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Czyzynska-Cichon I, Kotlinowski J, Blacharczyk O, Giergiel M, Szymanowski K, Metwally S, Wojnar-Lason K, Dobosz E, Koziel J, Lekka M, Chlopicki S, Zapotoczny B. Early and late phases of liver sinusoidal endothelial cell (LSEC) defenestration in mouse model of systemic inflammation. Cell Mol Biol Lett 2024; 29:139. [PMID: 39528938 PMCID: PMC11556108 DOI: 10.1186/s11658-024-00655-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Liver sinusoidal endothelial cells (LSECs) have transcellular pores, called fenestrations, participating in the bidirectional transport between the vascular system and liver parenchyma. Fenestrated LSECs indicate a healthy phenotype of liver while loss of fenestrations (defenestration) in LSECs is associated with liver pathologies. METHODS We introduce a unique model of systemic inflammation triggered by the deletion of Mcpip1 in myeloid leukocytes (Mcpip1fl/flLysMCre) characterised by progressive alterations in LSEC phenotype. We implement multiparametric characterisation of LSECs by using novel real-time atomic force microscopy supported with scanning electron microscopy and quantitative fluorescence microscopy. In addition, we provide genetic profiling, searching for characteristic genes encoding proteins that might be connected with the structure of fenestrations. RESULTS We demonstrate that LSECs in Mcpip1fl/flLysMCre display two phases of defenestration: the early phase, with modest defenestration that was fully reversible using cytochalasin B and the late phase, with severe defenestration that is mostly irreversible. By thorough analysis of LSEC porosity, elastic modulus and actin abundance in Mcpip1fl/flLysMCre and in response to cytochalasin B, we demonstrate that proteins other than actin must be additionally responsible for inducing open fenestrations. We highlight several genes that were severely affected in the late but not in the early phase of LSEC defenestration shedding a light on complex structure of individual fenestrations. CONCLUSIONS The presented model of LSEC derived from Mcpip1fl/flLysMCre provides a valuable reference for developing novel strategies for LSEC refenestration in the early and late phases of liver pathology.
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Affiliation(s)
- Izabela Czyzynska-Cichon
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348, Krakow, Poland
| | - Jerzy Kotlinowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Oliwia Blacharczyk
- Institute of Nuclear Physics Polish Academy of Sciences, 31342, Krakow, Poland
| | - Magdalena Giergiel
- Centre for Nanometer-Scale Science and Advanced Materials (NANOSAM), Faculty of Physics, Astronomy, and Applied Computer Science, Jagiellonian University, Krakow, Poland
| | - Konrad Szymanowski
- Institute of Nuclear Physics Polish Academy of Sciences, 31342, Krakow, Poland
| | - Sara Metwally
- Institute of Nuclear Physics Polish Academy of Sciences, 31342, Krakow, Poland
| | - Kamila Wojnar-Lason
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531, Krakow, Poland
| | - Ewelina Dobosz
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Joanna Koziel
- Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland
| | - Malgorzata Lekka
- Institute of Nuclear Physics Polish Academy of Sciences, 31342, Krakow, Poland
| | - Stefan Chlopicki
- Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Bobrzynskiego 14, 30-348, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Grzegorzecka 16, 31-531, Krakow, Poland
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2
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Mou X, Leeman SM, Roye Y, Miller C, Musah S. Fenestrated Endothelial Cells across Organs: Insights into Kidney Function and Disease. Int J Mol Sci 2024; 25:9107. [PMID: 39201792 PMCID: PMC11354928 DOI: 10.3390/ijms25169107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/07/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
In the human body, the vascular system plays an indispensable role in maintaining homeostasis by supplying oxygen and nutrients to cells and organs and facilitating the removal of metabolic waste and toxins. Blood vessels-the key constituents of the vascular system-are composed of a layer of endothelial cells on their luminal surface. In most organs, tightly packed endothelial cells serve as a barrier separating blood and lymph from surrounding tissues. Intriguingly, endothelial cells in some tissues and organs (e.g., choroid plexus, liver sinusoids, small intestines, and kidney glomerulus) form transcellular pores called fenestrations that facilitate molecular and ionic transport across the vasculature and mediate immune responses through leukocyte transmigration. However, the development and unique functions of endothelial cell fenestrations across organs are yet to be fully uncovered. This review article provides an overview of fenestrated endothelial cells in multiple organs. We describe their development and organ-specific roles, with expanded discussions on their contributions to glomerular health and disease. We extend these discussions to highlight the dynamic changes in endothelial cell fenestrations in diabetic nephropathy, focal segmental glomerulosclerosis, Alport syndrome, and preeclampsia, and how these unique cellular features could be targeted for therapeutic development. Finally, we discuss emerging technologies for in vitro modeling of biological systems, and their relevance for advancing the current understanding of endothelial cell fenestrations in health and disease.
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Affiliation(s)
- Xingrui Mou
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Sophia M. Leeman
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
- Department of Computer Science, Duke University, Durham, NC 27710, USA
| | - Yasmin Roye
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
| | - Carmen Miller
- Department of Biology, Duke University, Durham, NC 27710, USA
| | - Samira Musah
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC 27710, USA
- Center for Biomolecular and Tissue Engineering, Duke University, Durham, NC 27710, USA
- Division of Nephrology, Department of Medicine, School of Medicine, Duke University, Durham, NC 27710, USA
- Department of Cell Biology, Duke University, Durham, NC 27710, USA
- Faculty of the Developmental and Stem Cell Biology Program, Duke Regeneration Center, Duke MEDx Initiative, Duke University, Durham, NC 27710, USA
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3
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Perez-Gutierrez L, Li P, Ferrara N. Endothelial cell diversity: the many facets of the crystal. FEBS J 2024; 291:3287-3302. [PMID: 36266750 DOI: 10.1111/febs.16660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 10/03/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
Endothelial cells (ECs) form the inner lining of blood vessels and play crucial roles in angiogenesis. While it has been known for a long time that there are considerable differences among ECs from lymphatic and blood vessels, as well as among arteries, veins and capillaries, the full repertoire of endothelial diversity is only beginning to be elucidated. It has become apparent that the role of ECs is not just limited to their exchange functions. Indeed, a multitude of organ-specific functions, including release of growth factors, regulation of immune functions, have been linked to ECs. Recent years have seen a surge into the identification of spatiotemporal molecular and functional heterogeneity of ECs, supported by technologies such as single-cell RNA sequencing (scRNA-seq), lineage tracing and intersectional genetics. Together, these techniques have spurred the generation of epigenomic, transcriptomic and proteomic signatures of ECs. It is now clear that ECs across organs and in different vascular beds, but even within the same vessel, have unique molecular identities and employ specialized molecular mechanisms to fulfil highly specialized needs. Here, we focus on the molecular heterogeneity of the endothelium in different organs and pathological conditions.
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Affiliation(s)
- Lorena Perez-Gutierrez
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Pin Li
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
| | - Napoleone Ferrara
- Department of Pathology, Moores Cancer Center, University of California, San Diego, CA, USA
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4
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Ramkissoon R, Cao S, Shah VH. The Pathophysiology of Portal Hypertension. Clin Liver Dis 2024; 28:369-381. [PMID: 38945632 DOI: 10.1016/j.cld.2024.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
This article reviews the pathophysiology of portal hypertension that includes multiple mechanisms internal and external to the liver. This article starts with a review of literature describing the cellular and molecular mechanisms of portal hypertension, microvascular thrombosis, sinusoidal venous congestion, portal angiogenesis, vascular hypocontractility, and hyperdynamic circulation. Mechanotransduction and the gut-liver axis, which are newer areas of research, are reviewed. Dysfunction of this axis contributes to chronic liver injury, inflammation, fibrosis, and portal hypertension. Sequelae of portal hypertension are discussed in subsequent studies.
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Affiliation(s)
- Resham Ramkissoon
- Department of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA
| | - Sheng Cao
- Mayo College of Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA
| | - Vijay H Shah
- Department of Gastroenterology & Hepatology, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA; Department of Internal Medicine, Mayo Clinic, 200 1st Street, SW, Rochester, MN 55902, USA.
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5
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He Q, He W, Dong H, Guo Y, Yuan G, Shi X, Wang D, Lu F. Role of liver sinusoidal endothelial cell in metabolic dysfunction-associated fatty liver disease. Cell Commun Signal 2024; 22:346. [PMID: 38943171 PMCID: PMC11214243 DOI: 10.1186/s12964-024-01720-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 06/20/2024] [Indexed: 07/01/2024] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that represent the interface between blood cells on one side and hepatocytes on the other side. LSECs not only form a barrier within the hepatic sinus, but also play important physiological functions such as regulating hepatic vascular pressure, anti-inflammatory and anti-fibrotic. Pathologically, pathogenic factors can induce LSECs capillarization, that is, loss of fenestra and dysfunction, which are conducive to early steatosis, lay the foundation for the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), and accelerate metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis. The unique localization, phenotype, and function of LSECs make them potential candidates for reducing liver injury, inflammation, and preventing or reversing fibrosis in the future.
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Affiliation(s)
- Qiongyao He
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Wu He
- Division of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Wuhan, 430030, China
| | - Hui Dong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yujin Guo
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Gang Yuan
- Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Xiaoli Shi
- Department of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Dingkun Wang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Fuer Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Medical College, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, China.
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6
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Rezzani R, Favero G, Gianò M, Pinto D, Labanca M, van Noorden CJ, Rinaldi F. Transient Receptor Potential Channels in the Healthy and Diseased Blood-Brain Barrier. J Histochem Cytochem 2024; 72:199-231. [PMID: 38590114 PMCID: PMC11020746 DOI: 10.1369/00221554241246032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 03/18/2024] [Indexed: 04/10/2024] Open
Abstract
The large family of transient receptor potential (TRP) channels are integral membrane proteins that function as environmental sensors and act as ion channels after activation by mechanical (touch), physical (heat, pain), and chemical stimuli (pungent compounds such as capsaicin). Most TRP channels are localized in the plasma membrane of cells but some of them are localized in membranes of organelles and function as intracellular Ca2+-ion channels. TRP channels are involved in neurological disorders but their precise role(s) and relevance in these disorders are not clear. Endothelial cells of the blood-brain barrier (BBB) express TRP channels such as TRP vanilloid 1-4 and are involved in thermal detection by regulating BBB permeability. In neurological disorders, TRP channels in the BBB are responsible for edema formation in the brain. Therefore, drug design to modulate locally activity of TRP channels in the BBB is a hot topic. Today, the application of TRP channel antagonists against neurological disorders is still limited.
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Affiliation(s)
- Rita Rezzani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Interdipartimental University Center of Research Adaption and Regeneration of Tissues and Organs - ARTO, University of Brescia, Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale - SISDO), Brescia, Italy
| | - Gaia Favero
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Interdipartimental University Center of Research Adaption and Regeneration of Tissues and Organs - ARTO, University of Brescia, Brescia, Italy
| | - Marzia Gianò
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Daniela Pinto
- Human Microbiome Advanced Project Institute, Milan, Italy
| | - Mauro Labanca
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Italian Society for the Study of Orofacial Pain (Società Italiana Studio Dolore Orofacciale - SISDO), Brescia, Italy
| | - Cornelis J.F. van Noorden
- Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia
| | - Fabio Rinaldi
- Human Microbiome Advanced Project Institute, Milan, Italy
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7
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Kotani K, Kawada N. Recent Advances in the Pathogenesis and Clinical Evaluation of Portal Hypertension in Chronic Liver Disease. Gut Liver 2024; 18:27-39. [PMID: 37842727 PMCID: PMC10791512 DOI: 10.5009/gnl230072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 06/16/2023] [Accepted: 06/25/2023] [Indexed: 10/17/2023] Open
Abstract
In chronic liver disease, hepatic stellate cell activation and degeneration of liver sinusoidal endothelial cells lead to structural changes, which are secondary to fibrosis and the presence of regenerative nodules in the sinusoids, and to functional changes, which are related to vasoconstriction. The combination of such changes increases intrahepatic vascular resistance and causes portal hypertension. The subsequent increase in splanchnic and systemic hyperdynamic circulation further increases the portal blood flow, thereby exacerbating portal hypertension. In clinical practice, the hepatic venous pressure gradient is the gold-standard measure of portal hypertension; a value of ≥10 mm Hg is defined as clinically significant portal hypertension, which is severe and is associated with the risk of liver-related events. Hepatic venous pressure gradient measurement is somewhat invasive, so evidence on the utility of risk stratification by elastography and serum biomarkers is needed. The various stages of cirrhosis are associated with different outcomes. In viral hepatitis-related cirrhosis, viral suppression or elimination by nucleos(t)ide analog or direct-acting antivirals results in recompensation of liver function and portal pressure. However, careful follow-up should be continued, because some cases have residual clinically significant portal hypertension even after achieving sustained virologic response. In this study, we reviewed the current and future prospects for portal hypertension.
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Affiliation(s)
- Kohei Kotani
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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8
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Fordjour FK, Abuelreich S, Hong X, Chatterjee E, Lallai V, Ng M, Saftics A, Deng F, Carnel-Amar N, Wakimoto H, Shimizu K, Bautista M, Phu TA, Vu NK, Geiger PC, Raffai RL, Fowler CD, Das S, Christenson LK, Jovanovic-Talisman T, Gould SJ. Exomap1 mouse: A transgenic model for in vivo studies of exosome biology. EXTRACELLULAR VESICLE 2023; 2:100030. [PMID: 39372847 PMCID: PMC11450736 DOI: 10.1016/j.vesic.2023.100030] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/08/2024]
Abstract
Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that are enriched in exosome marker proteins and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the Exomap1 transgenic mouse, which in response to Cre recombinase expresses the most highly enriched exosomal marker protein known, human CD81, fused to mNeonGreen (HsCD81mNG), and prior to Cre expresses a mitochondrial red fluorescent protein. Validation of the exomap1 mouse with eight distinct Cre drivers demonstrated that HsCD81mNG was expressed only in response to Cre, that murine cells correctly localized HsCD81mNG to the plasma membrane, and that this led to the secretion of HsCD81mNG in EVs that had the size (~70-80 nm), topology, and composition of exosomes. Furthermore, cell type-specific activation of the exomap1 transgene allowed us to use quantitative single molecule localization microscopy to calculate the cell type-specific contribution to biofluid exosome populations. Specifically, we show that neurons contribute ~1% to plasma and cerebrospinal fluid exosome populations whereas hepatocytes contribute ~15% to plasma exosome populations, numbers that reflect the known vascular permeabilities of brain and liver. These observations validate the use of Exomap1 mouse models for in vivo studies of exosome biology.
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Affiliation(s)
- Francis K. Fordjour
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA
| | - Sarah Abuelreich
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Xiaoman Hong
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Emeli Chatterjee
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Valeria Lallai
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA
| | - Martin Ng
- Northern California Institute for Research and Education, San Francisco, CA, 94121, USA
| | - Andras Saftics
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Fengyan Deng
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Natacha Carnel-Amar
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Kazuhide Shimizu
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA
| | - Malia Bautista
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA
| | - Tuan Anh Phu
- Northern California Institute for Research and Education, San Francisco, CA, 94121, USA
| | - Ngan K. Vu
- Northern California Institute for Research and Education, San Francisco, CA, 94121, USA
| | - Paige C. Geiger
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Robert L. Raffai
- Northern California Institute for Research and Education, San Francisco, CA, 94121, USA
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA, 94121, USA
- Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA, 94143, USA
| | - Christie D. Fowler
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA, 92697, USA
| | - Saumya Das
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Lane K. Christenson
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Tijana Jovanovic-Talisman
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Stephen J. Gould
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, 21205, USA
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Kyrrestad I, Larsen AK, Sánchez Romano J, Simón-Santamaría J, Li R, Sørensen KK. Infection of liver sinusoidal endothelial cells with Muromegalovirus muridbeta1 involves binding to neuropilin-1 and is dynamin-dependent. Front Cell Infect Microbiol 2023; 13:1249894. [PMID: 38029264 PMCID: PMC10665495 DOI: 10.3389/fcimb.2023.1249894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/23/2023] [Indexed: 12/01/2023] Open
Abstract
Liver sinusoidal endothelial cells (LSEC) are scavenger cells with a remarkably high capacity for clearance of several blood-borne macromolecules and nanoparticles, including some viruses. Endocytosis in LSEC is mainly via the clathrin-coated pit mediated route, which is dynamin-dependent. LSEC can also be a site of infection and latency of betaherpesvirus, but mode of virus entry into these cells has not yet been described. In this study we have investigated the role of dynamin in the early stage of muromegalovirus muridbeta1 (MuHV-1, murid betaherpesvirus 1, murine cytomegalovirus) infection in mouse LSECs. LSEC cultures were freshly prepared from C57Bl/6JRj mouse liver. We first examined dose- and time-dependent effects of two dynamin-inhibitors, dynasore and MitMAB, on cell viability, morphology, and endocytosis of model ligands via different LSEC scavenger receptors to establish a protocol for dynamin-inhibition studies in these primary cells. LSECs were challenged with MuHV-1 (MOI 0.2) ± dynamin inhibitors for 1h, then without inhibitors and virus for 11h, and nuclear expression of MuHV-1 immediate early antigen (IE1) measured by immune fluorescence. MuHV-1 efficiently infected LSECs in vitro. Infection was significantly and independently inhibited by dynasore and MitMAB, which block dynamin function via different mechanisms, suggesting that initial steps of MuHV-1 infection is dynamin-dependent in LSECs. Infection was also reduced in the presence of monensin which inhibits acidification of endosomes. Furthermore, competitive binding studies with a neuropilin-1 antibody blocked LSEC infection. This suggests that MuHV-1 infection in mouse LSECs involves virus binding to neuropilin-1 and occurs via endocytosis.
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Affiliation(s)
- Ingelin Kyrrestad
- Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway
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Sim BC, Kang YE, You SK, Lee SE, Nga HT, Lee HY, Nguyen TL, Moon JS, Tian J, Jang HJ, Lee JE, Yi HS. Hepatic T-cell senescence and exhaustion are implicated in the progression of fatty liver disease in patients with type 2 diabetes and mouse model with nonalcoholic steatohepatitis. Cell Death Dis 2023; 14:618. [PMID: 37735474 PMCID: PMC10514041 DOI: 10.1038/s41419-023-06146-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/06/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023]
Abstract
Immunosenescence and exhaustion are involved in the development and progression of type 2 diabetes (T2D) and metabolic liver diseases, including fatty liver, fibrosis, and cirrhosis, in humans. However, the relationships of the senescence and exhaustion of T cells with insulin resistance-associated liver diseases remain incompletely understood. To better define the relationship of T2D with nonalcoholic fatty liver disease, 59 patients (mean age 58.7 ± 11.0 years; 47.5% male) with T2D were studied. To characterize their systemic immunophenotypes, peripheral blood mononuclear cells were analyzed using flow cytometry. Magnetic resonance imaging (MRI)-based proton density fat fraction and MRI-based elastography were performed using an open-bore, vertical-field 3.0 T scanner to quantify liver fat and fibrosis, respectively. The participants with insulin resistance had a significantly larger population of CD28 - CD57+ senescent T cells among the CD4+ and CD8 + T cells than those with lower Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) values. The abundances of senescent CD4+ and CD8 + T cells and the HOMA-IR positively correlated with the severity of liver fibrosis, assessed using MRI-based elastography. Interleukin 15 from hepatic monocytes was found to be an inducer of bystander activation of T cells, which is associated with progression of liver disease in the participants with T2D. Furthermore, high expression of genes related to senescence and exhaustion was identified in CD4+ and CD8 + T cells from the participants with nonalcoholic steatohepatitis or liver cirrhosis. Finally, we have also demonstrated that hepatic T-cell senescence and exhaustion are induced in a diet or chemical-induced mouse model with nonalcoholic steatohepatitis. In conclusion, we have shown that T-cell senescence is associated with insulin resistance and metabolic liver disease in patients with T2D.
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Affiliation(s)
- Byeong Chang Sim
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Yea Eun Kang
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Sun Kyoung You
- Department of Radiology, Chungnam National University Hospital, Daejeon, Republic of Korea
| | - Seong Eun Lee
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Ha Thi Nga
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Ho Yeop Lee
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Thi Linh Nguyen
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Ji Sun Moon
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Jingwen Tian
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Hyo Ju Jang
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea
| | - Jeong Eun Lee
- Department of Radiology, Chungnam National University Hospital, Daejeon, Republic of Korea.
| | - Hyon-Seung Yi
- Laboratory of Endocrinology and Immune System, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
- Department of Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea.
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11
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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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12
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Mao H, Szafranska K, Kruse L, Holte C, Wolfson DL, Ahluwalia BS, Whitchurch CB, Cole L, Lockwood GP, Diekmann R, Le Couteur D, Cogger VC, McCourt PAG. Effect of caffeine and other xanthines on liver sinusoidal endothelial cell ultrastructure. Sci Rep 2023; 13:13390. [PMID: 37591901 PMCID: PMC10435486 DOI: 10.1038/s41598-023-40227-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/07/2023] [Indexed: 08/19/2023] Open
Abstract
Xanthines such as caffeine and theobromine are among the most consumed psychoactive stimulants in the world, either as natural components of coffee, tea and chocolate, or as added ingredients. The present study assessed if xanthines affect liver sinusoidal endothelial cells (LSEC). Cultured primary rat LSEC were challenged with xanthines at concentrations typically obtained from normal consumption of xanthine-containing beverages, food or medicines; and at higher concentrations below the in vitro toxic limit. The fenestrated morphology of LSEC were examined with scanning electron and structured illumination microscopy. All xanthine challenges had no toxic effects on LSEC ultrastructure as judged by LSEC fenestration morphology, or function as determined by endocytosis studies. All xanthines in high concentrations (150 μg/mL) increased fenestration frequency but at physiologically relevant concentrations, only theobromine (8 μg/mL) showed an effect. LSEC porosity was influenced only by high caffeine doses which also shifted the fenestration distribution towards smaller pores. Moreover, a dose-dependent increase in fenestration number was observed after caffeine treatment. If these compounds induce similar changes in vivo, age-related reduction of LSEC porosity can be reversed by oral treatment with theobromine or with other xanthines using targeted delivery.
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Affiliation(s)
- Hong Mao
- Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037, Tromsø, Norway.
- Optical Nanoscopy Research Group, Department of Physics and Technology, Faculty of Science and Technology, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
| | - Karolina Szafranska
- Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037, Tromsø, Norway.
| | - Larissa Kruse
- Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037, Tromsø, Norway
| | - Christopher Holte
- Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037, Tromsø, Norway
| | - Deanna L Wolfson
- Optical Nanoscopy Research Group, Department of Physics and Technology, Faculty of Science and Technology, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Balpreet Singh Ahluwalia
- Optical Nanoscopy Research Group, Department of Physics and Technology, Faculty of Science and Technology, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
| | - Cynthia B Whitchurch
- Microbial Imaging Facility, The ithree Institute, University of Technology Sydney, Ultimo, NSW, Australia
| | - Louise Cole
- Microbial Imaging Facility, The ithree Institute, University of Technology Sydney, Ultimo, NSW, Australia
| | - Glen P Lockwood
- Centre for Education and Research, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Robin Diekmann
- Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
- LaVision BioTec GmbH, Bielefeld, Germany
| | - David Le Couteur
- Centre for Education and Research, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Victoria C Cogger
- Centre for Education and Research, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Peter A G McCourt
- Vascular Biology Research Group, Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037, Tromsø, Norway
- Centre for Education and Research, ANZAC Research Institute, Concord Repatriation General Hospital, Concord, NSW, Australia
- The Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
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13
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Cooper SA, Kostallari E, Shah VH. Angiocrine Signaling in Sinusoidal Health and Disease. Semin Liver Dis 2023; 43:245-257. [PMID: 37442155 PMCID: PMC10798369 DOI: 10.1055/a-2128-5907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/15/2023]
Abstract
Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis, and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called "angiocrine signaling." In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, nonalcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising preclinical studies are paving the path toward LSEC-specific pharmacotherapies.
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Affiliation(s)
- Shawna A. Cooper
- Biochemistry and Molecular Biology Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota
| | - Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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14
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Fordjour FK, Abuelreich S, Hong X, Chatterjee E, Lallai V, Ng M, Saftics A, Deng F, Carnel-Amar N, Wakimoto H, Shimizu K, Bautista M, Phu TA, Vu NK, Geiger PC, Raffai RL, Fowler CD, Das S, Christenson LK, Jovanovic-Talisman T, Gould SJ. Exomap1 mouse: a transgenic model for in vivo studies of exosome biology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.29.542707. [PMID: 37398219 PMCID: PMC10312766 DOI: 10.1101/2023.05.29.542707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Exosomes are small extracellular vesicles (sEVs) of ~30-150 nm in diameter that have the same topology as the cell, are enriched in selected exosome cargo proteins, and play important roles in health and disease. To address large unanswered questions regarding exosome biology in vivo, we created the exomap1 transgenic mouse model. In response to Cre recombinase, exomap1 mice express HsCD81mNG, a fusion protein between human CD81, the most highly enriched exosome protein yet described, and the bright green fluorescent protein mNeonGreen. As expected, cell type-specific expression of Cre induced the cell type-specific expression of HsCD81mNG in diverse cell types, correctly localized HsCD81mNG to the plasma membrane, and selectively loaded HsCD81mNG into secreted vesicles that have the size (~80 nm), topology (outside out), and content (presence of mouse exosome markers) of exosomes. Furthermore, mouse cells expressing HsCD81mNG released HsCD81mNG-marked exosomes into blood and other biofluids. Using high-resolution, single-exosome analysis by quantitative single molecule localization microscopy, we show here that that hepatocytes contribute ~15% of the blood exosome population whereas neurons contribute <1% of blood exosomes. These estimates of cell type-specific contributions to blood EV population are consistent with the porosity of liver sinusoidal endothelial cells to particles of ~50-300 nm in diameter, as well as with the impermeability of blood-brain and blood-neuron barriers to particles >5 nm in size. Taken together, these results establish the exomap1 mouse as a useful tool for in vivo studies of exosome biology, and for mapping cell type-specific contributions to biofluid exosome populations. In addition, our data confirm that CD81 is a highly-specific marker for exosomes and is not enriched in the larger microvesicle class of EVs.
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Affiliation(s)
- Francis K. Fordjour
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, 21205 USA
| | - Sarah Abuelreich
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA
| | - Xiaoman Hong
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Emeli Chatterjee
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
| | - Valeria Lallai
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697 USA
| | - Martin Ng
- Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Andras Saftics
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA
| | - Fengyan Deng
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Natacha Carnel-Amar
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
| | - Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Kazuhide Shimizu
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Malia Bautista
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697 USA
| | - Tuan Anh Phu
- Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Ngan K. Vu
- Northern California Institute for Research and Education, San Francisco, CA 94121, USA
| | - Paige C. Geiger
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA
| | - Robert L. Raffai
- Northern California Institute for Research and Education, San Francisco, CA 94121, USA
- Department of Veterans Affairs, Surgical Service (112G), San Francisco VA Medical Center, San Francisco, CA 94121, USA
- Department of Surgery, Division of Vascular and Endovascular Surgery, University of California, San Francisco, CA 94143, USA
| | - Christie D. Fowler
- Department of Neurobiology & Behavior, University of California Irvine, Irvine, CA 92697 USA
| | - Saumya Das
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA
| | - Lane K. Christenson
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS 66160 USA
| | - Tijana Jovanovic-Talisman
- Department of Cancer Biology and Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA 91010 USA
| | - Stephen J. Gould
- Department of Biological Chemistry, Johns Hopkins University, Baltimore, MD, 21205 USA
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15
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Denzer L, Muranyi W, Schroten H, Schwerk C. The role of PLVAP in endothelial cells. Cell Tissue Res 2023; 392:393-412. [PMID: 36781482 PMCID: PMC10172233 DOI: 10.1007/s00441-023-03741-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 01/18/2023] [Indexed: 02/15/2023]
Abstract
Endothelial cells play a major part in the regulation of vascular permeability and angiogenesis. According to their duty to fit the needs of the underlying tissue, endothelial cells developed different subtypes with specific endothelial microdomains as caveolae, fenestrae and transendothelial channels which regulate nutrient exchange, leukocyte migration, and permeability. These microdomains can exhibit diaphragms that are formed by the endothelial cell-specific protein plasmalemma vesicle-associated protein (PLVAP), the only known protein component of these diaphragms. Several studies displayed an involvement of PLVAP in diseases as cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Besides an upregulation of PLVAP expression within these diseases, pro-angiogenic or pro-inflammatory responses were observed. On the other hand, loss of PLVAP in knockout mice leads to premature mortality due to disrupted homeostasis. Generally, PLVAP is considered as a major factor influencing the permeability of endothelial cells and, finally, to be involved in the regulation of vascular permeability. Following these observations, PLVAP is debated as a novel therapeutic target with respect to the different vascular beds and tissues. In this review, we highlight the structure and functions of PLVAP in different endothelial types in health and disease.
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Affiliation(s)
- Lea Denzer
- Department of Pediatrics, Pediatric Infectious Diseases, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Walter Muranyi
- Department of Pediatrics, Pediatric Infectious Diseases, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Horst Schroten
- Department of Pediatrics, Pediatric Infectious Diseases, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Christian Schwerk
- Department of Pediatrics, Pediatric Infectious Diseases, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
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16
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Suzuki K, Miura T, Okada H. The endothelial glycocalyx-All the same? No, it is not. Acute Med Surg 2023; 10:e896. [PMID: 37808968 PMCID: PMC10551284 DOI: 10.1002/ams2.896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/20/2023] [Accepted: 09/19/2023] [Indexed: 10/10/2023] Open
Abstract
The endothelial glycocalyx covers the lumen of blood vessels throughout the body and plays an important role in endothelial homeostasis. Advances in electron microscopy techniques have provided clues to better understand the structure and composition of identical vascular endothelial glycocalyx. The morphology and thickness of the endothelial glycocalyx differ from organ to organ. The content of the endothelial glycocalyx covering the vascular lumen differs even in the brain, heart, and lungs, which have the same continuous capillaries. Various types of inflammation are known to attenuate the endothelial glycocalyx; however, we found that the morphology of the glycocalyx damaged by acute inflammation differed from that damaged by chronic inflammation. Acute inflammation breaks the endothelial glycocalyx unevenly, whereas chronic inflammation leads to the overall shortening of the endothelial glycocalyx. The same drug has different effects on the endothelial glycocalyx, depending on the location of the target blood vessels. This difference in response may reflect not only the size and shape of the endothelial glycocalyx but also the different constituents. In the cardiac tissue, the expression of glypican-1, a core protein of the endothelial glycocalyx, was enhanced. By contrast, in the pulmonary tissue, the expression of heparan sulfate 6-O-sulfotransferase 1 and endothelial cell-specific molecule-1 significantly increased in the treatment group compared with that in the no-treatment group. In this review, we present the latest findings on the evolution of the vascular endothelial glycocalyx and consider the microstructural differences.
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Affiliation(s)
- Kodai Suzuki
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
- Department of Infection ControlGifu University Graduate School of MedicineGifuJapan
| | - Tomotaka Miura
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
| | - Hideshi Okada
- Department of Emergency and Disaster MedicineGifu University Graduate School of MedicineGifuJapan
- Center for One Medicine Innovative Translational ResearchGifu University Institute for Advanced StudyGifuJapan
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17
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Choaib A, Issa E, El Choueiry F, Eldin JN, Shbaklo K, Alhajj M, Sawaya RT, Assi G, Nader M, Chatila R, Faour WH. SARS-CoV-2-mediated liver injury: pathophysiology and mechanisms of disease. Inflamm Res 2022; 72:301-312. [PMID: 36539655 PMCID: PMC9767399 DOI: 10.1007/s00011-022-01683-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/13/2022] [Accepted: 12/16/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND SARS-CoV-2-induced severe inflammatory response can be associated with severe medical consequences leading to multi-organ failure, including the liver. The main mechanism behind this assault is the aggressive cytokine storm that induces cytotoxicity in various organs. Of interest, hepatic stellate cells (HSC) respond acutely to liver injury through several molecular mechanisms, hence furthering the perpetuation of the cytokine storm and its resultant tissue damage. In addition, hepatocytes undergo apoptosis or necrosis resulting in the release of pro-inflammatory and pro-fibrogenic mediators that lead to chronic liver inflammation. AIMS The aim of this review is to summarize available data on SARS-CoV-2-induced liver inflammation in addition to evaluate the potential effect of anti-inflammatory drugs in attenuating SARS-CoV-2-induced liver inflammation. METHODS Thorough PubMed search was done to gather and summarize published data on SARS-CoV-2-induced liver inflammation. Additionally, various anti-inflammatory potential treatments were also documented. RESULTS Published data documented SARS-CoV-2 infection of liver tissues and is prominent in most liver cells. Also, histological analysis showed various features of tissues damage, e.g., hepatocellular necrosis, mitosis, cellular infiltration, and fatty degeneration in addition to microvesicular steatosis and inflammation. Finally, the efficacy of the different drugs used to treat SARS-CoV-2-induced liver injury, in particular the anti-inflammatory remedies, are likely to have some beneficial effect to treat liver injury in COVID-19. CONCLUSION SARS-CoV-2-induced liver inflammation is a serious condition, and drugs with potent anti-inflammatory effect can play a major role in preventing irreversible liver damage in COVID-19.
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Affiliation(s)
- Ali Choaib
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Elio Issa
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Francesca El Choueiry
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Jade Nasser Eldin
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Khodor Shbaklo
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Maryline Alhajj
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Ramy Touma Sawaya
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Ghaith Assi
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
| | - Moni Nader
- Department of Physiology and Immunology, College of Medicine and Health Sciences, Khalifa University of Science and Technology, P.O. Box 127788, Abu Dhabi, United Arab Emirates
- Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, United Arab Emirates
| | - Rajaa Chatila
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon
- Internal Medicine-Gastroenterology, Lebanese American University Medical Center-Rizk Hospital (LAUMC-RH), Beirut, Lebanon
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, Lebanese American University, P.O. Box 36, Byblos, Lebanon.
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18
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Yang Z, Liu X, Cribbin EM, Kim AM, Li JJ, Yong KT. Liver-on-a-chip: Considerations, advances, and beyond. BIOMICROFLUIDICS 2022; 16:061502. [PMID: 36389273 PMCID: PMC9646254 DOI: 10.1063/5.0106855] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/25/2022] [Indexed: 05/14/2023]
Abstract
The liver is the largest internal organ in the human body with largest mass of glandular tissue. Modeling the liver has been challenging due to its variety of major functions, including processing nutrients and vitamins, detoxification, and regulating body metabolism. The intrinsic shortfalls of conventional two-dimensional (2D) cell culture methods for studying pharmacokinetics in parenchymal cells (hepatocytes) have contributed to suboptimal outcomes in clinical trials and drug development. This prompts the development of highly automated, biomimetic liver-on-a-chip (LOC) devices to simulate native liver structure and function, with the aid of recent progress in microfluidics. LOC offers a cost-effective and accurate model for pharmacokinetics, pharmacodynamics, and toxicity studies. This review provides a critical update on recent developments in designing LOCs and fabrication strategies. We highlight biomimetic design approaches for LOCs, including mimicking liver structure and function, and their diverse applications in areas such as drug screening, toxicity assessment, and real-time biosensing. We capture the newest ideas in the field to advance the field of LOCs and address current challenges.
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Affiliation(s)
| | | | - Elise M. Cribbin
- School of Biomedical Engineering, University of Technology Sydney, New South Wales 2007, Australia
| | - Alice M. Kim
- School of Biomedical Engineering, University of Technology Sydney, New South Wales 2007, Australia
| | - Jiao Jiao Li
- Authors to whom correspondence should be addressed: and
| | - Ken-Tye Yong
- Authors to whom correspondence should be addressed: and
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19
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Suzuki A, Tomita H, Okada H. Form follows function: The endothelial glycocalyx. Transl Res 2022; 247:158-167. [PMID: 35421613 DOI: 10.1016/j.trsl.2022.03.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 10/18/2022]
Abstract
Three types of capillaries, namely continuous, fenestrated, and sinusoidal, form the microvascular system; each type has a specialized structure and function to respond to the demands of the organs they supply. The endothelial glycocalyx, a gel-like layer of glycoproteins that covers the luminal surface of the capillary endothelium, is also thought to maintain organ and vascular homeostasis by exhibiting different morphologies based on the functions of the organs and capillaries in which it is found. Recent advances in analytical technology have enabled more detailed observations of the endothelial glycocalyx, revealing that it indeed differs in structure across various organs. Furthermore, differences in the lectin staining patterns suggest the presence of different endothelial glycocalyx components across various organs. Interestingly, injury to the endothelial glycocalyx due to various pathologic and physiological stimuli causes the release of these components into the blood. Thus, circulating glycocalyx components may be useful biomarkers of organ dysfunction and disease severity. Moreover, a recent study suggested that chronic injury to the glycocalyx reduces the production of these glycocalyx components and changes their structure, leading it to become more vulnerable to external stimuli. In this review, we have summarized the various endothelial glycocalyx structures and their functions.
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Affiliation(s)
- Akio Suzuki
- Department of Pharmacy, Gifu University Hospital, Gifu, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
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20
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Tuning of Liver Sieve: The Interplay between Actin and Myosin Regulatory Light Chain Regulates Fenestration Size and Number in Murine Liver Sinusoidal Endothelial Cells. Int J Mol Sci 2022; 23:ijms23179850. [PMID: 36077249 PMCID: PMC9456121 DOI: 10.3390/ijms23179850] [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: 06/30/2022] [Revised: 08/23/2022] [Accepted: 08/25/2022] [Indexed: 12/02/2022] Open
Abstract
Liver sinusoidal endothelial cells (LSECs) facilitate the efficient transport of macromolecules and solutes between the blood and hepatocytes. The efficiency of this transport is realized via transcellular nanopores, called fenestrations. The mean fenestration size is 140 ± 20 nm, with the range from 50 nm to 350 nm being mostly below the limits of diffraction of visible light. The cellular mechanisms controlling fenestrations are still poorly understood. In this study, we tested a hypothesis that both Rho kinase (ROCK) and myosin light chain (MLC) kinase (MLCK)-dependent phosphorylation of MLC regulates fenestrations. We verified the hypothesis using a combination of several molecular inhibitors and by applying two high-resolution microscopy modalities: structured illumination microscopy (SIM) and scanning electron microscopy (SEM). We demonstrated precise, dose-dependent, and reversible regulation of the mean fenestration diameter within a wide range from 120 nm to 220 nm and the fine-tuning of the porosity in a range from ~0% up to 12% using the ROCK pathway. Moreover, our findings indicate that MLCK is involved in the formation of new fenestrations—after inhibiting MLCK, closed fenestrations cannot be reopened with other agents. We, therefore, conclude that the Rho-ROCK pathway is responsible for the control of the fenestration diameter, while the inhibition of MLCK prevents the formation of new fenestrations.
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21
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Ander SE, Li FS, Carpentier KS, Morrison TE. Innate immune surveillance of the circulation: A review on the removal of circulating virions from the bloodstream. PLoS Pathog 2022; 18:e1010474. [PMID: 35511797 PMCID: PMC9070959 DOI: 10.1371/journal.ppat.1010474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Many viruses utilize the lymphohematogenous route for dissemination; however, they may not freely use this highway unchecked. The reticuloendothelial system (RES) is an innate defense system that surveys circulating blood, recognizing and capturing viral particles. Examination of the literature shows that the bulk of viral clearance is mediated by the liver; however, the precise mechanism(s) mediating viral vascular clearance vary between viruses and, in many cases, remains poorly defined. Herein, we summarize what is known regarding the recognition and capture of virions from the circulation prior to the generation of a specific antibody response. We also discuss the consequences of viral capture on viral pathogenesis and the fate of the captor cell. Finally, this understudied topic has implications beyond viral pathogenesis, including effects on arbovirus ecology and the application of virus-vectored gene therapies.
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Affiliation(s)
- Stephanie E. Ander
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Frances S. Li
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - Kathryn S. Carpentier
- Department of Natural Sciences, Greensboro College, Greensboro, North Carolina, United States of America
| | - Thomas E. Morrison
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America
- * E-mail:
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22
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Li H. Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma. Dig Liver Dis 2022; 54:598-613. [PMID: 34344577 DOI: 10.1016/j.dld.2021.07.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022]
Abstract
Intercellular crosstalk among various liver cells plays an important role in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Capillarization of liver sinusoidal endothelial cells (LSECs) precedes fibrosis and accumulating evidence suggests that the crosstalk between LSECs and other liver cells is critical in the development and progression of liver fibrosis. LSECs dysfunction, a key event in the progression from fibrosis to cirrhosis, and subsequently obstruction of hepatic sinuses and increased intrahepatic vascular resistance (IHVR) contribute to development of portal hypertension (PHT) and cirrhosis. More importantly, immunosuppressive tumor microenvironment (TME), which is closely related to the crosstalk between LSECs and immune liver cells like CD8+ T cells, promotes advances tumorigenesis, especially HCC. However, the connections within the crosstalk between LSECs and other liver cells during the progression from liver fibrosis to cirrhosis to HCC have yet to be discussed. In this review, we first summarize the current knowledge of how different crosstalk between LSECs and other liver cells, including hepatocytes, hepatic stellate cells (HSCs), macrophoges, immune cells in liver and extra cellular matrix (ECM) contribute to the physiological function and the progrssion from liver fibrosis to cirrhosis, or even to HCC. Then we examine current treatment strategies for LSECs crosstalk in liver fibrosis, cirrhosis and HCC.
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Affiliation(s)
- Hui Li
- Central Laboratory, Hospital of Chengdu University of Traditional Chinese Medicine, NO. 39 Shi-er-qiao Road, Chengdu, 610072, Sichuan Province, PR China.
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23
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Mak KM, Kee D, Cheng CP. A review of hepatic fibrosis-associated histopathology in aged cadavers. Anat Rec (Hoboken) 2022; 306:1031-1053. [PMID: 35446463 DOI: 10.1002/ar.24931] [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: 01/26/2022] [Revised: 03/09/2022] [Accepted: 03/10/2022] [Indexed: 11/08/2022]
Abstract
This article reviews hepatic fibrosis-associated histopathology of aged cadavers (mean age 82 years). A study of 68 livers identified steatosis in 35.5%, central vein fibrosis in 49.2%, perisinusoidal fibrosis in 63.2%, portal tract fibrosis in 47.7%, septa formation in 44.1%, bridging fibrosis in 30.8%, and cirrhosis in 4.4% of the samples as well as one hepatocellular carcinoma and six metastatic tumors. Other studies have revealed that collagens I, III, IV, V, and VI and fibronectin constitute the matrices of fibrous central veins, perisinusoidal space, portal tracts, and septa. Elastin is rich in portal tracts and fibrous septa but absent from the perisinusoidal space. Hepatic stellate cells are ubiquitous in the liver parenchyma while myofibroblasts localize in fibrotic foci. Factor VIII-related antigen expression signals sinusoidal to systemic vascular endothelium transformation while collagen IV and laminin codistribution indicates formation of perisinusoidal membranes. Their coincidence reflects focalized capillarization of sinusoids in the aged liver. In response to fibrogenesis, hepatic progenitor cells residing in the canal of Hering in the periportal parenchyma undergo expansion and migration deep into the lobule. Concomitantly, intermediate hepatocyte-like cells increase in advanced fibrosis stages, which is possibly related to hepatic regeneration. Metabolic zonation of glutamine synthetase expands from the perivenous to non-perivenous parenchyma in fibrosis progression but its expression is lost in cirrhosis, while cytochrome P-4502E1 expression is maintained in centrilobular and midlobular zones in fibrosis progression and expressed in cirrhosis. Hence, cadaveric livers provide a platform for further investigation of hepatic histopathologies associated with the aging liver.
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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
| | - Christopher P Cheng
- 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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24
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Pattipeiluhu R, Arias-Alpizar G, Basha G, Chan KYT, Bussmann J, Sharp TH, Moradi MA, Sommerdijk N, Harris EN, Cullis PR, Kros A, Witzigmann D, Campbell F. Anionic Lipid Nanoparticles Preferentially Deliver mRNA to the Hepatic Reticuloendothelial System. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2201095. [PMID: 35218106 PMCID: PMC9461706 DOI: 10.1002/adma.202201095] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Indexed: 05/04/2023]
Abstract
Lipid nanoparticles (LNPs) are the leading nonviral technologies for the delivery of exogenous RNA to target cells in vivo. As systemic delivery platforms, these technologies are exemplified by Onpattro, an approved LNP-based RNA interference therapy, administered intravenously and targeted to parenchymal liver cells. The discovery of systemically administered LNP technologies capable of preferential RNA delivery beyond hepatocytes has, however, proven more challenging. Here, preceded by comprehensive mechanistic understanding of in vivo nanoparticle biodistribution and bodily clearance, an LNP-based messenger RNA (mRNA) delivery platform is rationally designed to preferentially target the hepatic reticuloendothelial system (RES). Evaluated in embryonic zebrafish, validated in mice, and directly compared to LNP-mRNA systems based on the lipid composition of Onpattro, RES-targeted LNPs significantly enhance mRNA expression both globally within the liver and specifically within hepatic RES cell types. Hepatic RES targeting requires just a single lipid change within the formulation of Onpattro to switch LNP surface charge from neutral to anionic. This technology not only provides new opportunities to treat liver-specific and systemic diseases in which RES cell types play a key role but, more importantly, exemplifies that rational design of advanced RNA therapies must be preceded by a robust understanding of the dominant nano-biointeractions involved.
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Affiliation(s)
- Roy Pattipeiluhu
- Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, 2333 CC, The Netherlands
- BioNanoPatterning, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2333 RC, The Netherlands
| | - Gabriela Arias-Alpizar
- Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, 2333 CC, The Netherlands
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, 2333 CC, The Netherlands
| | - Genc Basha
- NanoMedicines Research Group, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, Canada
| | - Karen Y T Chan
- NanoMedicines Research Group, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, Canada
| | - Jeroen Bussmann
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, 2333 CC, The Netherlands
| | - Thomas H Sharp
- BioNanoPatterning, Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, 2333 RC, The Netherlands
| | - Mohammad-Amin Moradi
- Materials and Interface Chemistry, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology, Eindhoven, 5600 MB, The Netherlands
| | - Nico Sommerdijk
- Department of Biochemistry, Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, 6500 HB, The Netherlands
| | - Edward N Harris
- Department of Biochemistry, University of Nebraska, Lincoln, NE, 68588, USA
| | - Pieter R Cullis
- NanoMedicines Research Group, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, Canada
- NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, V6T 1Z3, Canada
- NanoVation Therapeutics Inc., 2405 Wesbrook Mall 4th Floor, Vancouver, V6T 1Z3, Canada
| | - Alexander Kros
- Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, 2333 CC, The Netherlands
| | - Dominik Witzigmann
- NanoMedicines Research Group, Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, Canada
- NanoMedicines Innovation Network (NMIN), University of British Columbia, Vancouver, V6T 1Z3, Canada
- NanoVation Therapeutics Inc., 2405 Wesbrook Mall 4th Floor, Vancouver, V6T 1Z3, Canada
| | - Frederick Campbell
- Supramolecular and Biomaterials Chemistry, Leiden Institute of Chemistry, Leiden University, Leiden, 2333 CC, The Netherlands
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25
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Kobayashi M, Ehama Y, Hirayama S. The Necessity of Individualized Treatment for Sepsis-Associated Disseminated Intravascular Coagulation by Infected Organ. Open Access Emerg Med 2022; 14:133-140. [PMID: 35418787 PMCID: PMC9000919 DOI: 10.2147/oaem.s359216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 03/22/2022] [Indexed: 11/23/2022] Open
Abstract
Objective Several studies have shown that anticoagulation can improve survival outcomes in patients with sepsis-associated disseminated intravascular coagulation (DIC). A guideline from Japan in 2020 suggested two therapeutic agents for sepsis-associated DIC treatment: antithrombin (AT) replacement therapy and recombinant thrombomodulin (rTM) preparation. In 2021, our preliminary study proposed that different organs of septic infection might lead to distinct treatment outcomes following different therapies against DIC. In this study, we created a subanalysis on the influence of AT replacement therapy and rTM preparations on overall survival (OS) by comparing two causative organs: biliary and respiratory tract infections. Patients and Methods This retrospective cohort study in a single institution involved patients with sepsis-associated DIC treated by either AT or rTM who were categorized based on sources of infection. The two groups defined for this study were biliary (n = 62) and respiratory tract infection (n = 84). To assess the clinical efficacy of AT and rTM, 30-day OS was examined using a stepwise variable selection for a Cox proportional hazards model. Results The analysis of factors influencing OS by each group showed that rTM preparation remained a significant factor in the biliary tract infection group (HR 0.306, 95% CI 0.133–0.706). In the respiratory tract infection group, the score of the Acute Physiology and Chronic Health Evaluation II (HR 1.109, 95% CI 1.051–1.170), polymyxin B hemoperfusion (HR 0.390, 95% CI 0.161–0.944), and AT replacement therapy (HR 0.510, 95% CI 0.261–0.997) were established as significant factors. Conclusion This study revealed that the OS of patients with biliary tract and respiratory tract infections differed depending on the DIC therapeutic agent. Based on these results, we could suggest that it is necessary to develop individualized treatment strategies for septic infections, taking into consideration the differences in the infected organs.
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Affiliation(s)
- Makoto Kobayashi
- Intensive Care Center, Hakodate Goryoukaku Hospital, Hakodate City, Hokkaido, Japan
- Correspondence: Makoto Kobayashi, Hakodate Goryoukaku Hospital, 38-3 Goryoukaku-cho, Hakodate City, Hokkaido, 040-8611, Japan, Tel +81-138-51-2295, Fax +81-138-56-2695, Email
| | - Yoshimatsu Ehama
- Department of Emergency Medicine, Hakodate Goryoukaku Hospital, Hakodate City, Hokkaido, Japan
| | - Suguru Hirayama
- Department of Emergency Medicine, Hakodate Goryoukaku Hospital, Hakodate City, Hokkaido, Japan
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26
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Dhawan P, Vasishta S, Balakrishnan A, Joshi MB. Mechanistic insights into glucose induced vascular epigenetic reprogramming in type 2 diabetes. Life Sci 2022; 298:120490. [DOI: 10.1016/j.lfs.2022.120490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/22/2022] [Accepted: 03/16/2022] [Indexed: 12/13/2022]
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27
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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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28
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Abstract
Intestinal microbiota, dominated by bacteria, plays an important role in the occurrence and the development of alcohol-associated liver disease (ALD), which is one of the most common liver diseases around the world. With sufficient studies focusing on the gut bacterial community, chronic alcohol consumption is now known as a key factor that alters the composition of gut bacterial community, increases intestinal permeability, causes intestinal dysfunction, induces bacterial translocation, and exacerbates the process of ALD via gut-liver axis. However, gut non-bacterial communities including fungi, viruses, and archaea, which may also participate in the disease, has received little attention relative to the gut bacterial community. This paper will systematically collect the latest literatures reporting non-bacterial communities in mammalian health and disease, and review their mechanisms in promoting the development of ALD including CLEC7A pathway, Candidalysin (a peptide toxin secreted by Candida albicans), metabolites, and other chemical substances secreted or regulated by gut commensal mycobiome, virome, and archaeome, hoping to bring novel insights on our current knowledge of ALD.
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Affiliation(s)
- Wenkang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yixin Zhu
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Jin Ye
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,CONTACT Huikuan Chu Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China
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29
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Werner M, Schefczyk S, Trippler M, Treckmann JW, Baba HA, Gerken G, Schlaak JF, Broering R. Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3. Viruses 2022; 14:218. [PMID: 35215812 PMCID: PMC8874605 DOI: 10.3390/v14020218] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1-9 ligands for 6-24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.
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Affiliation(s)
- Melanie Werner
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Stefan Schefczyk
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Martin Trippler
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
| | - Juergen W. Treckmann
- Department of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Hideo A. Baba
- Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany;
| | - Guido Gerken
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- Helios Hospital, Gastroenterology, Hepatology and Palliative Medicine, Robert-Koch-Straße 2, 42549 Velbert, Germany
| | - Joerg F. Schlaak
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
- AMEOS Hospital, St. Clemens, Internal Medicine—Hepatology, Gastroenterology, Infectiology and Diabetology, Wilhelmstr. 34, 46145 Oberhausen, Germany
| | - Ruth Broering
- Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; (M.W.); (S.S.); (M.T.); (G.G.); (J.F.S.)
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30
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Lei T, Wang R, Zhang Y, Wan Y, Liu C, Nandi AK. DefED-Net: Deformable Encoder-Decoder Network for Liver and Liver Tumor Segmentation. IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES 2022. [DOI: 10.1109/trpms.2021.3059780] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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31
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Lim AR, Ghajar CM. Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse. Semin Cancer Biol 2022; 78:104-123. [PMID: 33979673 PMCID: PMC9595433 DOI: 10.1016/j.semcancer.2021.05.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 02/07/2023]
Abstract
Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
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Affiliation(s)
- Andrea R Lim
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Graduate Program in Molecular and Cellular Biology, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Cyrus M Ghajar
- Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
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32
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Akkoc Y, Gozuacik D. Autophagy and Hepatic Tumor Microenvironment Associated Dormancy. J Gastrointest Cancer 2021; 52:1277-1293. [PMID: 34921672 DOI: 10.1007/s12029-021-00774-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/19/2021] [Indexed: 02/08/2023]
Abstract
The goal of successful cancer treatment is targeting the eradication of cancer cells. Although surgical removal of the primary tumors and several rounds of chemo- and radiotherapy reduce the disease burden, in some cases, asymptomatic dormant cancer cells may still exist in the body. Dormant cells arise from the disseminated tumor cells (DTCs) from the primary lesion. DTCs escape from immune system and cancer therapy and reside at the secondary organ without showing no sign of proliferation. However, under some conditions. dormant cells can be re-activated and enter a proliferative state even after decades. As a stress response mechanism, autophagy may help the adaptation of DTCs at this futile foreign microenvironment and may control the survival and re-activation of dormant cells. Studies indicate that hepatic microenvironment serves a favorable condition for cancer cell dormancy. Although, no direct study was pointing out the role of autophagy in liver-assisted dormancy, involvement of autophagy in both liver microenvironment, health, and disease conditions has been indicated. Therefore, in this review article, we will summarize cancer dormancy and discuss the role and importance of autophagy and hepatic microenvironment in this context.
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Affiliation(s)
- Yunus Akkoc
- Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, 34010, Turkey.
| | - Devrim Gozuacik
- Koç University Research Centre for Translational Medicine (KUTTAM), Istanbul, 34010, Turkey.,Koç University School of Medicine, Istanbul, 34010, Turkey
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33
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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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Verhulst S, van Os EA, De Smet V, Eysackers N, Mannaerts I, van Grunsven LA. Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases. Front Med (Lausanne) 2021; 8:750044. [PMID: 34746184 PMCID: PMC8564042 DOI: 10.3389/fmed.2021.750044] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 09/21/2021] [Indexed: 01/22/2023] Open
Abstract
Liver sinusoidal endothelial cells have a gatekeeper function in liver homeostasis by permitting substrates from the bloodstream into the space of Disse and regulating hepatic stellate cell activation status. Maintenance of LSEC's highly specialized phenotype is crucial for liver homeostasis. During liver fibrosis and cirrhosis, LSEC phenotype and functions are lost by processes known as capillarization and LSEC dysfunction. LSEC capillarization can be demonstrated by the loss of fenestrae (cytoplasmic pores) and the manifestation of a basement membrane. Currently, no protein or genetic markers can clearly distinguish healthy from damaged LSECs in acute or chronic liver disease. Single cell (sc)RNA sequencing efforts have identified several LSEC populations in mouse models for liver disease and in human cirrhotic livers. Still, there are no clearly defined genesets that can identify LSECs or dysfunctional LSEC populations in transcriptome data. Here, we developed genesets that are enriched in healthy and damaged LSECs which correlated very strongly with healthy and early stage- vs. advanced human liver diseases. A damaged LSEC signature comprised of Fabp4/5 and Vwf/a1 was established which could efficiently identify damaged endothelial cells in single cell RNAseq data sets. In LSECs from an acute CCl4 liver injury mouse model, Fabp4/5 and Vwf/a1 expression is induced within 1-3 days while in cirrhotic human livers these 4 genes are highly enriched in damaged LSECs. In conclusion, our newly developed gene signature of damaged LSECs can be applicable to a wide range of liver disease etiologies, implicating a common transcriptional alteration mechanism in LSEC damage.
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Affiliation(s)
- Stefaan Verhulst
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Elise Anne van Os
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Vincent De Smet
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Nathalie Eysackers
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Inge Mannaerts
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
| | - Leo A van Grunsven
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussel, Belgium
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Bhandari S, Larsen AK, McCourt P, Smedsrød B, Sørensen KK. The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease. Front Physiol 2021; 12:757469. [PMID: 34707514 PMCID: PMC8542980 DOI: 10.3389/fphys.2021.757469] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.
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Affiliation(s)
- Sabin Bhandari
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Anett Kristin Larsen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Peter McCourt
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Bård Smedsrød
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
| | - Karen Kristine Sørensen
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø (UiT) - The Arctic University of Norway, Tromsø, Norway
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Szafranska K, Kruse LD, Holte CF, McCourt P, Zapotoczny B. The wHole Story About Fenestrations in LSEC. Front Physiol 2021; 12:735573. [PMID: 34588998 PMCID: PMC8473804 DOI: 10.3389/fphys.2021.735573] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations - transcellular pores with diameters in the range of 50-300 nm - typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.
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Affiliation(s)
- Karolina Szafranska
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Larissa D Kruse
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Christopher Florian Holte
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Peter McCourt
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Bartlomiej Zapotoczny
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway.,Department of Biophysical Microstructures, Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, Poland
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Wisse E, Braet F, Shami GJ, Zapotoczny B, Vreuls C, Verhaegh P, Frederik P, Peters PJ, Olde Damink S, Koek G. Fat causes necrosis and inflammation in parenchymal cells in human steatotic liver. Histochem Cell Biol 2021; 157:27-38. [PMID: 34524512 PMCID: PMC8755686 DOI: 10.1007/s00418-021-02030-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2021] [Indexed: 02/07/2023]
Abstract
Adapted fixation methods for electron microscopy allowed us to study liver cell fine structure in 217 biopsies of intact human livers over the course of 10 years. The following novel observations and concepts arose: single fat droplets in parenchymal cells can grow to a volume four times larger than the original cell, thereby extremely marginalizing the cytoplasm with all organelles. Necrosis of single parenchymal cells, still containing one huge fat droplet, suggests death by fat in a process of single-cell steatonecrosis. In a later stage of single-cell steatonecrosis, neutrophils and erythrocytes surround the single fat droplet, forming an inflammatory fat follicle indicating the apparent onset of inflammation. Also, fat droplets frequently incorporate masses of filamentous fragments and other material, most probably representing Mallory substance. No other structure or material was found that could possibly represent Mallory bodies. We regularly observe the extrusion of huge fat droplets, traversing the peripheral cytoplasm of parenchymal cells, the Disse space and the endothelium. These fat droplets fill the sinusoid as a sinusoidal lipid embolus. In conclusion, adapted methods of fixation applied to human liver tissue revealed that single, huge fat droplets cause necrosis and inflammation in single parenchymal cells. Fat droplets also collect Mallory substance and give rise to sinusoidal fat emboli. Therefore, degreasing of the liver seems to be an essential therapeutic first step in the self-repairing of non-alcoholic fatty liver disease. This might directly reduce single-cell steatotic necrosis and inflammation as elements in non-alcoholic steatohepatitis progression.
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Affiliation(s)
- Eddie Wisse
- Division of Nanoscopy, University of Maastricht Multimodal Molecular Imaging Institute, Maastricht, 6229, The Netherlands.
| | - Filip Braet
- School of Medical Sciences (Discipline of Anatomy and Histology) & Australian Centre for Microscopy & Microanalysis, The University of Sydney, Sydney, NSW, 2006, Australia.
| | - Gerald J Shami
- School of Medical Sciences (Discipline of Anatomy and Histology) & Australian Centre for Microscopy & Microanalysis, The University of Sydney, Sydney, NSW, 2006, Australia
| | | | - Celien Vreuls
- Department of Pathology, Utrecht University Medical Centre, Utrtecht, The Netherlands
| | - Pauline Verhaegh
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
| | - Peter Frederik
- Emeritus of Maastricht University, Jekerstraat 39, 6211 NS, Maastricht, The Netherlands
| | - Peters J Peters
- Division of Nanoscopy, University of Maastricht Multimodal Molecular Imaging Institute, Maastricht, 6229, The Netherlands
| | - Steven Olde Damink
- Department of Surgery, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
| | - Ger Koek
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, 6229 HX, Maastricht, The Netherlands
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Seternes T, Bøgwald J, Dalmo RA. Scavenger endothelial cells of fish, a review. JOURNAL OF FISH DISEASES 2021; 44:1385-1397. [PMID: 33999444 DOI: 10.1111/jfd.13396] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/28/2021] [Indexed: 06/12/2023]
Abstract
The definition of scavenger endothelial cells (SEC) is exclusively based on functional and structural characteristics. The following characteristics are common hallmarks for the vertebrate SEC: (a) All vertebrates examined are furnished with a population of special SEC that plays a role in the catabolism of physiologic and non-physiologic soluble waste macromolecules. (b) From the ligands that are endocytosed, SEC in all seven vertebrate classes appear to express the collagen α-chain receptor and the scavenger receptors. In addition, the hyaluronan and the mannose receptors are present on SEC of mammalia (several species) and osteichthyes (e.g., salmon and cod). It is likely that all four receptor types are present in all vertebrate classes. (c) Like liver endothelial cells (LEC) in mammals, SEC in all vertebrate classes are geared to endocytosis of soluble macromolecules, but phagocytic uptake of particles is taken care of mainly by macrophages. (d) The most primitive vertebrates (hagfish, lamprey and ray) carry their SEC in gill vessels, whereas phylogenetically younger fishes (salmon, carp, cod and plaice) carry their SEC in either kidney or heart and in all terrestrial vertebrates-SEC are found exclusively in the liver. (e) SEC of all vertebrates are localized in blood sinusoids or trabeculae that carry large amounts of slowly flowing and O2 poor blood. (f) SEC differs functionally and structurally from what is normally associated with "conventional vascular endothelium."
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Affiliation(s)
- Tore Seternes
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Jarl Bøgwald
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
| | - Roy A Dalmo
- Faculty of Biosciences, Fisheries and Economics, UiT - The Arctic University of Norway, Tromsø, Norway
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Vacani-Martins N, Meuser-Batista M, dos Santos CDLP, Hasslocher-Moreno AM, Henriques-Pons A. The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View. Pathogens 2021; 10:pathogens10091074. [PMID: 34578107 PMCID: PMC8465576 DOI: 10.3390/pathogens10091074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/05/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Chagas disease was described more than a century ago and, despite great efforts to understand the underlying mechanisms that lead to cardiac and digestive manifestations in chronic patients, much remains to be clarified. The disease is found beyond Latin America, including Japan, the USA, France, Spain, and Australia, and is caused by the protozoan Trypanosoma cruzi. Dr. Carlos Chagas described Chagas disease in 1909 in Brazil, and hepatomegaly was among the clinical signs observed. Currently, hepatomegaly is cited in most papers published which either study acutely infected patients or experimental models, and we know that the parasite can infect multiple cell types in the liver, especially Kupffer cells and dendritic cells. Moreover, liver damage is more pronounced in cases of oral infection, which is mainly found in the Amazon region. However, the importance of liver involvement, including the hepatic immune response, in disease progression does not receive much attention. In this review, we present the very first paper published approaching the liver's participation in the infection, as well as subsequent papers published in the last century, up to and including our recently published results. We propose that, after infection, activated peripheral T lymphocytes reach the liver and induce a shift to a pro-inflammatory ambient environment. Thus, there is an immunological integration and cooperation between peripheral and hepatic immunity, contributing to disease control.
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Affiliation(s)
- Natalia Vacani-Martins
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | - Marcelo Meuser-Batista
- Depto de Anatomia Patológica e Citopatologia, Instituto Fernandes Figueira, Fundação Oswaldo Cruz, Rio de Janeiro 22250-020, Brazil;
| | - Carina de Lima Pereira dos Santos
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
| | | | - Andrea Henriques-Pons
- Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro 21041-361, Brazil; (N.V.-M.); (C.d.L.P.d.S.)
- Correspondence:
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Petrillo S, Manco M, Altruda F, Fagoonee S, Tolosano E. Liver Sinusoidal Endothelial Cells at the Crossroad of Iron Overload and Liver Fibrosis. Antioxid Redox Signal 2021; 35:474-486. [PMID: 32689808 DOI: 10.1089/ars.2020.8168] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Significance: Liver fibrosis results from different etiologies and represents one of the most serious health issues worldwide. Fibrosis is the outcome of chronic insults on the liver and is associated with several factors, including abnormal iron metabolism. Recent Advances: Multiple mechanisms underlying the profibrogenic role of iron have been proposed. The pivotal role of liver sinusoidal endothelial cells (LSECs) in iron-level regulation, as well as their morphological and molecular dedifferentiation occurring in liver fibrosis, has encouraged research on LSECs as prime regulators of very early fibrotic events. Importantly, normal differentiated LSECs may act as gatekeepers of fibrogenesis by maintaining the quiescence of hepatic stellate cells, while LSECs capillarization precedes the onset of liver fibrosis. Critical Issues: In the present review, the morphological and molecular alterations occurring in LSECs after liver injury are addressed in an attempt to highlight how vascular dysfunction promotes fibrogenesis. In particular, we discuss in depth how a vicious loop can be established in which iron dysregulation and LSEC dedifferentiation synergize to exacerbate and promote the progression of liver fibrosis. Future Directions: LSECs, due to their pivotal role in early liver fibrosis and iron homeostasis, show great promises as a therapeutic target. In particular, new strategies can be devised for restoring LSECs differentiation and thus their role as regulators of iron homeostasis, hence preventing the progression of liver fibrosis or, even better, promoting its regression. Antioxid. Redox Signal. 35, 474-486.
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Affiliation(s)
- Sara Petrillo
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Marta Manco
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Fiorella Altruda
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
| | - Sharmila Fagoonee
- Institute of Biostructure and Bioimaging, CNR c/o Molecular Biotechnology Center, Torino, Italy
| | - Emanuela Tolosano
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy
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Thurner GC, Haybaeck J, Debbage P. Targeting Drug Delivery in the Elderly: Are Nanoparticles an Option for Treating Osteoporosis? Int J Mol Sci 2021; 22:8932. [PMID: 34445639 PMCID: PMC8396227 DOI: 10.3390/ijms22168932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022] Open
Abstract
Nanoparticles bearing specific targeting groups can, in principle, accumulate exclusively at lesion sites bearing target molecules, and release therapeutic agents there. However, practical application of targeted nanoparticles in the living organism presents challenges. In particular, intravasally applied nanoparticles encounter physical and physiological barriers located in blood vessel walls, blocking passage from the blood into tissue compartments. Whereas small molecules can pass out of the blood, nanoparticles are too large and need to utilize physiological carriers enabling passage across endothelial walls. The issues associated with crossing blood-tissue barriers have limited the usefulness of nanoparticles in clinical applications. However, nanoparticles do not encounter blood-tissue barriers if their targets are directly accessible from the blood. This review focuses on osteoporosis, a disabling and common disease for which therapeutic strategies are limited. The target sites for therapeutic agents in osteoporosis are located in bone resorption pits, and these are in immediate contact with the blood. There are specific targetable biomarkers within bone resorption pits. These present nanomedicine with the opportunity to treat a major disease by use of simple nanoparticles loaded with any of several available effective therapeutics that, at present, cannot be used due to their associated side effects.
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Affiliation(s)
- Gudrun C. Thurner
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Müllerstraße 44, 6020 Innsbruck, Austria;
| | - Johannes Haybaeck
- Institute of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, Müllerstraße 44, 6020 Innsbruck, Austria;
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
| | - Paul Debbage
- Department of Anatomy, Histology and Embryology, Medical University of Innsbruck, Müllerstraße 59, 6020 Innsbruck, Austria
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Iwakiri Y, Trebicka J. Portal hypertension in cirrhosis: Pathophysiological mechanisms and therapy. JHEP Rep 2021; 3:100316. [PMID: 34337369 PMCID: PMC8318926 DOI: 10.1016/j.jhepr.2021.100316] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 04/19/2021] [Accepted: 05/12/2021] [Indexed: 12/14/2022] Open
Abstract
Portal hypertension, defined as increased pressure in the portal vein, develops as a consequence of increased intrahepatic vascular resistance due to the dysregulation of liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), frequently arising from chronic liver diseases. Extrahepatic haemodynamic changes contribute to the aggravation of portal hypertension. The pathogenic complexity of portal hypertension and the unsuccessful translation of preclinical studies have impeded the development of effective therapeutics for patients with cirrhosis, while counteracting hepatic and extrahepatic mechanisms also pose a major obstacle to effective treatment. In this review article, we will discuss the following topics: i) cellular and molecular mechanisms of portal hypertension, focusing on dysregulation of LSECs, HSCs and hepatic microvascular thrombosis, as well as changes in the extrahepatic vasculature, since these are the major contributors to portal hypertension; ii) translational/clinical advances in our knowledge of portal hypertension; and iii) future directions.
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Key Words
- ACE2, angiogenesis-converting enzyme 2
- ACLF, acute-on-chronic liver failure
- AT1R, angiotensin II type I receptor
- CCL2, chemokine (C-C motif) ligand 2
- CCl4, carbon tetrachloride
- CLD, chronic liver disease
- CSPH, clinically significant portal hypertension
- Dll4, delta like canonical Notch ligand 4
- ECM, extracellular matrix
- EUS, endoscopic ultrasound
- FXR
- FXR, farnesoid X receptor
- HCC, hepatocellular carcinoma
- HRS, hepatorenal syndrome
- HSC
- HSCs, hepatic stellate cells
- HVPG, hepatic venous pressure gradient
- Hsp90, heat shock protein 90
- JAK2, Janus kinase 2
- KO, knockout
- LSEC
- LSEC, liver sinusoidal endothelial cells
- MLCP, myosin light-chain phosphatase
- NET, neutrophil extracellular trap
- NO
- NO, nitric oxide
- NSBB
- NSBBs, non-selective beta blockers
- PDE, phosphodiesterase
- PDGF, platelet-derived growth factor
- PIGF, placental growth factor
- PKG, cGMP-dependent protein kinase
- Rho-kinase
- TIPS
- TIPS, transjugular intrahepatic portosystemic shunt
- VCAM1, vascular cell adhesion molecule 1
- VEGF
- VEGF, vascular endothelial growth factor
- angiogenesis
- eNOS, endothelial nitric oxide synthase
- fibrosis
- liver stiffness
- statins
- β-Arr2, β-arrestin 2
- β1-AR, β1-adrenergic receptor
- β2-AR, β2-adrenergic receptor
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Affiliation(s)
- Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, University Clinic Frankfurt, Frankfurt, Germany
- European Foundation for the Study of Chronic Liver Failure-EF Clif, Barcelona, Spain
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Yokomori H, Ando W, Oda M. Plasmalemmal Vesicle-Associated Protein Is Associated with Endothelial Cells Sprouting from the Peribiliary Capillary Plexus in Human Cirrhotic Liver. J Vasc Res 2021; 58:361-369. [PMID: 34280928 DOI: 10.1159/000516923] [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: 02/04/2021] [Accepted: 04/19/2021] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Plasmalemmal vesicle-associated protein (PLVAP) is an endothelial-specific integral membrane glycoprotein that localizes to caveolae and fenestrae in animal models; however, little is known about PLVAP in endothelial cells (ECs) in hepatic sinusoids during liver cirrhosis (LC). Here, we aimed to elucidate PLVAP localization and expression in the human liver during LC progression. METHODS PLVAP protein expression was detected in specimens from normal control livers and hepatitis C-related cirrhotic livers using immunohistochemistry, Western blotting, and immunoelectron microscopy. RESULTS PLVAP mainly localized to the peribiliary capillary plexus (PCP) and was rarely observed in hepatic artery branches and portal venules in control tissue, but was aberrantly expressed in capillarized sinusoids and proliferated capillaries in fibrotic septa within cirrhotic liver tissue. Ultrastructural analysis indicated that PLVAP localized to thin ECs in some caveolae, whereas PLVAP localized primarily to caveolae-like structures and proliferative sinusoid capillary EC vesicles in cirrhotic liver tissue. Western blot analysis confirmed that PLVAP was overexpressed at the protein level in advanced cirrhotic liver tissue. CONCLUSION PLVAP was strongly expressed in the caveolae of proliferated capillaries directly connected with sinusoids linked with the PCP, suggesting that it plays a role in angiogenesis and sinusoidal remodeling in LC.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan
| | - Wataru Ando
- Department of Pharmaceutical Science, Kitasato University, Tokyo, Japan
| | - Masaya Oda
- The Chunichi Newspapers, The Main Tokyo Clinic, Tokyo, Japan
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Abstract
Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia-reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.
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Grémy O, Mougin-Degraef M, Devilliers K, Berdal M, Laroche P, Miccoli L. DTPA-Coated Liposomes as a New Delivery Vehicle for Plutonium Decorporation. Radiat Res 2021; 195:77-92. [PMID: 33180911 DOI: 10.1667/rade-20-00142.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 10/05/2020] [Indexed: 11/03/2022]
Abstract
Administration of diethylenetriaminepentaacetic acid (DTPA) is the treatment approach used to promote the decorporation of internalized plutonium. Here we evaluated the efficacy of PEGylated liposomes coated with DTPA, primarily designed to prevent enhanced plutonium accumulation in bones, compared to marketed nonliposomal DTPA and liposomes encapsulating DTPA. The comparative effects were examined in terms of reduction of activity in tissues of plutonium-injected rats. The prompt treatment with DTPA-coated liposomes elicited an even greater efficacy than that with liposome-encapsulated DTPA in limiting skeletal plutonium. This advantage, undoubtedly due to the anchorage of DTPA to the outer layer of liposomes, is discussed, as well as the reason for the loss of this superiority at delayed times after contamination. Plutonium complexed with DTPA-coated liposomes in extracellular compartments was partly diverted into the liver and the spleen. These complexes and those directly formed inside hepatic and splenic cells appeared to be degraded, then released from cells at extremely slow rates. This transitory accumulation of activity, which could not be counteracted by combining both liposomal forms, entailed an underestimation of the efficacy of DTPA-coated liposomes on soft tissue plutonium until total elimination probably more than one month after treatment. DTPA-coated liposomes may provide the best delivery vehicle of DTPA for preventing plutonium deposition in tissues, especially in bone where nuclides become nearly impossible to remove once fixed. Additional development efforts are needed to limit the diversion or to accelerate cell release of plutonium bound to DTPA-coated liposomes, using a labile bond for DTPA attachment.
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Affiliation(s)
- Olivier Grémy
- Laboratoire de RadioToxicologie, CEA, Université de Paris-Saclay, Bruyères-le-Châtel, France
| | - Marie Mougin-Degraef
- CRCINA, INSERM, CNRS, Université d'Angers, Université de Nantes, Nantes, France.,Nuclear Medicine, University Hospital, Nantes, France
| | - Karine Devilliers
- Laboratoire de RadioToxicologie, CEA, Université de Paris-Saclay, Bruyères-le-Châtel, France
| | - Marion Berdal
- Nuclear Medicine, University Hospital, Nantes, France
| | - Pierre Laroche
- Direction of Health, Security, Environment and Radioprotection, ORANO, Paris, France
| | - Laurent Miccoli
- Laboratoire de RadioToxicologie, CEA, Université de Paris-Saclay, Bruyères-le-Châtel, France
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46
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Angiodiversity and organotypic functions of sinusoidal endothelial cells. Angiogenesis 2021; 24:289-310. [PMID: 33745018 PMCID: PMC7982081 DOI: 10.1007/s10456-021-09780-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/04/2021] [Indexed: 02/08/2023]
Abstract
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
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Kong C, Bobe S, Pilger C, Lachetta M, Øie CI, Kirschnick N, Mönkemöller V, Hübner W, Förster C, Schüttpelz M, Kiefer F, Huser T, Schulte Am Esch J. Multiscale and Multimodal Optical Imaging of the Ultrastructure of Human Liver Biopsies. Front Physiol 2021; 12:637136. [PMID: 33679449 PMCID: PMC7925637 DOI: 10.3389/fphys.2021.637136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/27/2021] [Indexed: 12/30/2022] Open
Abstract
The liver as the largest organ in the human body is composed of a complex macroscopic and microscopic architecture that supports its indispensable function to maintain physiological homeostasis. Optical imaging of the human liver is particularly challenging because of the need to cover length scales across 7 orders of magnitude (from the centimeter scale to the nanometer scale) in order to fully assess the ultrastructure of the entire organ down to the subcellular scale and probe its physiological function. This task becomes even more challenging the deeper within the organ one hopes to image, because of the strong absorption and scattering of visible light by the liver. Here, we demonstrate how optical imaging methods utilizing highly specific fluorescent labels, as well as label-free optical methods can seamlessly cover this entire size range in excised, fixed human liver tissue and we exemplify this by reconstructing the biliary tree in three-dimensional space. Imaging of tissue beyond approximately 0.5 mm length requires optical clearing of the human liver. We present the successful use of optical projection tomography and light-sheet fluorescence microscopy to derive information about the liver architecture on the millimeter scale. The intermediate size range is covered using label-free structural and chemically sensitive methods, such as second harmonic generation and coherent anti-Stokes Raman scattering microscopy. Laser-scanning confocal microscopy extends the resolution to the nanoscale, allowing us to ultimately image individual liver sinusoidal endothelial cells and their fenestrations by super-resolution structured illumination microscopy. This allowed us to visualize the human hepatobiliary system in 3D down to the cellular level, which indicates that reticular biliary networks communicate with portal bile ducts via single or a few ductuli. Non-linear optical microscopy enabled us to identify fibrotic regions extending from the portal field to the parenchyma, along with microvesicular steatosis in liver biopsies from an older patient. Lastly, super-resolution microscopy allowed us to visualize and determine the size distribution of fenestrations in human liver sinusoidal endothelial cells for the first time under aqueous conditions. Thus, this proof-of-concept study allows us to demonstrate, how, in combination, these techniques open up a new chapter in liver biopsy analysis.
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Affiliation(s)
- Cihang Kong
- Department of Physics, Bielefeld University, Bielefeld, Germany
| | - Stefanie Bobe
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | | | - Mario Lachetta
- Department of Physics, Bielefeld University, Bielefeld, Germany
| | - Cristina Ionica Øie
- Vascular Biology Research Group, Department of Medical Biology, University of Tromsø - The Arctic University of Norway, Tromsø, Norway
| | - Nils Kirschnick
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | | | - Wolfgang Hübner
- Department of Physics, Bielefeld University, Bielefeld, Germany.,Forschungsverbund BioMedizin Bielefeld (FBMB), Bielefeld, Germany
| | | | - Mark Schüttpelz
- Department of Physics, Bielefeld University, Bielefeld, Germany
| | - Friedemann Kiefer
- European Institute for Molecular Imaging, University of Münster, Münster, Germany
| | - Thomas Huser
- Department of Physics, Bielefeld University, Bielefeld, Germany.,Forschungsverbund BioMedizin Bielefeld (FBMB), Bielefeld, Germany
| | - Jan Schulte Am Esch
- Forschungsverbund BioMedizin Bielefeld (FBMB), Bielefeld, Germany.,Department of General and Visceral Surgery, Evangelisches Klinikum Bethel gGmbH, University Hospital OWL of the University of Bielefeld, Bielefeld, Germany
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Sanz-García C, Fernández-Iglesias A, Gracia-Sancho J, Arráez-Aybar LA, Nevzorova YA, Cubero FJ. The Space of Disse: The Liver Hub in Health and Disease. LIVERS 2021; 1:3-26. [DOI: 10.3390/livers1010002] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Since it was first described by the German anatomist and histologist, Joseph Hugo Vincenz Disse, the structure and functions of the space of Disse, a thin perisinusoidal area between the endothelial cells and hepatocytes filled with blood plasma, have acquired great importance in liver disease. The space of Disse is home for the hepatic stellate cells (HSCs), the major fibrogenic players in the liver. Quiescent HSCs (qHSCs) store vitamin A, and upon activation they lose their retinol reservoir and become activated. Activated HSCs (aHSCs) are responsible for secretion of extracellular matrix (ECM) into the space of Disse. This early event in hepatic injury is accompanied by loss of the pores—known as fenestrations—of the endothelial cells, triggering loss of balance between the blood flow and the hepatocyte, and underlies the link between fibrosis and organ dysfunction. If the imbalance persists, the expansion of the fibrotic scar followed by the vascularized septae leads to cirrhosis and/or end-stage hepatocellular carcinoma (HCC). Thus, researchers have been focused on finding therapeutic targets that reduce fibrosis. The space of Disse provides the perfect microenvironment for the stem cells niche in the liver and the interchange of nutrients between cells. In the present review article, we focused on the space of Disse, its components and its leading role in liver disease development.
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Affiliation(s)
- Carlos Sanz-García
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Anabel Fernández-Iglesias
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Hepatology, Department of Biomedical Research, University of Bern, 3012 Bern, Switzerland
| | - Luis Alfonso Arráez-Aybar
- Department of Anatomy and Embriology, Complutense University School of Medicine, 28040 Madrid, Spain
| | - Yulia A. Nevzorova
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- Department of Internal Medicine III, University Hospital RWTH Aachen, 52074 Aachen, Germany
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain
- 12 de Octubre Health Research Institute (imas12), 28040 Madrid, Spain
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Zhong Y, Xu M, Hu J, Huang X, Lin N, Deng M. Inhibiting Th1/2 cells influences hepatic capillarization by adjusting sinusoidal endothelial fenestrae through Rho-ROCK-myosin pathway. Aging (Albany NY) 2021; 13:5069-5086. [PMID: 33535174 PMCID: PMC7950229 DOI: 10.18632/aging.202425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 11/10/2020] [Indexed: 12/24/2022]
Abstract
CD4+ T cells are considered to be vital in chronic liver diseases, but their exact roles in hepatic capillarization, the typical characteristic of liver fibrosis, are poorly understood. This study aimed to assess the roles of typical subtype of CD4+ T cells, named T helper 1 (Th1) and Th2 cells in liver fibrosis. Taking advantage of well established fibrotic rat model, we conducted in vitro and in vivo experiments to explore the interactions between liver sinusoidal endothelial cells (LSECs) and Th1/2 cells; meanwhile we evaluated the degree of hepatic capillarization when inhibiting these interactions with inhibitory antibodies. Our results showed that prohibiting interactions between Th2 cells and LSECs caused the restoration of fenestrae, increased cytokine level of Th1 cells and reduction of hepatic capillarization; inhibiting the interaction between Th1 cells and LSECs produced the opposite effects. Moreover, increased Rho and myosin light chain phosphorylation were observed when Th1 cells were inhibited with the corresponding inhibitory antibody; Th2 cell inhibition yielded the opposite results. This study indicated that Th1/2 cells steer the capillarization process in different directions and this effect is probably mediated by the Rho-Rho kinase (ROCK)-myosin signaling pathway.
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Affiliation(s)
- Yuesi Zhong
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Mingxing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Jingxiong Hu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Xi Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Meihai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
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50
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Su T, Yang Y, Lai S, Jeong J, Jung Y, McConnell M, Utsumi T, Iwakiri Y. Single-Cell Transcriptomics Reveals Zone-Specific Alterations of Liver Sinusoidal Endothelial Cells in Cirrhosis. Cell Mol Gastroenterol Hepatol 2020; 11:1139-1161. [PMID: 33340713 PMCID: PMC7903131 DOI: 10.1016/j.jcmgh.2020.12.007] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 12/01/2020] [Accepted: 12/09/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Dysfunction of liver sinusoidal endothelial cells (LSECs) is permissive for the progression of liver fibrosis and cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal vs cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using scRNA-seq technology. APPROACH & RESULTS Cirrhosis was generated in endothelial specific green fluorescent protein (GFP) reporter mice through carbon tetrachloride inhalation for 12 weeks. GFP-positive liver EC populations were isolated from control and cirrhotic mice by FACS. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. Based on previously reported LSEC-landmarks, we mapped the 3 clusters of LSECs in zones 1, 2, and 3, and determined phenotypic changes in each zone between control and cirrhotic mice. We found genes representing capillarization of LSECs (eg, CD34) as well as extracellular matrix genes were most upregulated in LSECs of zone 3 in cirrhotic mice, which may contribute to the development of basement membranes. LSECs in cirrhotic mice also demonstrated decreased expression of endocytic receptors, most remarkably in zone 3. Transcription factors (Klf2 [Kruppel-like factor-2], Klf4 [Kruppel-like factor-4], and AP-1) that induce nitric oxide production in response to shear stress were downregulated in LSECs of all zones in cirrhotic mice, implying increased intrahepatic vascular resistance. CONCLUSION This study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most dysfunctional liver ECs.
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Affiliation(s)
- Tingting Su
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut; Department of Gastroenterology, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
| | - Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Sanchuan Lai
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Yirang Jung
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Matthew McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut.
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