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Szafranska K, Sørensen KK, Lalor PF, McCourt P. Sinusoidal cells and liver immunology. SINUSOIDAL CELLS IN LIVER DISEASES 2024:53-75. [DOI: 10.1016/b978-0-323-95262-0.00003-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Lotto J, Stephan TL, Hoodless PA. Fetal liver development and implications for liver disease pathogenesis. Nat Rev Gastroenterol Hepatol 2023; 20:561-581. [PMID: 37208503 DOI: 10.1038/s41575-023-00775-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/21/2023]
Abstract
The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver's specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ's small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.
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Affiliation(s)
- Jeremy Lotto
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Tabea L Stephan
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Pamela A Hoodless
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada.
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada.
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Mîndrilă B, Buteică SA, Mîndrilă I, Mihaiescu DE, Mănescu MD, Rogoveanu I. Administration Routes as Modulators of the Intrahepatic Distribution and Anti-Anemic Activity of Salicylic Acid/Fe3O4 Nanoparticles. Biomedicines 2022; 10:biomedicines10051213. [PMID: 35625949 PMCID: PMC9138897 DOI: 10.3390/biomedicines10051213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/19/2022] [Accepted: 05/21/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is a key organ in the pharmacokinetics of iron oxide nanoparticles (IONPs). This paper examined how the intravenous (IV) or intragastric (IG) route of administration influenced the intrahepatic distribution or therapeutic effects of IONPs. Wistar rats, some with bleeding-induced anemia, and iron oxide nanoparticles functionalized with salicylic acid (SaIONPs), with an average hydrodynamic diameter of 73 nm, compatible with rat sinusoid fenestrations, were used in this study. Light microscopy and multispectral camera analysis of Prussian blue labeled SaIONPs allowed mapping of intrahepatic nanoparticle deposits and revealed intrahepatic distribution patterns specific to each route of administration: loading of Kupffer cells and periportal hepatocytes when the IV route was used and predominant loading of hepatocytes when the IG route was used. Reducing the time to return to baseline values for hemoglobin (HGB) in rats with bleeding-induced anemia with IV or IG therapy has proven the therapeutic potential of SaIONPs in such anemias. The long-term follow-up showed that IV therapy resulted in higher HGB values. Proper use of the administration routes may modulate intrahepatic distribution and therapeutic effects of nanoparticles. These results may be beneficial in theragnosis of liver disease.
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Affiliation(s)
- Bogdan Mîndrilă
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (B.M.); (M.-D.M.)
| | - Sandra-Alice Buteică
- Faculty of Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Ion Mîndrilă
- Department of Morphology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
- Correspondence:
| | - Dan-Eduard Mihaiescu
- Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, 011061 Bucharest, Romania;
| | - Marina-Daniela Mănescu
- Doctoral School, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (B.M.); (M.-D.M.)
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
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Gifre-Renom L, Daems M, Luttun A, Jones EAV. Organ-Specific Endothelial Cell Differentiation and Impact of Microenvironmental Cues on Endothelial Heterogeneity. Int J Mol Sci 2022; 23:ijms23031477. [PMID: 35163400 PMCID: PMC8836165 DOI: 10.3390/ijms23031477] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/14/2022] [Accepted: 01/19/2022] [Indexed: 02/04/2023] Open
Abstract
Endothelial cells throughout the body are heterogeneous, and this is tightly linked to the specific functions of organs and tissues. Heterogeneity is already determined from development onwards and ranges from arterial/venous specification to microvascular fate determination in organ-specific differentiation. Acknowledging the different phenotypes of endothelial cells and the implications of this diversity is key for the development of more specialized tissue engineering and vascular repair approaches. However, although novel technologies in transcriptomics and proteomics are facilitating the unraveling of vascular bed-specific endothelial cell signatures, still much research is based on the use of insufficiently specialized endothelial cells. Endothelial cells are not only heterogeneous, but their specialized phenotypes are also dynamic and adapt to changes in their microenvironment. During the last decades, strong collaborations between molecular biology, mechanobiology, and computational disciplines have led to a better understanding of how endothelial cells are modulated by their mechanical and biochemical contexts. Yet, because of the use of insufficiently specialized endothelial cells, there is still a huge lack of knowledge in how tissue-specific biomechanical factors determine organ-specific phenotypes. With this review, we want to put the focus on how organ-specific endothelial cell signatures are determined from development onwards and conditioned by their microenvironments during adulthood. We discuss the latest research performed on endothelial cells, pointing out the important implications of mimicking tissue-specific biomechanical cues in culture.
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Affiliation(s)
- Laia Gifre-Renom
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven (KU Leuven), BE-3000 Leuven, Belgium; (L.G.-R.); (M.D.); (A.L.)
| | - Margo Daems
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven (KU Leuven), BE-3000 Leuven, Belgium; (L.G.-R.); (M.D.); (A.L.)
| | - Aernout Luttun
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven (KU Leuven), BE-3000 Leuven, Belgium; (L.G.-R.); (M.D.); (A.L.)
| | - Elizabeth A. V. Jones
- Centre for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Katholieke Universiteit Leuven (KU Leuven), BE-3000 Leuven, Belgium; (L.G.-R.); (M.D.); (A.L.)
- Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, 6229 ER Maastricht, The Netherlands
- Correspondence:
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5
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The Hepatic Sinusoid in Chronic Liver Disease: The Optimal Milieu for Cancer. Cancers (Basel) 2021; 13:cancers13225719. [PMID: 34830874 PMCID: PMC8616349 DOI: 10.3390/cancers13225719] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 11/08/2021] [Accepted: 11/11/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary During the development of chronic liver disease, the hepatic sinusoid undergoes major changes that further compromise the hepatic function, inducing persistent inflammation and the formation of scar tissue, together with alterations in liver hemodynamics. This diseased background may induce the formation and development of hepatocellular carcinoma (HCC), which is the most common form of primary liver cancer and a major cause of mortality. In this review, we describe the ways in which the dysregulation of hepatic sinusoidal cells—including liver sinusoidal cells, Kupffer cells, and hepatic stellate cells—may have an important role in the development of HCC. Our review summarizes all of the known sinusoidal processes in both health and disease, and possible treatments focusing on the dysregulation of the sinusoid; finally, we discuss how some of these alterations occurring during chronic injury are shared with the pathology of HCC and may contribute to its development. Abstract The liver sinusoids are a unique type of microvascular beds. The specialized phenotype of sinusoidal cells is essential for their communication, and for the function of all hepatic cell types, including hepatocytes. Liver sinusoidal endothelial cells (LSECs) conform the inner layer of the sinusoids, which is permeable due to the fenestrae across the cytoplasm; hepatic stellate cells (HSCs) surround LSECs, regulate the vascular tone, and synthetize the extracellular matrix, and Kupffer cells (KCs) are the liver-resident macrophages. Upon injury, the harmonic equilibrium in sinusoidal communication is disrupted, leading to phenotypic alterations that may affect the function of the whole liver if the damage persists. Understanding how the specialized sinusoidal cells work in coordination with each other in healthy livers and chronic liver disease is of the utmost importance for the discovery of new therapeutic targets and the design of novel pharmacological strategies. In this manuscript, we summarize the current knowledge on the role of sinusoidal cells and their communication both in health and chronic liver diseases, and their potential pharmacologic modulation. Finally, we discuss how alterations occurring during chronic injury may contribute to the development of hepatocellular carcinoma, which is usually developed in the background of chronic liver disease.
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Mak KM, Kee D, Shin DW. Alcohol-associated capillarization of sinusoids: A critique since the discovery by Schaffner and Popper in 1963. Anat Rec (Hoboken) 2021; 305:1592-1610. [PMID: 34766732 DOI: 10.1002/ar.24829] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 10/07/2021] [Accepted: 10/12/2021] [Indexed: 11/07/2022]
Abstract
This article reviews the literature on capillarization of hepatic sinusoids since its discovery in 1963. Liver sinusoidal endothelial cells are uniquely fenestrated and lack an underlying basement membrane. In chronic liver disease, the sinusoids capillarize and transform into systemic capillaries, a process termed capillarization of sinusoids. The histopathology is marked by defenestration, basement membrane formation, and space of Disse fibrogenesis. Capillarized sinusoids compromise the bidirectional exchange of materials between sinusoids and hepatocytes, leading to hepatocellular dysfunction. Sinusoidal capillarization was first described in active cirrhosis of alcoholics in 1963. Since then, it has been found in early and progressive stages of alcoholic hepatic fibrosis before the onset of cirrhosis. The sinusoidal structure is not altered in alcoholic steatosis without fibrosis. Defenestration impairs the ability of the endothelium to filter chylomicron remnants from sinusoids into the Disse's space, contributing to alcohol-induced postprandial hyperlipidemia and possibly atherosclerosis. Ethanol also modulates the fenestration dynamics in animals. In baboons, chronic alcohol consumption diminishes endothelial porosity in concomitance with hepatic fibrogenesis and in rats defenestrates the endothelium in the absence of fibrosis, and sometimes capillarizes the sinusoids. Acute ethanol ingestion enlarges fenestrations in rats and contracts fenestrations in rabbits. In sinusoidal endothelial cell culture, ethanol elicits fenestration dilation, which is likely related to its interaction with fenestration-associated cytoskeleton. Ethanol potentiates sinusoidal injury caused by cocaine, acetaminophen or lipopolysaccharide in mice and rats. Understanding ethanol's mechanisms on pathogenesis of sinusoidal capillarization and fenestration dynamics will lead to development of methods to prevent risks for atherosclerosis in alcoholism.
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Affiliation(s)
- Ki M Mak
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Dustin Kee
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Da Wi Shin
- Department of Medical Education, Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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Auvinen K, Lokka E, Mokkala E, Jäppinen N, Tyystjärvi S, Saine H, Peurla M, Shetty S, Elima K, Rantakari P, Salmi M. Fenestral diaphragms and PLVAP associations in liver sinusoidal endothelial cells are developmentally regulated. Sci Rep 2019; 9:15698. [PMID: 31666588 PMCID: PMC6821839 DOI: 10.1038/s41598-019-52068-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 10/11/2019] [Indexed: 12/30/2022] Open
Abstract
Endothelial cells contain several nanoscale domains such as caveolae, fenestrations and transendothelial channels, which regulate signaling and transendothelial permeability. These structures can be covered by filter-like diaphragms. A transmembrane PLVAP (plasmalemma vesicle associated protein) protein has been shown to be necessary for the formation of diaphragms. The expression, subcellular localization and fenestra-forming role of PLVAP in liver sinusoidal endothelial cells (LSEC) have remained controversial. Here we show that fenestrations in LSEC contain PLVAP-diaphragms during the fetal angiogenesis, but they lose the diaphragms at birth. Although it is thought that PLVAP only localizes to diaphragms, we found luminal localization of PLVAP in adult LSEC using several imaging techniques. Plvap-deficient mice revealed that the absence of PLVAP and diaphragms did not affect the morphology, the number of fenestrations or the overall vascular architecture in the liver sinusoids. Nevertheless, PLVAP in fetal LSEC (fenestrations with diaphragms) associated with LYVE-1 (lymphatic vessel endothelial hyaluronan receptor 1), neuropilin-1 and VEGFR2 (vascular endothelial growth factor receptor 2), whereas in the adult LSEC (fenestrations without diaphragms) these complexes disappeared. Collectively, our data show that PLVAP can be expressed on endothelial cells without diaphragms, contradict the prevailing concept that biogenesis of fenestrae would be PLVAP-dependent, and reveal previously unknown PLVAP-dependent molecular complexes in LSEC during angiogenesis.
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Affiliation(s)
- Kaisa Auvinen
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Emmi Lokka
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Elias Mokkala
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Norma Jäppinen
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Sofia Tyystjärvi
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Heikki Saine
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Markus Peurla
- Institute of Biomedicine, University of Turku, Turku, Finland
| | - Shishir Shetty
- Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Kati Elima
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Pia Rantakari
- MediCity Research Laboratory, University of Turku, Turku, Finland.,Institute of Biomedicine, University of Turku, Turku, Finland
| | - Marko Salmi
- MediCity Research Laboratory, University of Turku, Turku, Finland. .,Institute of Biomedicine, University of Turku, Turku, Finland.
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Abstract
This update focuses on two main topics. First, recent developments in our understanding of liver sinusoidal endothelial cell (LSEC) function will be reviewed, specifically elimination of blood-borne waste, immunological function of LSECs, interaction of LSECs with liver metastases, LSECs and liver regeneration, and LSECs and hepatic fibrosis. Second, given the current emphasis on rigor and transparency in biomedical research, the update discusses the need for standardization of methods to demonstrate identity and purity of isolated LSECs, pitfalls in methods that might lead to a selection bias in the types of LSECs isolated, and questions about long-term culture of LSECs. Various surface markers used for immunomagnetic selection are reviewed.
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Affiliation(s)
- Laurie D. DeLeve
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | - Ana C. Maretti-Mira
- Division of Gastrointestinal and Liver Diseases and the USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, California
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9
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Sørensen KK, Simon‐Santamaria J, McCuskey RS, Smedsrød B. Liver Sinusoidal Endothelial Cells. Compr Physiol 2015; 5:1751-74. [DOI: 10.1002/cphy.c140078] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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10
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Cogger VC, Roessner U, Warren A, Fraser R, Le Couteur DG. A Sieve-Raft Hypothesis for the regulation of endothelial fenestrations. Comput Struct Biotechnol J 2013; 8:e201308003. [PMID: 24688743 PMCID: PMC3962122 DOI: 10.5936/csbj.201308003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 07/31/2013] [Accepted: 08/11/2013] [Indexed: 01/13/2023] Open
Affiliation(s)
- Victoria C Cogger
- Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney NSW, Australia ; Charles Perkins Centre, University of Sydney NSW Australia
| | - Ute Roessner
- Metabolomics Australia and Australian Centre for Plant Functional Genomics, The University of Melbourne, 3010 Victoria, Australia
| | - Alessandra Warren
- Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney NSW, Australia ; Charles Perkins Centre, University of Sydney NSW Australia
| | - Robin Fraser
- Christchurch School of Medicine, University of Otago, Christchurch NZ
| | - David G Le Couteur
- Centre for Education and Research on Ageing and ANZAC Research Institute, Concord Hospital and University of Sydney, Sydney NSW, Australia ; Charles Perkins Centre, University of Sydney NSW Australia
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11
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Abstract
SUMMARY The 'liver sieve' is a term developed to describe the appearance and the role of fenestrations in the liver sinusoidal endothelial cell (LSEC). LSECs are gossamer-thin cells that line the hepatic sinusoid and they are perforated with pores called fenestrations clustered in sieve plates. There is growing evidence that fenestrations act like a permselective ultrafiltration system which is important for the hepatic uptake of many substrates, particularly chylomicron remnant lipoproteins. The liver sieve is a very efficient exchange system, however in conditions such as hepatic cirrhosis and fibrosis, diabetes mellitus and old age, there is defenestration of the liver sieve. Such defenestration has been shown to influence the hepatic uptake of various substrates including lipoproteins. In the future, pharmacological manipulation of the liver sieve may play a number of therapeutic roles including the management of dyslipidaemia; increasing the efficiency of liver-targeted gene therapy; and improving regeneration of old livers.
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Yokomori H, Oda M, Yoshimura K, Hibi T. Recent advances in liver sinusoidal endothelial ultrastructure and fine structure immunocytochemistry. Micron 2011; 43:129-34. [PMID: 21906955 DOI: 10.1016/j.micron.2011.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 08/04/2011] [Accepted: 08/04/2011] [Indexed: 01/28/2023]
Abstract
Ultrastructure reports have described that liver sinusoidal endothelial cell (LSEC)s contain a cytoskeletal framework of filamentous actin. Small G protein has emerged as an important regulator of the actin cytoskeleton, and consequently, of cell morphology and motility. We investigated actin filaments in relation to SEF in LSECs using a heavy meromyosin-decorated reaction and thereby elucidated the roles of small G protein and actin cytoskeleton in the morphological and functional alterations of SEF. Caveolin-1 expression has also been found in fenestrations with many characteristics of liver sinusoidal endothelial cells. Currently, fenestral studies and human disease are revealing ways to increase the liver sieve's porosity, which is reduced through pathological mechanisms. Hepatic sinusoidal endothelial dysfunction, which is known to impair endothelium-dependent relaxation in the liver microcirculation, contributes to increased intrahepatic vascular resistance.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine, Kitasato Medical Center Hospital, Saitama, Japan.
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Vidal-Vanaclocha F. Architectural and Functional Aspects of the Liver with Implications for Cancer Metastasis. LIVER METASTASIS: BIOLOGY AND CLINICAL MANAGEMENT 2011. [DOI: 10.1007/978-94-007-0292-9_2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Goto Y, Ohashi K, Utoh R, Yamamoto M, Okano T. Hepatocyte transplantation through the hepatic vein: a new route of cell transplantation to the liver. Cell Transplant 2010; 20:1259-70. [PMID: 21176398 DOI: 10.3727/096368910x547417] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The efficiency of hepatocyte transplantation into the liver varies with the method of administration. This study investigated whether retrograde infusion via the hepatic vein provides a sufficient number of donor cells for the liver. Donor hepatocytes were isolated from dipeptidyl peptidase IV (DPPIV(+)) rats and transplanted into DPPIV(-) rat livers either by antegrade portal vein infusion or retrograde hepatic vein infusion. Hepatocyte engraftment ratios and localization were evaluated by histological DPPIV enzymatic staining at 1 week and 8 weeks after the transplantation. No significant differences in engraftment efficiency were observed at either 1 week or 8 weeks after transplantation by either route. However, the localization of the transplanted hepatocytes differed with the administration route. Portal vein infusion resulted in predominantly periportal engraftment, whereas hepatic vein infusion led to pericentral zone engraftment. Immunohistochemical analysis showed that the transplanted hepatocytes engrafted in the pericentral zone after retrograde infusion displayed intense CYP2E1 staining similar to the surrounding native hepatocytes. CYP2E1 staining was further enhanced by administration of isosafrole, an inducing agent for various cytochrome P450 enzymes, including CYP2E1. This study demonstrates a novel approach of transplanting hepatocytes into the liver through retrograde hepatic vein infusion as the means to target cell implantation to the pericentral zone.
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Affiliation(s)
- Yuichiro Goto
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
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15
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Xie G, Wang L, Wang X, Wang L, DeLeve LD. Isolation of periportal, midlobular, and centrilobular rat liver sinusoidal endothelial cells enables study of zonated drug toxicity. Am J Physiol Gastrointest Liver Physiol 2010; 299:G1204-10. [PMID: 20813915 PMCID: PMC2993174 DOI: 10.1152/ajpgi.00302.2010] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Accepted: 08/27/2010] [Indexed: 01/31/2023]
Abstract
Many liver sinusoidal endothelial cell (LSEC)-dependent processes, including drug-induced liver injury, ischemia-reperfusion injury, acute and chronic rejection, fibrosis, and the HELLP (hemolytic anemia, elevated liver enzymes, low platelet count) syndrome, may have a lobular distribution. Studies of the mechanism of this distribution would benefit from a reliable method to isolate LSEC populations from different regions. We established and verified a simple method to isolate periportal, midlobular, and centrilobular LSEC. Three subpopulations of LSEC were isolated by immunomagnetic separation on the basis of CD45 expression. Flow cytometry showed that 78.2 ± 2.3% of LSEC were CD45 positive and that LSEC could be divided into CD45 bright (28.6 ± 2.7% of total population), dim (49.6 ± 1.0%), and negative populations (21.8 ± 2.3%). Immunohistochemistry confirmed that in vivo expression of CD45 in LSEC had a lobular distribution with enhanced CD45 staining in periportal LSEC. Cell diameter, fenestral diameter, number of fenestrae per sieve plate and per cell, porosity, and lectin uptake were significantly different in the subpopulations, consistent with the literature. Endocytosis of low concentrations of the LSEC-specific substrate, formaldehyde-treated serum albumin, was restricted to CD45 bright and dim LSEC. Acetaminophen was more toxic to the CD45 dim and negative populations than to the CD45 bright population. In conclusion, CD45 is highly expressed in periportal LSEC, low in midlobular LSEC, and negative in centrilobular LSEC, and this provides an easy separation method to isolate LSEC from the three different hepatic regions. The LSEC subpopulations obtained by this method are adequate for functional studies and drug toxicity testing.
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Affiliation(s)
- Guanhua Xie
- Division of Gastrointestinal and Liver Diseases and the Research Center for Liver Diseases, University of Southern California Keck School of Medicine 90033, USA
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16
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A review of mast cells and liver disease: What have we learned? Dig Liver Dis 2010; 42:529-36. [PMID: 20363674 DOI: 10.1016/j.dld.2010.02.016] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Revised: 02/19/2010] [Accepted: 02/25/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Mast cells are recognized as diverse and highly complicated cells. Aside from their notorious role in allergic inflammatory reactions, mast cells are being implicated in numerous disease processes from heart disease to cancer. Mast cells have been implicated in liver pathogenesis including hepatitis and host allograft rejection after liver transplantation. AIMS The aim of this review is to discuss the traditional function of mast cells, their location and anatomy with regards to hepatic vasculature and the role of mast cells in hepatic diseases including liver regeneration and rejection. Finally, we will touch on the role of mast cells in liver cancer. In conclusion, we hope that the reader comes away with a better understanding of the diverse and potential role(s) that mast cells may play in liver pathologies.
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17
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Cheluvappa R, Denning GM, Lau GW, Grimm MC, Hilmer SN, Le Couteur DG. Pathogenesis of the hyperlipidemia of Gram-negative bacterial sepsis may involve pathomorphological changes in liver sinusoidal endothelial cells. Int J Infect Dis 2010; 14:e857-67. [PMID: 20609608 DOI: 10.1016/j.ijid.2010.02.2263] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 11/30/2009] [Accepted: 02/25/2010] [Indexed: 12/11/2022] Open
Abstract
The Gram-negative bacterium Pseudomonas aeruginosa is one of the most common opportunistic pathogens, especially after liver transplantation. Pathophysiological alterations of liver sinusoidal endothelial cells (LSECs) have far-reaching repercussions on the liver and on metabolism. LSECs are perforated with fenestrations, pores that facilitate the transfer of lipoproteins and macromolecules between blood and hepatocytes. Gram-negative bacterial endotoxin (lipopolysaccharide, LPS) and the P. aeruginosa toxin, pyocyanin, have marked effects on LSECs. Initial loss of LSEC porosity (defenestration) induced by P. aeruginosa pyocyanin and LPS may confer subsequent immune tolerance to circulating bacterial antigens and toxins. This review collates the known immune responses of the liver to Gram-negative bacterial toxins, with a focus on LSECs. Hyperlipidemia is an important response to Gram-negative bacterial sepsis. The mechanisms proposed for sepsis-associated hyperlipidemia include tissue lipoprotein lipase inhibition and upregulated hepatic triglyceride production. In this review, we propose defenestration of the LSECs by bacterial toxins as an additional mechanism for the hyperlipidemia of sepsis. Given the role of LSECs in hyperlipidemia and liver allograft rejection, LSEC changes induced by P. aeruginosa toxins including LPS and pyocyanin may have significant clinical implications.
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Affiliation(s)
- Rajkumar Cheluvappa
- Department of Medicine, St. George Clinical School and Centre for Infection and Inflammation Research, School of Medical Sciences, Wallace Wurth Building, University of New South Wales, Gate 9 High Street, Sydney, NSW 2052, Australia.
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18
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Warren A, Cogger VC, Arias IM, McCuskey RS, Le Couteur DG. Liver sinusoidal endothelial fenestrations in caveolin-1 knockout mice. Microcirculation 2010; 17:32-8. [PMID: 20141598 DOI: 10.1111/j.1549-8719.2009.00004.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Fenestrations are pores in the liver sinusoidal endothelium that facilitate the transfer of particulate substrates between the sinusoidal lumen and hepatocytes. Fenestrations express caveolin-1 and have structural similarities to caveolae, therefore might be a form of caveolae and caveolin-1 may be integral to fenestration structure and function. Therefore, fenestrations were studied in the livers of caveolin-1 knockout mice. METHODS Scanning, transmission and immunogold electron microscopic techniques were used to study the liver sinusoidal endothelium and other tissues in caveolin-1 knockout and wild-type mice. RESULTS Comparison of fenestrations in wild-type and knockout mice did not reveal any differences on either scanning or transmission electron microscopy. The diameter of the fenestrations was not significantly different (74 +/- 13 nm knockout mice vs 78 +/- 12 nm wild-type mice) nor was the fenestration porosity (6.5 +/- 2.1 knockout vs 7.3 +/- 2.4% wild-type mice). In contrast, adipocytes and blood vessels in other tissues lacked caveolae in the knockout mice. Caveolin-1 immunogold of livers of wild-type mice indicated sparse expression in sinusoidal endothelial cells. CONCLUSIONS The normal structure of fenestrations in the liver sinusoidal endothelium is not dependent upon caveolin-1 and fenestrations are not a form of caveolae.
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Affiliation(s)
- Alessandra Warren
- Centre for Education and Research on Ageing and ANZAC Research Institute, University of Sydney and Concord RG Hospital, Sydney, Australia
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19
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Onori P, Gaudio E, Franchitto A, Alpini G, Francis H. Histamine regulation of hyperplastic and neoplastic cell growth in cholangiocytes. World J Gastrointest Pathophysiol 2010; 1:38-49. [PMID: 21607141 PMCID: PMC3097946 DOI: 10.4291/wjgp.v1.i2.38] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Revised: 04/03/2010] [Accepted: 04/10/2010] [Indexed: 02/06/2023] Open
Abstract
Histamine has long been known to be involved in inflammatory events. The discovery of antihistamines dates back to the first half of the 20th century when a Swiss-Italian pharmacologist, Daniel Bovet began his work. In 1957 he was awarded a Nobel Prize for his production of antihistamines for allergy relief. Since that time, histamine has been found to play a role in other events besides allergic reaction. Possibly unbelievable to Bovet and his peers, histamine has now been marked as playing a role in liver pathologies including hepatobiliary diseases.
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20
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Dollé L, Best J, Mei J, Al Battah F, Reynaert H, van Grunsven LA, Geerts A. The quest for liver progenitor cells: a practical point of view. J Hepatol 2010; 52:117-29. [PMID: 19913937 DOI: 10.1016/j.jhep.2009.10.009] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Many chronic liver diseases can lead to hepatic dysfunction with organ failure. At present, orthotopic liver transplantation represents the benchmark therapy of terminal liver disease. However this practice is limited by shortage of donor grafts, the need for lifelong immunosuppression and very demanding state-of-the-art surgery. For this reason, new therapies have been developed to restore liver function, primarily in the form of hepatocyte transplantation and artificial liver support devices. While already offered in very specialized centers, both of these modalities still remain experimental. Recently, liver progenitor cells have shown great promise for cell therapy, and consequently they have attracted a lot of attention as an alternative or supportive tool for liver transplantation. These liver progenitor cells are quiescent in the healthy liver and become activated in certain liver diseases in which the regenerative capacity of mature hepatocytes and/or cholangiocytes is impaired. Although reports describing liver progenitor cells are numerous, they have not led to a consensus on the identity of the liver progenitor cell. In this review, we will discuss some of the characteristics of these cells and the different ways that have been used to obtain these from rodents. We will also highlight the challenges that researchers are facing in their quest to identify and use liver progenitor cells.
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Affiliation(s)
- Laurent Dollé
- Department of Cell Biology, Vrije Universiteit Brussel, Belgium
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21
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Mccuskey RS. The Hepatic Microvascular System in Health and Its Response to Toxicants. Anat Rec (Hoboken) 2008; 291:661-71. [DOI: 10.1002/ar.20663] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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22
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Lalor PF, Lai WK, Curbishley SM, Shetty S, Adams DH. Human hepatic sinusoidal endothelial cells can be distinguished by expression of phenotypic markers related to their specialised functions in vivo. World J Gastroenterol 2006; 12:5429-39. [PMID: 17006978 PMCID: PMC4088223 DOI: 10.3748/wjg.v12.i34.5429] [Citation(s) in RCA: 131] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The hepatic sinusoids are lined by a unique population of hepatic sinusoidal endothelial cells (HSEC), which is one of the first hepatic cell populations to come into contact with blood components. However, HSEC are not simply barrier cells that restrict the access of blood-borne compounds to the parenchyma. They are functionally specialised endothelial cells that have complex roles, including not only receptor-mediated clearance of endotoxin, bacteria and other compounds, but also the regulation of inflammation, leukocyte recruitment and host immune responses to pathogens. Thus understanding the differentiation and function of HSEC is critical for the elucidation of liver biology and pathophysiology. This article reviews methods for isolating and studying human hepatic endothelial cell populations using in vitro models. We also discuss the expression and functions of phenotypic markers, such as the presence of fenestrations and expression of VAP-1, Stabilin-1, L-SIGN, which can be used to identify sinusoidal endothelium and to permit discrimination from vascular and lymphatic endothelial cells.
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MESH Headings
- Amine Oxidase (Copper-Containing)/genetics
- Amine Oxidase (Copper-Containing)/metabolism
- Biomarkers/metabolism
- Cell Adhesion Molecules/genetics
- Cell Adhesion Molecules/metabolism
- Cell Adhesion Molecules, Neuronal/genetics
- Cell Adhesion Molecules, Neuronal/metabolism
- Cells, Cultured
- Endothelial Cells/metabolism
- Endothelium, Lymphatic/cytology
- Endothelium, Vascular/cytology
- Gene Expression Regulation/genetics
- Humans
- Lectins, C-Type/genetics
- Lectins, C-Type/metabolism
- Liver/blood supply
- Liver/cytology
- Liver/metabolism
- Liver Circulation
- Phenotype
- Receptors, Cell Surface/genetics
- Receptors, Cell Surface/metabolism
- Receptors, Lymphocyte Homing/genetics
- Receptors, Lymphocyte Homing/metabolism
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Affiliation(s)
- P F Lalor
- Liver Research Group, Institute of Biomedical Research, Division of Medical Science, University of Birmingham, Birmingham B15 2TT, United Kingdom.
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23
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Hodges BL, Taylor KM, Chu Q, Scull SE, Serriello RG, Anderson SC, Wang F, Scheule RK. Local Delivery of a Viral Vector Mitigates Neutralization by Antiviral Antibodies and Results in Efficient Transduction of Rabbit Liver. Mol Ther 2005; 12:1043-51. [PMID: 16139571 DOI: 10.1016/j.ymthe.2005.06.475] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2005] [Revised: 06/04/2005] [Accepted: 06/11/2005] [Indexed: 11/21/2022] Open
Abstract
Antiviral antibodies within the human population remain a barrier to the effective clinical use of viral gene transfer vectors. We have asked whether local, balloon catheter-mediated delivery of a viral vector to the rabbit liver using a hepatic vein might mitigate the neutralizing effects of antiviral antibodies. We have compared directly the ability of adenovirus (Ad2) encoding nuclear-localized beta-galactosidase to infect the rabbit liver after local and systemic delivery in both the presence and the absence of defined anti-Ad2 antibody titers. In naive rabbits, local delivery resulted in higher beta-galactosidase expression compared to systemic delivery. In the presence of passively administered anti-Ad2 antibodies, local delivery resulted in expression levels that were comparable to those obtained in naive rabbits by systemic delivery. Local delivery also resulted in the majority of expression originating from hepatocytes, even in passively immunized animals, a result that could not be duplicated using the systemic approach. Since systemic delivery of adenovirus in naive animal models results in transgene expression levels often regarded as therapeutic, these results predict that local hepatic vein delivery of a viral vector is a clinically practical approach to mitigate neutralizing antiviral antibodies and generate therapeutic levels of transgene expression.
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Affiliation(s)
- Bradley L Hodges
- Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA
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24
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Abstract
Hydrodynamic delivery is an efficient and inexpensive procedure to deliver a wide range of nucleic acids to hepatic tissues and other organs in vivo. The successful application of hydrodynamic delivery is dependent on the rapid injection of a large aqueous volume containing DNA, RNA or other molecules into the vasculature of the liver. In this review, the development of the procedures for hydrodynamic delivery will be described and the parameters necessary for attaining maximal gene expression will be highlighted. A review of the mechanisms for transfecting hepatocytes, as well as potential uses of this approach in various research and clinical applications, will also be discussed.
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Affiliation(s)
- Bradley L Hodges
- Genzyme Corporation, 31 New York Avenue, Framingham, MA 01701, USA.
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25
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Massimi M, Lear SR, Williams DL, Jones AL, Erickson SK. Differential expression of apolipoprotein E messenger RNA within the rat liver lobule determined by in situ hybridization. Hepatology 1999; 29:1549-55. [PMID: 10216141 DOI: 10.1002/hep.510290504] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Apolipoprotein (Apo) E plays a key role in the metabolism of lipoproteins. It also modulates immunoregulation, cell growth and differentiation and the response to nerve injury. The liver is a major site of ApoE synthesis. Most of the circulating ApoE is thought to be of hepatic origin with most synthesized in hepatocytes. We showed that total liver ApoE messenger RNA (mRNA) levels were greater in normal adult female rats than in male and that gender-specific patterns of liver ApoE mRNA expression were present by in situ hybridization. In the male liver, the signal was strongest in the portal area, decreasing toward the central vein with the weakest signal in pericentral hepatocytes, resulting in a hepatic lobular gradient of expression. In female liver, a strong periportal signal also was observed that decreased in Zone 2, similar to that in males, but which then increased in pericentral hepatocytes resulting in a bowl-like distribution in marked contrast with that of the male. The results suggest that ApoE mRNA level is regulated differentially in hepatocytes within the liver plate and that the regulation is gender-dependent. Further, the results suggest that in males, hepatocytes in the portal area are the major contributors of ApoE to the plasma and/or sinusoidal pool, whereas in females, both portal and central area hepatocytes play an equal role.
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Affiliation(s)
- M Massimi
- Department of Medicine, University of California, San Francisco, CA, USA
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26
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Dini L, Carla EC. Hepatic sinusoidal endothelium heterogeneity with respect to the recognition of apoptotic cells. Exp Cell Res 1998; 240:388-93. [PMID: 9597012 DOI: 10.1006/excr.1998.4015] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The recognition and removal of human apoptotic peripheral lymphocytes in selected populations of periportal and perivenous endothelial cells was studied in in situ and in vitro experiments. Apoptotic peripheral blood lymphocytes once injected into the liver circulation were retained by the sinusoids showing a large heterogeneity of distribution: apoptotic cells are found in the periportal tract double the amount found in the perivenous region. Apoptotic PBL adhesion was lowered to a sixth of the control after preinjection with a sugar mixture (Mannose, N-acetylgalactosamine, N-acetylglucosamine, D-galactose), as suggested by the expression of modified surface glycoconjugates on the plasma membrane of apoptotic cells. A bimodal profile of the distribution of the hepatic sinusoidal cell population, regarding the number of galactose and mannose receptors and the porosity index, was found. Two endothelial cell subsets were present: low porosity cells (average index 14 +/- 6%; periportal tract) with a high number of carbohydrate binding sites, and high porosity cells (average index 26 +/- 7%; perivenous tract), with a low number of carbohydrate binding sites.
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Affiliation(s)
- L Dini
- Department of Biology, University of Lecce, Italy.
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27
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Daneker GW, Lund SA, Caughman SW, Swerlick RA, Fischer AH, Staley CA, Ades EW. Culture and characterization of sinusoidal endothelial cells isolated from human liver. In Vitro Cell Dev Biol Anim 1998; 34:370-7. [PMID: 9639099 DOI: 10.1007/s11626-998-0018-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although most vascular models use large vessel endothelial cells from human umbilical veins, there is marked heterogeneity among endothelial cells from different vascular beds and organs. More accurate modeling of endothelial involvement in liver diseases, including metastasis, may result from the use of human hepatic sinusoidal endothelial cells. Liver resection specimens were sectioned, then treated with a 1.2 U/ml dispase solution. The tissue slurry was mechanically disaggregated and separated by centrifugation on a Percoll density gradient. Cells were then cultured in an endothelial-specific media with growth factors. These techniques resulted in a homogeneous monolayer consistent with endothelial cells by light microscopy. An endothelial origin was further confirmed by the expression of Factor VIII, binding of Ulex lectin, and uptake of acetylated low density lipoprotein. Electron microscopy showed transcellular fenestrations consistent with a sinusoidal origin. These human hepatic sinusoidal endothelial cells were then studied for expression of the adhesion molecules CD31/PECAM, CD34, E-selectin, ICAM-1, L-selectin, LFA-3, P-selectin, and VCAM-1 plus the binding of wheat germ agglutinin lectin. The patterns of adhesion molecule expression and lectin binding by these cells are characteristic of hepatic sinusoidal endothelia. In this paper, we have described a method for isolation and culture of human cells with the morphologic and phenotypic characteristics of hepatic sinusoidal endothelia.
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Affiliation(s)
- G W Daneker
- Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA
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28
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Shin YC. Revaluation on the types and pattern of distribution of sinusoidal fenestrations in the lobule of normal rat liver. Anat Rec (Hoboken) 1997; 247:206-13. [PMID: 9026000 DOI: 10.1002/(sici)1097-0185(199702)247:2<206::aid-ar7>3.0.co;2-v] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
BACKGROUND There is a need to identify the existence of large fenestrations and to evaluate the type and pattern of the distribution of sinusoidal fenestrations in the hepatic lobule. METHODS The sinusoidal fenestrations in the rat liver lobule were investigated by scanning electron microscopy of perfusion-fixed specimens and by transmission electron microscopy of freeze-fracture replicas from immersion-fixed specimens. Ringer solution used for precleaning was equilibrated with 84%/16% O2/CO2 at 37 degrees C, and the perfusion pressure was maintained at 5-10 mmHg in the portal vein. RESULTS The fenestrations were recognized on the luminal surface of sinusoids on the basis of regional difference in size and distribution within the lobule and divided into three types: small, medium-sized, and large. The small fenestrations were numerous in each region. The number of medium-sized fenestrations was large in the pericentral and intermediate regions, while that of large fenestrations was predominant in the intermediate region. Based on the occurrence of fenestrations, the sinusoids were also divided into three types. The type I sinusoid mainly showed small fenestrations and was predominant in the periportal region. The type II sinusoid showed small and medium-sized fenestrations and was predominant in the pericentral region. The type III sinusoid showed all the types of fenestrations including large ones and was predominant in the intermediate region. The images showing dumbbell-shaped or irregularly shaped margins were observed between small or medium-sized fenestrations on the freeze-fracture replica. CONCLUSIONS 1) The fenestrations are divided into three types according to the size and pattern of distribution within the lobule. 2) The sinusoids are also divided into three types based on the distribution pattern of each type of fenestrations. 3) The small fenestrations are evenly distributed throughout the entire lobule, while the medium-sized and large fenestrations show the regional difference within the lobule. 4) The large fenestrations exist as real structures of the endothelial lining cells of sinusoids and may result from the fusion of contiguous smaller ones.
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Affiliation(s)
- Y C Shin
- Department of Anatomy, Korea University, College of Medicine, Seoul, Korea
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29
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Affiliation(s)
- P M Huet
- Centre de Recherche Clinique André-Viallet, Hôpital Saint-Luc, Montreal, Québec, Canada
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30
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Scoazec JY, Racine L, Couvelard A, Flejou JF, Feldmann G. Endothelial cell heterogeneity in the normal human liver acinus: in situ immunohistochemical demonstration. LIVER 1994; 14:113-23. [PMID: 8078390 DOI: 10.1111/j.1600-0676.1994.tb00059.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
While a certain degree of structural and functional intra-lobular heterogeneity of sinusoidal endothelial cells has been observed in rodents, little information is available about the zonal characteristics of sinusoidal endothelial cells in the human liver acinus. We have therefore examined the intra-acinar distribution of a panel of endothelial markers in the normal human liver, including: (a) structural markers of continuous and sinusoidal endothelia (PECAM-1, CD-34 protein, VE-cadherin, 1F10 antigen), (b) functional markers specific for sinusoidal endothelial cells, as previously determined in the laboratory (CD4 protein, the lipopolysaccharide-binding protein receptor (CD 14), aminopeptidase N, ICAM-1, receptors II and III for the Fc fragment of immunoglobulins G), (c) endothelial cell-matrix adhesion proteins and leukocyte-endothelial cell adhesion molecules. We observed a heterogeneous distribution for: (a) the 1F10 antigen, whose distribution in the human liver acinus was restricted to vessels situated along the axis of acinar zone 1, (b) the lipopolysaccharide-binding protein receptor and the receptor III for the Fc fragment of IgG, not expressed or only barely expressed in acinar zone 1. The distribution of the other markers tested did not display significant intra-lobular variation. Our in situ results suggest the existence of a degree of zonal heterogeneity in the structural and functional characteristics of sinusoidal endothelial cells in the human liver acinus. This might contribute to the constitution of distinct microenvironments within the human liver parenchyma.
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Affiliation(s)
- J Y Scoazec
- Laboratoire de Biologie Cellulaire, INSERM U327, Faculté de Médecine Xavier Bichat, Paris, France
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31
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Vidal-Vanaclocha F, Rocha M, Asumendi A, Barberá-Guillem E. Isolation and enrichment of two sublobular compartment-specific endothelial cell subpopulations from liver sinusoids. Hepatology 1993. [PMID: 8340061 DOI: 10.1002/hep.1840180217] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Similar to the well-recognized phenotypical heterogeneity of hepatocytes, in situ sublobular variations have recently been detected in the cell structure, fenestration patterns, filtrating efficiency, surface glycosylation, scavenger function and pathological responses of the sinusoidal lining endothelium. However, unlike other liver cell populations, until now no endothelial cell subpopulations had been isolated or defined with clarity, much less with sublobular/acinar zone-related differential properties. On the basis of our previous studies showing that periportal segments of mouse liver sinusoids express a significantly higher number of wheat germ agglutinin-binding sites than do perivenous ones, we used this differential feature for in vitro labeling of the specific sublobular derivation of isolated sinusoidal lining endothelial cells to correlate their original lobular position with other features determined on flow cytometry, centrifugal elutriation, discontinuous arabinogalactan density gradients and electron microscopy. Our results revealed additional heterogeneous properties whose association with high or low wheat germ agglutinin-binding capacity made it possible to define in vitro two dominant endothelial cell subpopulations that appear similar to the differential features in the periportal and perivenous sinusoidal segments. Type 1 endothelial cells had low forward angle light scatter and high integrated side scatter, low cytoplasmic porosity index (12% +/- 5%) and high wheat germ agglutinin-binding efficiency (160 +/- 35 fluorescence intensity units/cell size); these findings are similar to what was observed in situ in the periportal sinusoidal endothelium. On the other hand, type 2 endothelial cells, with high forward angle light scatter and low integrated side scatter, had a high cytoplasmic porosity index (25% +/- 8%) and low wheat germ agglutinin-binding efficiency (60 +/- 15 fluorescence intensity units/cell size), findings similar to in situ observations of the perivenous sinusoidal lining endothelium. Moreover, these physical and morphological differences entail different cell sedimentation behaviors: type 1 endothelial cell sedimented at high centrifugal elutriation counterflow rates (23 to 37 ml/min) and high arabinogalactan density gradient levels (10% to 15%), whereas type 2 endothelial cell sedimented at low counterflow rates (18 to 23 ml/min) and low density levels (6% to 10%). The combination of these separation procedures made it possible to isolate a 90%-enriched type 1 endothelial cell population in the 12% to 15% interphase of the 23 and 37 ml/min elutriation flow rates and a 75%-enriched type 2 endothelial cell population in the 6% to 10% interphase of the 18 and 23 ml/min flow rates.
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Affiliation(s)
- F Vidal-Vanaclocha
- Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Vizcaya, Spain
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32
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Barberá-Guillem E, Rocha M, Alvarez A, Vidal-Vanaclocha F. Differences in the lectin-binding patterns of the periportal and perivenous endothelial domains in the liver sinusoids. Hepatology 1991; 14:131-9. [PMID: 1906044 DOI: 10.1002/hep.1840140122] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We have studied the distribution patterns of carbohydrate terminals on the endothelial surface of the mouse liver microvasculature. For this purpose, a wide battery of FITC lectins specific to glucose, mannose, galactose, fucose, N-acetyl-neuraminic acid, N-acetyl-galactosamine and N-acetyl-glucosamine residues were incubated on liver cryostat sections or intraportally perfused under physiological conditions. All the resulting hepatic sections were examined under fluorescent microscopy and confocal laser scanning microscopy. With the exception of N-acetyl-galactosamine- and fucose-binding lectins, all the perfused lectins specifically bound to the microvascular wall as confirmed by blocking methods using their corresponding sugars. A wide range of binding was, however, observed among the lectins, and the latter were classified into four groups according to their affinities for the different segments of the hepatic microvasculature: (a) equal affinity for all segments (concanavalin A); (b) different affinities depending on acinar zone (wheat germ agglutinin, Ricinus communis toxin, phytohemagglutinin E, Erythrina cristagalli agglutinin and Pisum sativum agglutinin); (c) preferential binding to the sinusoidal network (Lathyrus odoratus, phytohemagglutinin); and (d) lectins that fail to bind to the hepatic microvasculature (N-acetyl-galactosamine- and fucose-binding lectins). Sinusoidal segment walls in acinar zone 1 expressed a higher concentration of certain lectin-binding carbohydrate residues (N-acetyl-neuraminic acid, N-acetyl-galactosamine, galactose, mannose and glucose) than in acinar zone 3. The labeling patterns obtained through the incubation of liver sections or through in vivo perfusion with the different lectins did not always coincide. Only concanavalin A, wheat germ agglutinin and phytohemagglutinin E lectins proved to be concordant (i.e., they produced identical labeling patterns in both procedures).(ABSTRACT TRUNCATED AT 250 WORDS)
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Affiliation(s)
- E Barberá-Guillem
- Department of Cell Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
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33
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Barberá-Guillem E, Alonso-Varona A, Boyano MD, Vidal-Vanaclocha F. Estimating anatomical-functional position coordinates in liver tissue. Anat Rec (Hoboken) 1990; 228:267-76. [PMID: 2260782 DOI: 10.1002/ar.1092280306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hepatocyte enzyme activity was demonstrated by examining adult C57BL/6 mouse liver cryostat sections under a succinate dehydrogenase (SDH) histochemical reaction, and quantified by microspectrophotometry and microdensitometry. The hepatocyte SDH activity gradient along the path between the portal veins (PV) and efferent terminal hepatic venules (THV) was analyzed by measuring the concentration of the chromophore precipitated in 10 consecutive hepatic parenchymal domains located along imaginary lines drawn across the entire PV-to-THV distance. The profiles of intensity or of normalized relative optical density obtained on a high number of lines were correlated with distance values along the PV-to-THV pathway, enabling us to establish a general mathematical function relating SDH activity (chromophore concentration) to position values on a scale of 0 to 10 corresponding to the theoretical PV-to-THV distance. The equation can be used to interpolate the SDH activity surrounding any intrahepatic object located between the PV and the THV, thus making it possible to calculate the object's anatomical-functional position coordinates in the liver acinus. To demonstrate how this method is used, we have calibrated the intrahepatic position of hemopoietic foci induced in the liver tissue of adult mice treated with phenylhydrazine (PHZ), and show that these foci are located on coordinate 3.31 (maximum range 1.25-4.86) of the sinusoidal domain-that is, on the borderline between Rappaport's acinar zones 1 and 2.
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Affiliation(s)
- E Barberá-Guillem
- Department of Cell Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Leioa, Vizcaya, Spain
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Vidal-Vanaclocha F, Alonso-Varona A, Ayala R, Barberá-Guillem E. Functional variations in liver tissue during the implantation process of metastatic tumour cells. VIRCHOWS ARCHIV. A, PATHOLOGICAL ANATOMY AND HISTOPATHOLOGY 1990; 416:189-95. [PMID: 2105557 DOI: 10.1007/bf01678977] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
We have examined several properties of sinusoidal cells in the unaffected tissue of micrometastasis-containing livers. Tumour cells from either B16 melanoma (B16F10) or Lewis lung carcinoma (LLC) were injected intrasplenically in syngeneic mice and sacrificed on the 7th day. Light and scanning electron microscopy (SEM) showed tumour cells in hepatic veins and sinusoids in close contact with endothelial walls and macrophages. Following quantitative analysis of SEM images from sinusoidal walls it was found that endothelial fenestrae from B16F10 or LLC-colonized livers were diffusely reduced both in size and density/microns 2 throughout the sinusoid wall, although especially affected zone 3 segments. Following the intrasplenic injection of 1 microns fluorescent latex particles 1 h prior to sacrifice of the mice a significant reduction of the latex particle uptake by sinusoidal cells was detected in B16F10-colonized livers (27% of controls) which was in contrast to the significant increase in LLC-colonized mice (180% of controls). Despite the focal character of the tumour cell implantation process, hepatic sinusoidal cells reacted diffusely to metastatic cells. However, over liver acini, endothelial cell changes were mainly expressed in zone 3 while phagocytic properties mainly varied in zone 1 and depending on the tumour type. Although the significance of these sinusoidal changes on metastatic development is unclear, data suggests that "soil" conditions in the liver are different before and after being metastasized by tumour cells.
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Affiliation(s)
- F Vidal-Vanaclocha
- Department of Cell Biology and Morphological Sciences, School of Medicine, University of the Basque Country, Vizcaya, Spain
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De Leeuw AM, Brouwer A, Knook DL. Sinusoidal endothelial cells of the liver: fine structure and function in relation to age. JOURNAL OF ELECTRON MICROSCOPY TECHNIQUE 1990; 14:218-36. [PMID: 2187063 DOI: 10.1002/jemt.1060140304] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Liver endothelial cells form a continuous lining of the liver capillaries, or sinusoids, separating parenchymal cells and fat-storing cells from sinusoidal blood. Liver sinusoidal endothelial cells differ in fine structure from endothelial cells lining larger blood vessels and from other capillary endothelia in that they lack a distinct basement membrane and also contain open pores, or fenestrae, in the thin cytoplasmic projections which constitute the sinusoidal wall. This distinctive morphology supports the protective role played by liver endothelium, the cells forming a general barrier against pathogenic agents and serving as a selective sieve for substances passing from the blood to parenchymal and fat-storing cells, and vice versa. Sinusoidal endothelial cells, furthermore, significantly participate in the metabolic and clearance functions of the liver. They have been shown to be involved in the endocytosis and metabolism of a wide range of macromolecules, including glycoproteins, lipoproteins, extracellular matrix components, and inert colloids, establishing endothelial cells as a vital link in the complex network of cellular interactions and cooperation in the liver. Fine structural studies in combination with the development of cell isolation and culture techniques from both experimental animal and human liver have greatly contributed to the elucidation of these endothelial cell functions. Morphological and biochemical investigations have both revealed little changes with age except for an accumulation of iron ferritin and a decrease in the activities of glucose-6-phosphatase, Mg-ATPase, and in glucagon-stimulated adenylcyclase. Future studies are likely to disclose more fully the role of sinusoidal endothelial cells in the regulation of liver hemodynamics, in liver metabolism and blood clearance, in the maintenance of hepatic structure, in the pathogenesis of various liver diseases, and in the aging process in the liver.
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Affiliation(s)
- A M De Leeuw
- Department of Ophthalmology, University of Washington, Seattle 98195
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Sciot R, de Vos R, van Eyken P, van der Steen K, Moerman P, Desmet VJ. In situ localization of melanotransferrin (melanoma-associated antigen P97) in human liver. A light- and electronmicroscopic immunohistochemical study. LIVER 1989; 9:110-9. [PMID: 2540389 DOI: 10.1111/j.1600-0676.1989.tb00387.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Using an indirect immunoperoxidase technique on frozen sections with the monoclonal antibody 96.5, we investigated the in situ distribution of melanotransferrin, a transferrin (Tf) and transferrin receptor (TfR) related glycoprotein, in human liver. Specimens included normal liver, liver in iron overload, hepatocellular carcinoma, angioma and foetal liver. On light microscopy, immunoreactivity was almost exclusively present on sinusoidal lining cells, apparently endothelial cells; the pattern was similar in normal and in iron-loaded liver. A gradient of more enhanced staining in acinar zone II and III was observed. The endothelial localization of the staining was supported by the positivity of the central vein endothelium and of the angiomas. Immunoelectron microscopy on three liver specimens showed positivity on sinusoidal endothelial cells but not on Ito and Kupffer cells. In addition, positivity on rough endoplasmic reticulum vesicles of some hepatocytes was also present. Four hepatocellular carcinomas showed an intense staining in tumour cells, 3 were weakly positive and 3 were negative. In the foetal livers, the central vein endothelium was positive from 21 weeks of gestation onward and additional positivity of zone III sinusoidal endothelial cells was present from 27 weeks on. The present results show that in the liver melanotransferrin has a localization different from Tf and the TfR. These latter molecules are predominantly localized in parenchymal cells. In addition, there does not appear to be a coordinate regulation secondary to iron storage, between melanotransferrin, Tf and the TfR. The observed gradient in the staining pattern in foetal and adult liver specimens further supports the heterogeneity of the endothelial cell population in the liver and suggests a developmental relationship between endothelial cells of sinusoids and central vein.
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Affiliation(s)
- R Sciot
- Department of Pathology II, University Hospital St. Rafaël, Catholic University of Leuven, Belgium
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Barberá-Guillem E, Ayala R, Vidal-Vanaclocha F. Differential location of hemopoietic colonies within liver acini of postnatal and phenylhydrazine-treated adult mice. Hepatology 1989; 9:29-36. [PMID: 2908867 DOI: 10.1002/hep.1840090106] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
We have measured the location of embryonic and adult hemopoietic foci in the liver tissue of postnatal and adult phenylhydrazine-treated mice. Differentiation of acinar domains in liver tissue was made possible by carrying out succinate dehydrogenase histochemical reactions on liver cryostat sections. To determine the position of hemopoietic foci within the lobular gradient of the hepatocyte succinate dehydrogenase activity, this enzyme was measured in hepatocytes surrounding both portal and central veins and hemopoietic foci. Then, assuming the periportal succinate dehydrogenase activity value to be 1.00 +/- 0.2, succinate dehydrogenase activity around postnatal hemopoietic foci was 0.65 +/- 0.19, around phenylhydrazine-induced hemopoietic foci 0.83 +/- 0.24 and around central veins 0.44 +/- 0.11. Scaling the portal to central vein distance and taking 1 as the portal vein point and 0 as the central vein point, the relative position of hemopoietic foci, indirectly calculated from succinate dehydrogenase activity values, was 0.35 +/- 0.13 in postnatal livers and 0.73 +/- 0.12 in phenylhydrazine-treated adult livers. Hemopoietic foci frequencies varied according to both the origin and the liver acinar domain: in postnatal liver acini, it was 37.1% in zone 1, 22.8% in zone 2 and 40% in zone 3; in phenylhydrazine-treated adult acini, it was 89.4% in zone 1 and 10.6% in zone 2. Postnatal hemopoietic foci mainly occurred extrasinusoidally, between hepatocytes and reticular-like cells, whereas adult hemopoietic foci were mostly intrasinusoidal and closely associated to macrophage-like cells. Adult hemopoietic colonies
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Affiliation(s)
- E Barberá-Guillem
- Department of Cellular Biology and Morphological Sciences, School of Medicine and Dentistry, University of the Basque Country, Vizcaya, Spain
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Steffan AM, Gendrault JL, Kirn A. Increase in the number of fenestrae in mouse endothelial liver cells by altering the cytoskeleton with cytochalasin B. Hepatology 1987; 7:1230-8. [PMID: 3679088 DOI: 10.1002/hep.1840070610] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Endothelial cells of the hepatic sinusoid isolated from mice livers and maintained in culture display typical fenestrae grouped in sieve plates. Treatment with cytochalasin B led to no significant change in the mean diameter of the fenestrae but to an increase in their number and in the porosity of the cells (percentage of the cellular surface opened by the fenestrae) which attained up to 300% of that of the controls. Scanning electron microscopic observations of Triton-extracted cells revealed that these modifications were related to an alteration of the cytoskeleton. The effect of cytochalasin B could be reversed; 3 hr after removal of the drug, the cells recovered their original aspect with sieve plates scattered over their surface. These observations demonstrate that endothelial fenestrae are inducible structures and that the cytoskeleton seems to be involved in their formation.
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Affiliation(s)
- A M Steffan
- INSERM U 74, Faculté de Médecine de Strasbourg, France
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Horn T, Christoffersen P, Henriksen JH. Alcoholic liver injury: defenestration in noncirrhotic livers--a scanning electron microscopic study. Hepatology 1987; 7:77-82. [PMID: 3542781 DOI: 10.1002/hep.1840070117] [Citation(s) in RCA: 112] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
The fenestration of hepatic sinusoidal endothelial cells in 15 needle biopsies obtained from chronic alcoholics without cirrhosis was studied by scanning electron microscopy. As compared to nonalcoholics, a significant reduction in the number of fenestrae and porosity of the sinusoidal lining wall (fractional area of fenestrae) was observed in acinar Zone 3, both in biopsies with and without Zone 3 fibrosis as judged by light microscopy. A significant reduction of porosity as shown in this study may influence the blood hepatocytic exchange and contribute to the alcohol-induced liver injury.
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Barberá-Guillem E, Arrue JM, Ballesteros J, Vidal-Vanaclocha F. Structural changes in endothelial cells of developing rat liver in the transition from fetal to postnatal life. JOURNAL OF ULTRASTRUCTURE AND MOLECULAR STRUCTURE RESEARCH 1986; 97:197-206. [PMID: 3453369 DOI: 10.1016/s0889-1605(86)80018-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Endothelial fenestrae in the microcirculatory walls of fetal (18th and 21st days), newborn (1st and 5th days), and adult rat livers have been studied by an interactive analysis of scanning electron microscope images. Our results show that liver endothelial cells contain different fenestration patterns depending on both their specific location in the liver acinus and the developing period. Portal vessels have a continuous endothelium in both fetal and postnatal livers as in the adult liver. Endothelial cells in central veins change from highly fenestrated in the fetal and neonatal livers to continuous in the adult liver. The number of fenestrae per square micrometer of endothelium is similar along the sinusoidal network of fetal liver, but increases in the zone 3 sinusoids of newborn liver through the adult liver, where it has tripled the number in the zone 1 sinusoids. Porosity values in sinusoidal endothelium progressively decrease in the fetal to postnatal transition due to the disappearance of large fenestrae (greater than 250 nm) which accompanies the residual hemopoietic activity. While we do not known which factors specifically regulate these fenestration patterns, their configuration in fetal liver, before hepatic tissue has assumed its heterogeneous functioning postnatally, is worthy of note.
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Affiliation(s)
- E Barberá-Guillem
- Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, Basque Country University, Vizcaya, Spain
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