Article: 139.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this 'hepatostat' will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver.
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Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Bharat Bhushan
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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13
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14
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Hoffmann K, Nagel AJ, Tanabe K, Fuchs J, Dehlke K, Ghamarnejad O, Lemekhova A, Mehrabi A. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg 2020; 20:31. [PMID: 32050952 PMCID: PMC7017496 DOI: 10.1186/s12893-019-0664-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.
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Affiliation(s)
- Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany.
| | - Alexander Johannes Nagel
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Kazukata Tanabe
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | | | - Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Anastasia Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
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15
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Adams JM, Jafar-Nejad H. The Roles of Notch Signaling in Liver Development and Disease. Biomolecules 2019; 9:biom9100608. [PMID: 31615106 PMCID: PMC6843177 DOI: 10.3390/biom9100608] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/07/2019] [Accepted: 10/07/2019] [Indexed: 02/07/2023] Open
Abstract
The Notch signaling pathway plays major roles in organ development across animal species. In the mammalian liver, Notch has been found critical in development, regeneration and disease. In this review, we highlight the major advances in our understanding of the role of Notch activity in proper liver development and function. Specifically, we discuss the latest discoveries on how Notch, in conjunction with other signaling pathways, aids in proper liver development, regeneration and repair. In addition, we review the latest in the role of Notch signaling in the pathogenesis of liver fibrosis and chronic liver disease. Finally, recent evidence has shed light on the emerging connection between Notch signaling and glucose and lipid metabolism. We hope that highlighting the major advances in the roles of Notch signaling in the liver will stimulate further research in this exciting field and generate additional ideas for therapeutic manipulation of the Notch pathway in liver diseases.
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Affiliation(s)
- Joshua M Adams
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
- Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Hamed Jafar-Nejad
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
- Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
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16
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Wnt ligand and receptor patterning in the liver. Curr Opin Cell Biol 2019; 62:17-25. [PMID: 31509785 DOI: 10.1016/j.ceb.2019.07.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 12/18/2022]
Abstract
In the liver, the tight spatiotemporal regulation of Wnt/β-catenin signaling is required to establish and maintain a metabolic form of tissue polarity termed zonation. In this review, we discuss the latest technologies applied in the study of liver zonation and provide a summary of the Wnt ligand and receptor expression patterns in the hepatic lobule. We further discuss the mechanisms, by which Wnt instructive cues might be spatially confined and propagated along the central vein-portal triad axis.
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17
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Valizadeh A, Majidinia M, Samadi-Kafil H, Yousefi M, Yousefi B. The roles of signaling pathways in liver repair and regeneration. J Cell Physiol 2019; 234:14966-14974. [PMID: 30770551 DOI: 10.1002/jcp.28336] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Revised: 12/23/2018] [Accepted: 01/10/2019] [Indexed: 01/24/2023]
Abstract
The liver has remarkable regeneration potency that restores liver mass and sustains body hemostasis. Liver regeneration through signaling pathways following resection or moderate damages are well studied. Various cell signaling, growth factors, cytokines, receptors, and cell types implicated in liver regeneration undergo controlled hypertrophy and proliferation. Some aspects of liver regeneration have been discovered and many investigations have been carried out to identify its mechanisms. However, for optimizing liver regeneration more should be understood about mechanisms that control the growth of hepatocytes and other liver cell types in adults. The current paper deals with the possible applicability of liver regeneration signaling pathways as a target for therapeutic approaches and preventing various liver damages. Furthermore, the latest findings of spectrum-specific signaling pathway mechanisms that underlie liver regeneration are briefly described.
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Affiliation(s)
- Amir Valizadeh
- Stem Cells Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidinia
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Hossein Samadi-Kafil
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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18
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Hessheimer AJ, Martínez de la Maza L, Adel Al Shwely F, Espinoza AS, Ausania F, Fondevila C. Somatostatin and the "Small-For-Size" Liver. Int J Mol Sci 2019; 20:2512. [PMID: 31121844 PMCID: PMC6566601 DOI: 10.3390/ijms20102512] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/07/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
"Small-for-size" livers arising in the context of liver resection and transplantation are vulnerable to the effects of increased portal flow in the immediate postoperative period. Increased portal flow is an essential stimulus for liver regeneration. If the rise in flow and stimulus for regeneration are excessive; however, liver failure and patient death may result. Somatostatin is an endogenous peptide hormone that may be administered exogenously to not only reduce portal blood flow but also offer direct protection to different cells in the liver. In this review article, we describe key changes that transpire in the liver following a relative size reduction occurring in the context of resection and transplantation and the largely beneficial effects that peri-operative somatostatin therapy may help achieve in this setting.
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Affiliation(s)
- Amelia J Hessheimer
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Lilia Martínez de la Maza
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Farah Adel Al Shwely
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Arlena Sofía Espinoza
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Fabio Ausania
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
| | - Constantino Fondevila
- Hepatopancreatobiliary Surgery and Transplantation, General & Digestive Surgery, Metabolic & Digestive Diseases Institute (ICMDM), Hospital Clínic, CIBERehd, IDIBAPS, University of Barcelona, 08036 Barcelona, Spain.
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19
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Bartas M, Červeň J, Oppelt J, Peteja M, Vávra P, Zonča P, Procházka V, Brázda V, Pečinka P. Liver regeneration during the associating liver partition and portal vein ligation for staged hepatectomy procedure in Sus scrofa is positively modulated by stem cells. Oncol Lett 2018; 15:6309-6321. [PMID: 29616108 PMCID: PMC5876427 DOI: 10.3892/ol.2018.8108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Accepted: 11/02/2017] [Indexed: 11/17/2022] Open
Abstract
This present study investigated the impact of the application of stem cells to liver regeneration following the first stage of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). The experiment was conducted on a pig model (n=6, 3 that did not receive application of stem cells, 3 that received application stem cells). Collected samples of liver (day 0 and 9 following surgery) were subjected to complete transcriptome sequencing. In total, 39 differentially expressed genes were found in the group without the application of the stem cells (genes of unwanted processes such as fibrosis and inflammation). In the group that did receive application of stem cells, no significantly differentially expressed genes were found, indicating a properly regenerated liver remnant. The present study therefore demonstrated, to the best of our knowledge for the first time, the positive effect of stem cells application in the liver regeneration process during ALPPS procedure in the pig model.
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Affiliation(s)
- Martin Bartas
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic
| | - Jiri Červeň
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic.,Institute of Environmental Technologies, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic
| | - Jan Oppelt
- Centre for Structural Biology, Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic.,National Centre for Biomolecular Research, Centre for Structural Biology, Central European Institute of Technology, Masaryk University, 62500 Brno, 70852 Ostrava, Czech Republic
| | - Matus Peteja
- Department of Surgery, University Hospital in Ostrava, 70852 Ostrava, Czech Republic.,Department of Surgical Studies, Faculty of Medicine, University of Ostrava, 70852 Ostrava, Czech Republic
| | - Petr Vávra
- Department of Surgery, University Hospital in Ostrava, 70852 Ostrava, Czech Republic.,Department of Surgical Studies, Faculty of Medicine, University of Ostrava, 70852 Ostrava, Czech Republic
| | - Pavel Zonča
- Department of Surgery, University Hospital in Ostrava, 70852 Ostrava, Czech Republic.,Department of Surgical Studies, Faculty of Medicine, University of Ostrava, 70852 Ostrava, Czech Republic
| | - Vaclav Procházka
- Department of Radiology, University Hospital in Ostrava, 70852 Ostrava, Czech Republic
| | - Vaclav Brázda
- Institute of Biophysics, Academy of Sciences of The Czech Republic, 61265 Brno, Czech Republic
| | - Petr Pečinka
- Department of Biology and Ecology, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic.,Institute of Environmental Technologies, Faculty of Science, University of Ostrava, 71000 Ostrava, Czech Republic
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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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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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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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Angiogenesis in the Transplanted Donor Graft After Living-Donor Liver Transplantation. Transplantation 2017; 102:e26-e29. [PMID: 28991124 DOI: 10.1097/tp.0000000000001972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND There is no direct evidence for the role of angiogenesis in liver regeneration in humans. This study aimed to determine whether angiogenesis is involved in the regeneration of transplanted donor grafts in human living-donor liver transplantation (LDLT) and to examine the impact of donor graft volume on angiogenesis. METHODS Clinical data and liver tissue characteristics were analyzed in 4 patients who received adult-to-adult LDLT with dual left lobe grafts from 2 living donors. Liver tissues from transplanted donor grafts were obtained and immunohistochemically examined at 3 to 4 weeks after transplantation using the endothelial marker Ki67+ and CD31+. RESULTS All recipients showed recovery of normal liver function and a significant increase in the volume of engrafted left lobes after transplantation. Immunohistochemistry showed a remarkable increase in Ki67+ single hepatocyte proliferation, implying the role of hepatocytes in liver reconstitution, and a high density of blood vessels and proliferative endothelium, suggesting in vivo angiogenesis. Furthermore, we found that Ki67+ nuclei in CD31+ sinusoidal endothelial cells were higher in recipients with smaller donor grafts than in those with larger donor grafts. CONCLUSIONS Our results suggested that angiogenesis is involved in the regeneration of transplanted liver in humans in inverse proportion to the donor graft volume.
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Does apparent diffusion coefficient predict the degree of liver regeneration of donor and recipient after living donor liver transplantation? Eur J Radiol 2017; 90:146-151. [PMID: 28583626 DOI: 10.1016/j.ejrad.2017.02.041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 02/23/2017] [Accepted: 02/27/2017] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To elucidate the relationship between the ADCs of the liver graft and the remnant liver and the degree of liver regeneration in LDLT. MATERIALS AND METHODS 15 recipients and 15 corresponding donors underwent magnetic resonance imaging and computed tomography 1-2 weeks after living donor liver transplantation (LDLT). For diffusion-weighted imaging (DWI), a single-shot echo-planar sequence with b-factors of 0, 500, and 1000s/mm2 was scanned. ADCs of the liver parenchyma were calculated at b factors of 0 and 500 and 1000 (ADC 0-500-1000) or 0 and 500 (ADC 0-500) or 500 and 1000 (ADC 500-1000). The liver volume ratio at LDLT, the mean ADCs and the regeneration rate were compared between the graft and the remnant liver using paired-t tests. RESULTS The mean liver volume ratio of the recipients (41.3±9.8%) tended to be smaller than that of the donors (51.8±13.8%). The mean ADC 0-500 of the remnant liver (1.72±0.33) was significantly higher than that of the graft (1.43±0.32). The regeneration rate of the graft (2.07±0.41) was significantly higher than that of the remnant liver (1.53±0.49). CONCLUSION ADC 0-500 can describe differences in blood perfusion between liver grafts and the remnant liver according to the degree of liver regeneration.
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Karidis NP, Delladetsima I, Theocharis S. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis. Gastroenterol Res Pract 2015; 2015:654105. [PMID: 25892989 PMCID: PMC4393903 DOI: 10.1155/2015/654105] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 03/16/2015] [Indexed: 12/29/2022] Open
Abstract
Chronic hepatitis C virus (HCV) infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even "similar" causes, such as hepatitis B virus- (HBV-) related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.
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Affiliation(s)
- Nikolaos P. Karidis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Ioanna Delladetsima
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
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Chen ZY, Liang J, Deng X. Efficacy and safety of thalidomide combined with transcatheter arterial chemoembolization for primary hepatic carcinoma: A systematic review. Shijie Huaren Xiaohua Zazhi 2015; 23:291-307. [DOI: 10.11569/wcjd.v23.i2.291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of thalidomide (TLD) combined with transcatheter arterial chemoembolization (TACE) for primary hepatic carcinoma (PHC).
METHODS: We searched all randomized controlled trials (RCTs) about TLD combined with TACE for PHC from the Cochrane Library (2014, Issue 3), Web of Science (1986 to March 2014), PubMed (1966 to March 2014), CNKI (1917 to March 2014), VIP (1989 to March 2014) and WanFang Databases (1998 to March 2014). The retrieved articles were screened by two reviewers according to the inclusion criteria, and the data were then extracted. The quality of the included RCTs was evaluated with reference to the Cochrane systematic review. Meta-analysis of overall response rate (ORR), disease control rate (DCR), change of KPS score, survival rate, the change of VEGF and rate of adverse effects was conducted using RevMan 5.2 software.
RESULTS: A total of 22 RCTs involving 1590 patients were included. The meta-analysis showed that compared with TACE alone, TLD combined with TACE was superior in ORR [relative risk (RR) = 1.29, 95% confidence interval (CI): 1.15-1.44], DCR (RR = 1.27, 95%CI: 1.16-1.39), change of KPS score [mean difference (MD) = 9.23, 95%CI: 6.90-11.55], 6-month survival rate (RR = 1.10, 95%CI: 1.01-1.20), 1-year survival rate (RR = 1.25, 95%CI: 1.13-1.39), 2-year survival rate (RR = 1.45, 95%CI: 1.18-1.78), 3-year survival rate (RR = 1.70, 95%CI: 1.16-2.50), and change of VEGF score (MD = -123.64, 95%CI: -143.72--103.55) (P < 0.05). TLD combined with TACE was associated with a higher incidence of drug rash compared with TACE alone (RR = 4.50, 95%CI: 2.34-8.64, P < 0.00001), although the two groups had comparable incidence of gastrointestinal reactions (RR = 1.08, 95%CI: 0.93-1.25), myelosuppression (RR = 1.12, 95%CI: 0.82-1.52), and liver dysfunction (RR = 1.00, 95%CI: 0.72-1.39) (P > 0.05).
CONCLUSION: The current research shows that compared with TACE alone, TLD combined with TACE was associated with higher ORR, DCR, change of KPS score, 0.5-, 1-, 2- and 3-year survival rates, and change of VEGF score, as well as a higher incidence of drug rash, although the incidence of gastrointestinal reactions, myelosuppression, and liver dysfunction was similar between the two groups.
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Kikuchi A, Monga SP. PDGFRα in liver pathophysiology: emerging roles in development, regeneration, fibrosis, and cancer. Gene Expr 2015; 16:109-27. [PMID: 25700367 PMCID: PMC4410163 DOI: 10.3727/105221615x14181438356210] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Platelet-derived growth factor receptor α (PDGFRα) is an isoform of the PDGFR family of tyrosine kinase receptors involved in cell proliferation, survival, differentiation, and growth. In this review, we highlight the role of PDGFRα and the current evidence of its expression and activities in liver development, regeneration, and pathology-including fibrosis, cirrhosis, and liver cancer. Studies elucidating PDGFRα signaling in processes ranging from profibrotic signaling, angiogenesis, and oxidative stress to epithelial-to-mesenchymal transition point toward PDGFRα as a potential therapeutic target in various hepatic pathologies, including hepatic fibrosis and liver cancer. Furthermore, PDGFRα localization and modulation during liver development and regeneration may lend insight into its potential roles in various pathologic states. We will also briefly discuss some of the current targeted treatments for PDGFRα, including multi receptor tyrosine kinase inhibitors and PDGFRα-specific inhibitors.
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Affiliation(s)
- Alexander Kikuchi
- Department of Pathology and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Prevention of liver fibrosis by intrasplenic injection of high-density cultured bone marrow cells in a rat chronic liver injury model. PLoS One 2014; 9:e103603. [PMID: 25255097 PMCID: PMC4177810 DOI: 10.1371/journal.pone.0103603] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 07/03/2014] [Indexed: 01/27/2023] Open
Abstract
Endothelial progenitor cells (EPCs) from bone marrow have proven to be functional for the prevention of liver fibrosis in chronic liver injury. However, expansion of EPCs in culture is complicated and expansive. Previously, we have established a simple method that could enrich and expand EPCs by simple seeding bone marrow cells in high density dots. The purpose of this study is to evaluate whether cells derived from high-density (HD) culture of rat bone marrow cells could prevent the liver fibrosis in a chronic liver injury rat model, induced by carbon tetrachloride (CCl4). Flow cytometric analysis showed that cells from HD culture were enriched for EPCs, expressing high levels of EPC markers. Intrasplenic injection of HD cultured bone marrow cells in the CCl4-induced liver injury rat showed an enhanced antifibrogenic effect compared with animals treated with cells from regular-density culture. The antifibrogenic effect was demonstrated by biochemical and histological analysis 4 weeks post-transplantation. Furthermore, cells from HD culture likely worked through increasing neovascularization, stimulating liver cell proliferation, and suppressing pro-fibrogenic factor expression. HD culture, which is a simple and cost-effective procedure, could potentially be used to expand bone marrow cells for the treatment of liver fibrosis.
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Tivers MS, House AK, Smith KC, Wheeler-Jones CPD, Lipscomb VJ. Markers of angiogenesis associated with surgical attenuation of congenital portosystemic shunts in dogs. J Vet Intern Med 2014; 28:1424-32. [PMID: 25132501 PMCID: PMC4895587 DOI: 10.1111/jvim.12411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2014] [Revised: 05/10/2014] [Accepted: 06/11/2014] [Indexed: 12/28/2022] Open
Abstract
Background Dogs with congenital portosystemic shunts (CPSS) have hypoplasia of the intrahepatic portal veins. Surgical CPSS attenuation results in the development of the intrahepatic portal vasculature, the precise mechanism for which is unknown, although new vessel formation by angiogenesis is suspected. Hypothesis That the degree of portal vascular development and the increase in portal vascularization after CPSS attenuation is significantly associated with hepatic vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) gene expression and serum VEGF concentration. Animals Client‐owned dogs with CPSS undergoing surgical treatment. Forty‐nine dogs were included in the gene expression data and 35 in the serum VEGF data. Materials and Methods Dogs surgically treated by partial or complete CPSS attenuation were prospectively recruited. Relative gene expression of VEGF and VEGFR2 was measured in liver biopsy samples taken at initial and follow‐up surgery using quantitative polymerase chain reaction. Serum VEGF concentration was measured before and after CPSS attenuation using a canine specific ELISA. Statistical significance was set at the 5% level (P ≤ .05). Results There was a significant increase in the mRNA expression of VEGFR2 after partial attenuation (P = .006). Dogs that could tolerate complete attenuation had significantly greater VEGFR2 mRNA expression than those that only tolerated partial attenuation (P = .037). Serum VEGF concentration was significantly increased at 24 (P < .001) and 48 (P = .003) hours after attenuation. Conclusions and Clinical Importance These findings suggest that intrahepatic angiogenesis is likely to occur after the surgical attenuation of CPSS in dogs, and contributes to the development of the intrahepatic vasculature postoperatively.
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Affiliation(s)
- M S Tivers
- Department of Veterinary Clinical Sciences, Royal Veterinary College, Hatfield, Hertfordshire, UK
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31
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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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Kang YBA, Rawat S, Cirillo J, Bouchard M, Noh HM. Layered long-term co-culture of hepatocytes and endothelial cells on a transwell membrane: toward engineering the liver sinusoid. Biofabrication 2013; 5:045008. [PMID: 24280542 DOI: 10.1088/1758-5082/5/4/045008] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This paper presents a novel liver model that mimics the liver sinusoid where most liver activities occur. A key aspect of our current liver model is a layered co-culture of primary rat hepatocytes (PRHs) and primary rat liver sinusoidal endothelial cells (LSECs) or bovine aortic endothelial cells (BAECs) on a transwell membrane. When a layered co-culture was attempted with a thin Matrigel layer placed between hepatocytes and endothelial cells to mimic the space of Disse, the cells did not form completely separated monolayers. However, when hepatocytes and endothelial cells were cultured on the opposite sides of a transwell membrane, PRHs co-cultured with LSECs or BAECs maintained their viability and normal morphology for 39 and 57 days, respectively. We assessed the presence of hepatocyte-specific differentiation markers to verify that PRHs remained differentiated in the long-term co-culture and analyzed hepatocyte function by monitoring urea synthesis. We also noted that the expression of cytochrome P-450 remained similar in the co-cultured system from day 1 to day 48. Thus, our novel liver model system demonstrated that primary hepatocytes can be cultured for extended times and retain their hepatocyte-specific functions when layered with endothelial cells.
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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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Welker MW, Trojan J. Antiangiogenic treatment in hepatocellular carcinoma: the balance of efficacy and safety. Cancer Manag Res 2013; 5:337-47. [PMID: 24204170 PMCID: PMC3804539 DOI: 10.2147/cmar.s35029] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a severe complication of advanced liver disease with a worldwide incidence of more than 600,000 patients per year. Liver function, clinical performance status, and tumor size are considered in the Barcelona Clinic Liver Cancer (BCLC) system. While curative treatment options are available for early stages, most patients present with intermediate- or advanced-stage HCC, burdened with a poor prognosis, substantially influenced by the degree of liver-function impairment. Hypervascularization is a major characteristic of HCC, and antiangiogenic treatments are the basis of treatment in noncurative stages, including interventional and pharmacological treatments. Currently, the tyrosine-kinase inhibitor sorafenib is still the only approved drug for HCC. Further improvements in survival in patients with intermediate- and advanced-stage HCC may be anticipated by both multimodal approaches, such as combination of interventional and systemic treatments, and new systemic treatment options. Until now, the Phase III development of other tyrosine-kinase inhibitors in patients with advanced HCC has failed due to minor efficacy and/or increased toxicity compared to sorafenib. However, promising Phase II data have been reported with MET inhibitors in this hard-to-treat population. This review gives a critical overview of antiangiogenic drugs and strategies in intermediate- and advanced-stage HCC, with a special focus on safety.
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Affiliation(s)
| | - Joerg Trojan
- Medizinische Klinik 1, Universitätsklinikum Frankfurt, Germany
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36
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Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met. Clin Exp Metastasis 2013; 31:1-14. [PMID: 23900501 DOI: 10.1007/s10585-013-9604-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 07/05/2013] [Indexed: 02/06/2023]
Abstract
Hepatic resection is the preferred option for curative treatment of colorectal liver metastasis (CLM). However, this is associated with significant recurrence rates in both hepatic and extrahepatic sites. The upregulation of growth factors required for liver regeneration after resection is thought to stimulate the growth of micrometastases. The current study describes temporal changes in the expression of hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR) and insulin growth factor I receptor (IGF-IR) in an orthotopic mouse model of liver resection and tumour induction. Mice underwent 70% hepatectomy and induction of liver metastases through intrasplenic injection of colorectal cancer cells. Control groups included sham-operated mice and 70% hepatectomy alone. The expression levels of liver and tumour c-Met, EGFR and IGF-IR were quantified by quantitative RT-PCR at different time points. 70% liver resection stimulates tumour growth; increases the expression of c-Met within established tumours and surrounding liver parenchyma; downregulates EGFR expression and increases IGF-IR expression within the liver parenchyma. In conclusion, we demonstrate in our mouse model that major hepatectomy stimulates engraftment and growth of CLM and that this effect is probably due to the upregulation of c-Met as a result of the liver regeneration process. Liver IGF-IR may also contribute to this phenomenon through a paracrine effect on tumour growth. This study provides support for the role of c-Met in the stimulation of tumour growth after resection possibly through the promotion of tumour cell proliferation.
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Kang LI, Mars WM, Michalopoulos GK. Signals and cells involved in regulating liver regeneration. Cells 2012; 1:1261-1292. [PMID: 24710554 PMCID: PMC3901148 DOI: 10.3390/cells1041261] [Citation(s) in RCA: 97] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2012] [Revised: 11/27/2012] [Accepted: 12/07/2012] [Indexed: 12/11/2022] Open
Abstract
Liver regeneration is a complex phenomenon aimed at maintaining a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes fail to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which transdifferentiate into hepatocytes and restore liver size.
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Affiliation(s)
- Liang-I Kang
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
| | - Wendy M Mars
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Filali EE, Hiralall JK, van Veen HA, Stolz DB, Seppen J. Human liver endothelial cells, but not macrovascular or microvascular endothelial cells, engraft in the mouse liver. Cell Transplant 2012; 22:1801-11. [PMID: 23044355 DOI: 10.3727/096368912x657594] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Liver cell transplantation has had limited clinical success so far, partly due to poor engraftment of hepatocytes. Instead of hepatocytes. other cell types, such as endothelial cells, could be used in ex vivo liver gene therapy. The goal of the present study was to compare the grafting and repopulation capacity of human endothelial cells derived from various tissues. Human endothelial cells were isolated from adult and fetal livers using anti-human CD31 antibody-conjugated magnetic beads. Human macrovascular endothelial cells were obtained from umbilical vein. Human microvascular endothelial cells were isolated from adipose tissue. Cells were characterized using flow cytometry. Liver engraftment and repopulation of endothelial cells was studied after intrasplenic transplantation in monocrotaline-treated immunodeficient mice. Following transplantation, human liver endothelial cells engrafted throughout the mouse liver. With immunoscanning electron microscopy, fenestrae in engrafted human liver endothelial cells were identified, a characteristic feature of liver sinusoidal endothelial cells. In contrast, CD31-negative liver cells, human macrovascular and microvascular endothelial cells were not capable of repopulating mouse liver. Characterization of human liver, macrovascular, and microvascular endothelial cells demonstrated expression of CD31, CD34, and CD146 but not CD45. Our study shows that only human liver endothelial cells, but not macro- and microvascular endothelial cells, have the unique capacity to engraft and repopulate the mouse liver. These results indicate that mature endothelial cells cannot transdifferentiate in vivo and thus do not exhibit phenotypic plasticity. Our results have set a basis for further research to the potential of human liver endothelial cells in liver-directed cell and gene therapy.
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Affiliation(s)
- Ebtisam El Filali
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Parlakgumus A, Colakoglu T, Kayaselcuk F, Colakoglu S, Ezer A, Calıskan K, Karakaya J, Yildirim S. Two drugs with paradoxical effects on liver regeneration through antiangiogenesis and antifibrosis: Losartan and Spironolactone: a pharmacologic dilemma on hepatocyte proliferation. J Surg Res 2012; 179:60-5. [PMID: 22989552 DOI: 10.1016/j.jss.2012.08.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Revised: 07/06/2012] [Accepted: 08/22/2012] [Indexed: 01/12/2023]
Abstract
BACKGROUND There is a strong relationship between liver regeneration and angiogenesis and fibrosis. It is known that Spironolactone, an aldosterone antagonist, acting on rennin-aldosterone axis, and Losartan, an angiotensin II type I antagonist, have both antifibrotic and antiangiogenic effects. Theoretically, the end result of these mechanisms with contradictory influences on liver regeneration is not known well. In this study, we aimed to reveal the effects on liver regeneration of administration of Spironolactone and Losartan, having contradicting effects on regeneration through antiangiogenesis and antifibrosis. MATERIALS AND METHODS A total of 72 Wistar albino rats were divided into control, Spironolactone, and Losartan groups and subdivided to conduct examinations on days 1, 3, 5, and 7. The specimens were treated with proliferating cell nuclear antigen to evaluate the characteristics of liver regeneration; with phosphorylated Smad2 (phospho-Smad2), serum transforming growth factor beta (TGF-B) 1, and tissue TGF-B1 to evaluate the termination of regeneration and with vascular endothelial growth factor receptor 2, Flk-1/KDR, to evaluate angiogenesis. RESULTS The proliferating cell nuclear antigen-labeling index was found to be significantly higher in Spironolactone and Losartan groups than in the control group on days 1, 3, and 5 (P = 0.031, 0.0023, and 0.032, respectively). Vascular endothelial growth factor receptor 2, Flk-1/KDR, expression was significantly lower in Spironolactone and Losartan groups than in the control group on days 3, 5, and 7 (P = 0.032, 0.0024, and 0.007, respectively). Phospho-Smad2 was significantly lower on days 1, 3, and 5 in Spironolactone and Losartan groups than in the control group (P = 0.011, 0.0020, and 0.05, respectively). Tissue TGF-B1 levels were significantly lower in Spironolactone and Losartan groups than in the control group only on day 3 (P = 0039). Serum TGF-B1 levels in Losartan groups were significantly different from those of control and Spironolactone groups only on day 1 (P < 0.05). CONCLUSIONS Liver regeneration, expected to decrease on day 3, was prolonged and increased even on day 5 despite antiangiogenic effects of Losartan and Spironolactone, which in fact inhibit fibrosis through phospho-Smad2 and increase regeneration. In addition, serum and tissue TGF-B1 levels are not sensitive enough to show active TGF-B1 for the evaluation of regeneration.
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Affiliation(s)
- Alper Parlakgumus
- Department of General Surgery, Adana Teaching and Research Center, Baskent University School of Medicine, Ankara, Turkey.
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"Inherent limitations" in donors: control matched study of consequences following a right hepatectomy for living donation and benign liver lesions. Ann Surg 2012; 255:528-33. [PMID: 22311131 DOI: 10.1097/sla.0b013e3182472152] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The aim of this study was to identify "inherent limitations" in healthy donors who are responsible for donor morbidity after right hepatectomy (RH) for adult-to-adult living donor liver transplantation (ALDLT). BACKGROUND Right hepatectomy for ALDLT remains a challenging procedure without significant improvement in morbidity over time. This suggests some "inherent limitations" in healthy individuals, which are beyond the recent improvements in the donor evaluation and selection process and refinements in surgical technique during the learning curve. METHODS To identify response of RH in ALDLT, we prospectively studied 32 patients requiring an RH for benign liver lesions (BL), matched with 32 living donors (LD) operated by same team. All patients underwent liver volume evaluation by computed tomographic (CT) volumetry preoperatively and 1 week after RH, postoperative complications graded with Clavien's system. RESULTS The comparison (LD vs BL) showed that remnant liver volume (RLV) on preoperative CT volumetry was higher in the BL group (450 ± 150 vs 646 ± 200 mL, P < 0.001) representing 31% ± 7% in LD group versus 36% ± 7% of the total liver volume in BL group (P = 0.03). On postoperative day 7, the RLV was similar in the 2 groups (866 ± 162 vs 941 ± 153 mL) resulting from a significantly higher regeneration rate in the LD group (89% vs 55%, P = 0.009). Overall complications rate was lower in the BL group (46% vs 21%, P = 0.035). CONCLUSIONS Right hepatectomy in LDLT induces a more severe deprivation of liver volume than in BL, which induce an accelerated regeneration. Accelerated regeneration could represent "inherent limitation" in healthy donors that makes them more vulnerable for postoperative complications.
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Crawford JM, Burt AD. Anatomy, pathophysiology and basic mechanisms of disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:1-77. [DOI: 10.1016/b978-0-7020-3398-8.00001-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Prognostic significance of cyclooxygenase-2, epidermal growth factor receptor 1, and microvascular density in gastric cancer. Med Oncol 2011; 29:1739-47. [PMID: 22048943 DOI: 10.1007/s12032-011-0098-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2011] [Accepted: 10/19/2011] [Indexed: 12/20/2022]
Abstract
Gastric cancer remains a significant global health burden with poor treatment outcome. New treatment modalities that target inflammation, proliferation, and angiogenesis have been used in various cancers, including gastric cancer. We sought to study the pattern of expression of two important proteins, cyclooxygenase-2 and epidermal growth factor receptor, and their association with microvascular density, clinicopathological features, and survival in Arab Omani patients with gastric cancer. Formalin-fixed, paraffin-embedded tumors were studied by immunohistochemistry using monoclonal antibodies to cyclooxygenase-2, epidermal growth factor receptor, and CD34. The immunohistochemical results were correlated with clinicopathological features and survival. In our study population, we found a male/female ratio of 72:43, a median age of 59 years, stage III and IV incidence of 66.9%, and a median follow-up of 96 months. Positive expression rates of cyclooxygenase-2 and epidermal growth factor receptor were 89.6 and 23.5%, respectively. The median microvascular density value was 52.5. When this value was determined as the cut-off point, 50% of patients were found to have high microvascular density. Epidermal growth factor receptor over-expression correlated with high microvascular density values, advanced lymph node involvement (N3), and TNM stage presentation (III and IV). Similarly, lymph node involvement was associated with cyclooxygenase-2 over-expression and high microvascular density. Univariate analysis showed that epidermal growth factor receptor over-expression, pathological T3 and T4 disease, and overall stage III and IV disease were adverse prognostic factors. On multivariate analysis using a Cox regression model, expression of epidermal growth factor receptor, and advanced TNM stage were significant adverse prognostic factors for overall survival. Expression of epidermal growth factor receptor in Arab Omani patients with gastric cancer correlates with aggressive tumor characteristics and is an independent prognostic factor. Further clinical studies are needed to evaluate the utility of epidermal growth factor receptor immunohistochemistry as a tool for gastric cancer treatment.
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Yoshida D, Akahoshi T, Kawanaka H, Yamaguchi S, Kinjo N, Taketomi A, Tomikawa M, Shirabe K, Maehara Y, Hashizume M. Roles of vascular endothelial growth factor and endothelial nitric oxide synthase during revascularization and regeneration after partial hepatectomy in a rat model. Surg Today 2011; 41:1622-9. [PMID: 21969195 DOI: 10.1007/s00595-010-4484-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2010] [Accepted: 12/20/2010] [Indexed: 01/13/2023]
Abstract
PURPOSE Angiogenesis is an essential process in liver regeneration. Nitric oxide (NO) and vascular endothelial growth factor (VEGF) are the main regulators of normal and pathological angiogenesis. This study aimed to determine the roles of NO derived from endothelial nitric oxide synthase (eNOS) and VEGF in sinusoidal endothelial cell (SEC) proliferation during liver regeneration. METHODS Sprague-Dawley rats underwent a 70% partial hepatectomy (PHx), and were euthanized 0, 24, 48, 72, or 168 h later. Liver regeneration and SEC proliferation were evaluated. The protein expression of VEGF and eNOS was examined by a Western blot analysis. The rats were also treated with the NO synthase inhibitor N (G)-nitro-L-arginine-methyl ester (L-NAME) to examine its effects on liver regeneration and SEC proliferation. RESULTS The proliferating cell nuclear antigen (PCNA) labeling index of hepatocytes was significantly increased at 24 h after PHx. The eNOS protein expression and NO production were significantly increased from 72 to 168 h. The expression of VEGF protein was significantly increased at 72 h. L-NAME significantly inhibited the increases in the liver mass and decreased the PCNA labeling index of hepatocytes at 24 h. L-NAME also inhibited the induction of VEGF protein at 72 h. CONCLUSIONS Endothelial NOS and VEGF coordinately regulate SEC proliferation during liver regeneration. Sinusoidal endothelial cell proliferation is necessary and is an important step in liver regeneration.
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Affiliation(s)
- Daisuke Yoshida
- Department of Disaster and Emergency Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Welker MW, Trojan J. Anti-angiogenesis in hepatocellular carcinoma treatment: current evidence and future perspectives. World J Gastroenterol 2011; 17:3075-81. [PMID: 21912449 PMCID: PMC3158406 DOI: 10.3748/wjg.v17.i26.3075] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 12/28/2010] [Accepted: 01/04/2011] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is among the most common cancer diseases worldwide. Arterial hypervascularisation is an essential step for HCC tumorigenesis and can be targeted by transarterial chemoembolization (TACE). This interventional method is the standard treatment for patients with intermediate stage HCC, but is also applied as "bridging" therapy for patients awaiting liver transplantation in many centers worldwide. Usually the devascularization effect induced by TACE is transient, consequently resulting in repeated cycles of TACE every 4-8 wk. Despite documented survival benefits, TACE can also induce the up-regulation of proangiogenic and growth factors, which might contribute to accelerated progression in patients with incomplete response. In 2007, sorafenib, a multi-tyrosine kinase and angiogenesis inhibitor, was approved as the first systemic treatment for advanced stage HCC. Other active targeted compounds, either inhibitors of angiogenesis and/or growth factors, are currently being investigated in numerous clinical trials. To overcome revascularisation or tumor progression under TACE treatment it seems therefore attractive to combine TACE with systemic targeted agents, which might theoretically block the effects of proangiogenic and growth factors. Over the last 12 mo, several retrospective or prospective cohort studies combining TACE and sorafenib have been published. Nevertheless, robust results of the efficacy and tolerability of such combination strategies as proven by randomized, controlled trials are awaited in the next two years.
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Ninomiya M, Shirabe K, Ijichi H, Toshima T, Harada N, Uchiyama H, Taketomi A, Yoshizumi T, Maehara Y. Temporal changes in the stiffness of the remnant liver and spleen after donor hepatectomy as assessed by acoustic radiation force impulse: A preliminary study. Hepatol Res 2011; 41:579-86. [PMID: 21561532 DOI: 10.1111/j.1872-034x.2011.00809.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM Virtual touch tissue quantification (VTTQ) is an implementation of ultrasound acoustic radiation force impulse imaging that provides numerical measurements of tissue stiffness. We have evaluated the temporal changes of the remnant liver and spleen after living donor hepatectomy with special reference to the differences between right and left liver donation. METHODS Nineteen living donors who received right lobectomy (small remnant liver [SRL] group; n = 7) or extended left and caudate lobectomy (large remnant liver [LRL] group; n = 12) were enrolled. They underwent measurement of liver and spleen VTTQ before and after donor surgery. RESULTS Virtual touch tissue quantification of the remnant liver increased postoperatively until postoperative day (POD) 3-5, and the values in the SRL group were significantly higher than those in the LRL group at POD 3-9. The values of the spleen also increased after donor surgery and the values in the SRL group were significantly higher than those in the LRL group at POD 3-14. A significant positive correlation between postoperative maximum value of VTTQ and postoperative maximum total bilirubin levels was observed. In liver transplant recipients, there was a significant positive correlation between preoperative spleen VTTQ and the corresponding actual portal venous pressure that was measured at the time of transplant surgery. CONCLUSION Stiffness of the remaining liver and spleen in the smaller remnant liver group became harder than that in the larger remnant liver group. Perioperative measurement of liver and spleen VTTQ seems to be a useful means for assessing the physiology of liver regeneration.
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Affiliation(s)
- Mizuki Ninomiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Idetsu A, Suehiro T, Okada K, Shimura T, Kuwano H. Hyperbaric oxygenation promotes regeneration of biliary cells and improves cholestasis in rats. World J Gastroenterol 2011; 17:2229-35. [PMID: 21633534 PMCID: PMC3092876 DOI: 10.3748/wjg.v17.i17.2229] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2010] [Revised: 09/25/2010] [Accepted: 10/02/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of hyperbaric oxygenation (HBO) on regeneration of the biliary ductal system and postoperative cholestasis in hepatectomized rats.
METHODS: HBO was performed in Wistar rats daily starting 12 h after a 70% partial hepatectomy. Regenerated liver weight, serum parameters and the proliferating cell nuclear antigen labeling index of hepatocytes and biliary ductal cells were measured. Hepatocyte growth factor (HGF), c-Met and transforming growth factor (TGF) β-1 mRNA expression levels were analyzed by quantitative reverse transcription polymerase chain reaction.
RESULTS: HBO improved the postoperative serum levels of total bile acid but not transaminase levels. HBO promoted hepatocyte and biliary ductal cell proliferation. The hematoxylin and eosin-stained specimens revealed fewer ballooned hepatocytes and higher cell densities in the HBO group compared to the control group. HBO suppressed c-Met mRNA levels at 15 h but did not modulate HGF or TGF β-1 mRNA expression levels.
CONCLUSION: HBO promoted regeneration of biliary ductal cells and improved postoperative cholestasis after a partial hepatectomy.
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Abstract
Liver regeneration is known to be a process involving highly organized and ordered tissue growth triggered by the loss of liver tissue, and remains a fascinating topic. A large number of genes are involved in this process, and there exists a sequence of stages that results in liver regeneration, while at the same time inhibitors control the size of the regenerated liver. The initiation step is characterized by priming of quiescent hepatocytes by factors such as TNF-α, IL-6 and nitric oxide. The proliferation step is the step during which hepatocytes enter into the cell cycle's G1 phase and are stimulated by complete mitogens including HGF, TGF-α and EGF. Hepatic stimulator substance, glucagon, insulin, TNF-α, IL-1 and IL-6 have also been implicated in regulating the regeneration process. Inhibitors and stop signals of hepatic regeneration are not well known and only limited information is available. Furthermore, the effects of other factors such as VEGF, PDGF, hypothyroidism, proliferating cell nuclear antigen, heat shock proteins, ischemic-reperfusion injury, steatosis and granulocyte colony-stimulating factor on liver regeneration are also systematically reviewed in this article. A tissue engineering approach using isolated hepatocytes for in vitro tissue generation and heterotopic transplantation of liver cells has been established. The use of stem cells might also be very attractive to overcome the limitation of donor liver tissue. Liver-specific differentiation of embryonic, fetal or adult stem cells is currently under investigation.
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Affiliation(s)
- Changku Jia
- Department of Hepatobiliary Surgery, Affiliated Hospital of Hainan Medical University, Haikou, Hainan Province, China.
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Kim Y, Larkin AL, Davis RM, Rajagopalan P. The design of in vitro liver sinusoid mimics using chitosan-hyaluronic acid polyelectrolyte multilayers. Tissue Eng Part A 2010; 16:2731-41. [PMID: 20491586 DOI: 10.1089/ten.tea.2009.0695] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interactions between hepatocytes and liver sinusoidal endothelial cells (LSECs) are essential for the development and maintenance of hepatic phenotypic functions. We report the assembly of three-dimensional liver sinusoidal mimics comprised of primary rat hepatocytes, LSECs, and an intermediate chitosan-hyaluronic acid polyelectrolyte multilayer (PEM). The height of the PEMs ranged from 30 to 55 nm and exhibited a shear modulus of approximately 100 kPa. Hepatocyte-PEM cellular constructs exhibited stable urea and albumin production over a 7-day period, and these values were either higher or similar to cells cultured in a collagen sandwich. This is of significance because the thickness of a collagen gel is approximately 1000-fold higher than the height of the chitosan-hyaluronic acid PEM. In the hepatocyte-PEM-LSEC liver-mimetic cellular constructs, LSEC phenotype was maintained, and these cultures exhibited stable urea and albumin production. CYP1A1/2 activity measured over a 7-day period was significantly higher in the hepatocyte-PEM-LSEC constructs than in collagen sandwich cultures. A 16-fold increase in CYP1A1/2 activity was observed for hepatocyte-PEM-10,000 LSEC samples, thereby suggesting that interactions between hepatocytes and LSECs are critical in enhancing the detoxification capability in hepatic cultures in vitro.
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Affiliation(s)
- Yeonhee Kim
- Department of Chemical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA
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Kato T, Ito Y, Hosono K, Suzuki T, Tamaki H, Minamino T, Kato S, Sakagami H, Shibuya M, Majima M. Vascular endothelial growth factor receptor-1 signaling promotes liver repair through restoration of liver microvasculature after acetaminophen hepatotoxicity. Toxicol Sci 2010; 120:218-29. [PMID: 21135413 DOI: 10.1093/toxsci/kfq366] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Vascular endothelial growth factor (VEGF) and its receptors promote liver regeneration. The objective of the present study was to examine the role of VEGF receptor 1 (VEGFR1) signaling in hepatic tissue repair after acetaminophen (N-acetyl-para-aminophenol) (APAP)-induced liver injury. To do this, we treated VEGFR1 tyrosine kinase knockout (VEGFR1 TK(-/-)) and wild-type (WT) mice with APAP (300 mg/kg, ip). In WT mice, serum levels of alanine aminotransferase (ALT) and the necrotic area peaked between 8 and 24 h and then declined. In VEGFR1 TK(-/-) mice, ALT levels remained high at 48 h and extensive hepatic necrosis and hemorrhage were observed, as well as high mortality. Downregulation of hepatic messenger RNA expression of VEGFR1 and VEGFR2 was also noted in VEGFR1 TK(-/-) mice. VEGFR1 TK(-/-) mice displayed lower expression of proliferating cell nuclear antigen and of growth factors including hepatocyte growth factor, CD31, and basic fibroblast growth factor than WT. The hepatic microvasculature in VEGFR1 TK(-/-) was compromised as evidenced by impaired sinusoidal perfusion, suppressed endocytosis in liver sinusoidal endothelial cells (LSECs), and the formation of large gaps in LSECs. In WT mice, immunofluorescence revealed that recruited VEGFR1(+) cells in the necrotic area were positive for CD11b. VEGFR1 TK(-/-) exhibited fewer VEGFR1(+) and VEGFR2(+) cells. These results suggest that VEGFR1 signaling facilitates liver recovery from APAP hepatotoxicity by preventing excessive hemorrhage and reconstituting the sinusoids through recruitment of VEGFR1-expressing macrophages to the injured area and also through affecting expression of genes including hepatotrophic and pro-angiogenic growth factors.
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Affiliation(s)
- Tetsuki Kato
- Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan
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