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Tan W, Deng J, Qi L, Tan Z. The role of hepatic sinusoidal microenvironment in NASH: pathogenesis, animal models, and therapeutic prospects. Front Pharmacol 2025; 16:1467950. [PMID: 40356963 PMCID: PMC12066276 DOI: 10.3389/fphar.2025.1467950] [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: 07/21/2024] [Accepted: 03/28/2025] [Indexed: 05/15/2025] Open
Abstract
The incidence of nonalcoholic steatohepatitis (NASH) is increasing annually, posing a significant threat to human health. NASH is typified by hepatic steatosis, inflammation, and hepatocellular injury, frequently culminating in fibrosis and cirrhosis. Yet, the precise pathogenesis of NASH remains to be fully elucidated. The hepatic sinusoid, which serves as the fundamental structural and functional unit of the liver, is intricately composed of endothelial cells, Kupffer cells, and hepatic stellate cells. Consequently, the homeostasis of the hepatic sinusoidal microenvironment may exert a pivotal influence on the progression and prognosis of NASH. However, the limitations of current NASH animal models have significantly impeded advancements in understanding the disease's pathogenesis and the development of effective therapeutic interventions. In light of these challenges, this review endeavors to delve deeper into the critical role of hepatic sinusoidal microenvironment homeostasis in the pathogenesis of NASH, critically analyze the commonly employed animal models, and comprehensively summarize the most recent and promising developments in drug research and development. It is anticipated that these efforts will collectively expedite the advancement of the field of NASH research and therapeutic innovation.
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Affiliation(s)
- Wanying Tan
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Jiangting Deng
- Sichuan Academy of Chinese Medicine Sciences, Sichuan Provincial Key Laboratory of Quality and Innovation Research of Chinese Materia Medica, Chengdu, Sichuan, China
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Lingjun Qi
- Affiliated Sichuan Gem Flower Hospital of North Sichuan Medical College, Chengdu, Sichuan, China
| | - Zhenghuai Tan
- Sichuan Academy of Chinese Medicine Sciences, Sichuan Provincial Key Laboratory of Quality and Innovation Research of Chinese Materia Medica, Chengdu, Sichuan, China
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Kisseleva T, Ganguly S, Murad R, Wang A, Brenner DA. Regulation of Hepatic Stellate Cell Phenotypes in Metabolic Dysfunction-Associated Steatohepatitis. Gastroenterology 2025:S0016-5085(25)00528-1. [PMID: 40120772 DOI: 10.1053/j.gastro.2025.03.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 02/13/2025] [Accepted: 03/05/2025] [Indexed: 03/25/2025]
Abstract
Hepatic stellate cells (HSCs) play a crucial role in the pathogenesis of liver fibrosis in metabolic dysfunction-associated steatohepatitis (MASH), a condition characterized by excessive fat accumulation in the hepatocytes, unrelated to alcohol consumption. In a healthy liver, HSCs are quiescent, store vitamin A, and function as pericytes. However, in response to liver injury and inflammation, HSCs become activated. In MASH, HSC activation is driven by metabolic stress, lipotoxicity, and chronic inflammation. Injured hepatocytes, recruited macrophage, capillarized sinusoidal endothelial cells, and permeable intestinal epithelium may each contribute to activating HSCS. This leads to a unique inflammatory environment that promotes fibrosis. MASH HSCs change their metabolism to favor glycolysis, glutaminolysis, and lactate generation. Activated HSCs transform into myofibroblast-like cells, producing excessive extracellular matrix components that result in fibrosis. In addition, HSCs in MASH have inflammatory and intermediate activated phenotypes. This fibrotic process is a key feature of MASH, which can lead to cirrhosis and liver cancer. Understanding the mechanisms of HSC activation and their role in MASH progression is essential for developing targeted therapies to treat and prevent liver fibrosis in affected individuals.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, California
| | | | - Rabi Murad
- Sanford Burnham Prebys, La Jolla, California
| | - Allen Wang
- Center for Epigenetics, University of California, San Diego, La Jolla, California
| | - David A Brenner
- Sanford Burnham Prebys, La Jolla, California; Department of Medicine, University of California, La Jolla California.
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3
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Normand A, Le Bris Y, Loussouarn D, Gournay J, Mosnier JF. Obliteration of liver sinusoids through platelet aggregates associated to extramedullary haematopoiesis in myeloid neoplasms. Virchows Arch 2025; 486:491-497. [PMID: 38877359 DOI: 10.1007/s00428-024-03844-2] [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: 01/05/2024] [Revised: 05/21/2024] [Accepted: 06/04/2024] [Indexed: 06/16/2024]
Abstract
Herein is reported a series of five patients with myeloid neoplasms presenting hepatic complications in whose liver biopsy revealed obstruction of sinusoids by platelet aggregates associated to liver extramedullary haematopoiesis. Indication of liver biopsies was jaundice, unexplained hepatomegaly or portal hypertension. Haematological disorders were classified according to the World Health Organisation. Molecular profile was established in all cases as well as grade of liver extramedullary haematopoiesis and myelofibrosis. The patients were four men and one woman aged from 50 to 82 years. Two patients had myeloproliferative neoplasm (triple negative primary myelofibrosis and JAK2-mutated essential thrombocytopenia), two patients had unclassifiable myelodysplastic/myeloproliferative neoplasm and one patient had chronic myelomonocytic leukaemia type 1. Liver biopsies revealed platelet aggregates occluding sinusoids in association with extramedullary haematopoiesis grade 1 in one patient, grade 2 in two patients and grade 3 in two patients. Two of these patients presented co-existing liver fibrosis due to chronic alcoholic consumption and ischemic heart failure. These five patients died from 2 to 23 months after liver biopsy due to acute myeloblastic leukaemia (three patients), portal hypertension (one patient) or other causes (acute heart failure). Intrahepatic sinusoidal microthromboses through platelet aggregates might cause portal hypertension or liver deficiency in patients with myeloid neoplasms, independently of JAK2 mutational status and grade of extramedullary haematopoiesis.
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Affiliation(s)
- Adeline Normand
- Department of Pathology, Hotel Dieu, 1 Place Ricordeau, CHU de Nantes, 44093, Nantes Cedex, France
| | - Yannick Le Bris
- Department of Haematology Biology, Hotel Dieu, CHU de Nantes, Nantes, France
| | - Delphine Loussouarn
- Department of Pathology, Hotel Dieu, 1 Place Ricordeau, CHU de Nantes, 44093, Nantes Cedex, France
| | - Jérôme Gournay
- Department of Gastro-Enterology and Hepatology, IMAD, CHU de Nantes, Nantes, France
| | - Jean-François Mosnier
- Department of Pathology, Hotel Dieu, 1 Place Ricordeau, CHU de Nantes, 44093, Nantes Cedex, France.
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Yang X, Xia L, Shen C, Li J, Dong X, Liu J. Curcumin alleviates heatstroke-induced liver injury in dry-heat environments by inhibiting the expression of NF-κB, iNOS, and ICAM-1 in rats. PLoS One 2024; 19:e0309598. [PMID: 39240880 PMCID: PMC11379272 DOI: 10.1371/journal.pone.0309598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 08/14/2024] [Indexed: 09/08/2024] Open
Abstract
we aimed to monitor liver injury in rat model during heat stress and heatstroke in dry-heat environment and investigate the effects of curcumin on heatstroke-induced liver injury and the underlying mechanisms. Sprague-Dawley (SD) rats were randomly divided into four groups: normal saline (NS), and 50 (50-cur), 100 (100-cur), and 200 mg/kg curcumin (200-cur) groups. They were administered the indicated doses of curcumin by gavage once daily for 7 days. On day 8, the rats were transferred to a simulated climate cabin, At 0, 50, 100, and 150 min, the core temperature (Tc) was measured respectively. After sacrificing the rats, tissue samples were collected, measure histology indices, serum enzymes, lipopolysaccharides (LPSs), cytokines, nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). The Tc increased with time in all groups. Curcumin alleviation of symptoms and improvement in pathological scores. The level of enzymes, LPS, and cytokines increased during heatstroke in the NS group, but curcumin decreased the levels of these indicators. The differences of the indicators between NS and 200-cur groups at 150 min were significant (P < 0.05). The expression of NF-κB p65, iNOS, and ICAM-1 was upregulated in the NS group at 150 min, but their expression was relatively lower in the curcumin groups (P < 0.05). Thus, our findings indicate acute liver injury during heat stress and heatstroke. The mechanism involves cascade-amplification inflammatory response induced by the gut endotoxin. Furthermore, curcumin alleviated heatstroke-induced liver injury in a dose-dependent manner by downregulating NF-κB, iNOS, and ICAM-1.
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Affiliation(s)
- Xinyue Yang
- Key Laboratory of Special Environmental Medicine of Xinjiang, Urumqi, China
- Graduate School of Xinjiang Medical University, Urumqi, China
| | - Liang Xia
- Beijing Luhe Hospital Affiliated to Capital Medical University, Beijing, China
| | - Caifu Shen
- Key Laboratory of Special Environmental Medicine of Xinjiang, Urumqi, China
| | - Jiajia Li
- Key Laboratory of Special Environmental Medicine of Xinjiang, Urumqi, China
| | - Xiang Dong
- Key Laboratory of Special Environmental Medicine of Xinjiang, Urumqi, China
| | - Jiangwei Liu
- Key Laboratory of Special Environmental Medicine of Xinjiang, Urumqi, China
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Venkatesh SK, Harper KC, Borhani AA, Furlan A, Thompson SM, Chen EZM, Idilman IS, Miller FH, Hoodeshenas S, Navin PJ, Gu CN, Welle CL, Torbenson MS. Hepatic Sinusoidal Disorders. Radiographics 2024; 44:e240006. [PMID: 39146204 DOI: 10.1148/rg.240006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/17/2024]
Abstract
Hepatic sinusoids are highly specialized microcirculatory conduits within the hepatic lobules that facilitate liver functions. The sinusoids can be affected by various disorders, including sinusoidal dilatation, sinusoidal obstruction syndrome (SOS), sinusoidal cellular infiltration, perisinusoidal infiltration, and endothelial neoplasms, such as hemangioendothelioma and angiosarcoma. While these disorders, particularly SOS and neoplasms, can be life threatening, their clinical manifestation is often nonspecific. Patients may present with right upper quadrant pain, jaundice, hepatomegaly, ascites, splenomegaly, and unexplained weight gain, although the exact manifestation depends on the cause, severity, and duration of the disease. Ultimately, invasive tests may be necessary to establish the diagnosis. A comprehensive understanding of imaging manifestations of various sinusoidal disorders contributes to early diagnosis and can help radiologists detect subclinical disease. Additionally, specific imaging features may assist in identifying the cause of the disorder, leading to a more focused and quicker workup. For example, a mosaic pattern of enhancement of the liver parenchyma is suggestive of sinusoidal dilatation; peripheral and patchy reticular hypointensity of the liver parenchyma on hepatobiliary MR images is characteristic of SOS; and associated diffuse multiple hyperintensities on diffusion-weighted images may be specific for malignant sinusoidal cellular infiltration. The authors provide an overview of the pathogenesis, clinical features, and imaging appearances of various hepatic sinusoidal disorders, with a special emphasis on SOS. ©RSNA, 2024 Supplemental material is available for this article.
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Affiliation(s)
- Sudhakar K Venkatesh
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Kelly C Harper
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Amir A Borhani
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Alessandro Furlan
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Scott M Thompson
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Eric Z M Chen
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Ilkay S Idilman
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Frank H Miller
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Safa Hoodeshenas
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Patrick J Navin
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Chris N Gu
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Christopher L Welle
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
| | - Michael S Torbenson
- From the Department of Radiology, Abdominal Imaging Division, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (S.K.V., K.C.H., S.M.T., S.H., P.J.N., C.N.G., C.L.W.); Department of Medical Imaging, University of Ottawa, Ottawa, Ontario, Canada (K.C.H.); Department of Abdominal Imaging, Northwestern Memorial Hospital, Chicago, Ill (A.A.B.); Department of Abdominal Imaging, University of Pittsburgh, Pittsburgh, Pa (A.F., F.H.M.); Department of Anatomic Pathology, Mayo Clinic, Rochester, Minn (E.Z.M.C., M.S.T.); and Department of Radiology, Hacettepe University, Ankara, Turkey (I.S.I.)
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Tang M, Zhang S, Yang M, Feng R, Lin J, Chen X, Xu Y, Yu R, Liao X, Li Z, Li X, Li M, Zhang Q, Chen S, Qian W, Liu Y, Song L, Li J. Infiltrative Vessel Co-optive Growth Pattern Induced by IQGAP3 Overexpression Promotes Microvascular Invasion in Hepatocellular Carcinoma. Clin Cancer Res 2024; 30:2206-2224. [PMID: 38470497 DOI: 10.1158/1078-0432.ccr-23-2933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/26/2023] [Accepted: 03/08/2024] [Indexed: 03/14/2024]
Abstract
PURPOSE Microvascular invasion (MVI) is a major unfavorable prognostic factor for intrahepatic metastasis and postoperative recurrence of hepatocellular carcinoma (HCC). However, the intervention and preoperative prediction for MVI remain clinical challenges due to the absent precise mechanism and molecular marker(s). Herein, we aimed to investigate the mechanisms underlying vascular invasion that can be applied to clinical intervention for MVI in HCC. EXPERIMENTAL DESIGN The histopathologic characteristics of clinical MVI+/HCC specimens were analyzed using multiplex immunofluorescence staining. The liver orthotopic xenograft mouse model and mechanistic experiments on human patient-derived HCC cell lines, including coculture modeling, RNA-sequencing, and proteomic analysis, were used to investigate MVI-related genes and mechanisms. RESULTS IQGAP3 overexpression was correlated significantly with MVI status and reduced survival in HCC. Upregulation of IQGAP3 promoted MVI+-HCC cells to adopt an infiltrative vessel co-optive growth pattern and accessed blood capillaries by inducing detachment of activated hepatic stellate cells (HSC) from the endothelium. Mechanically, IQGAP3 overexpression contributed to HCC vascular invasion via a dual mechanism, in which IQGAP3 induced HSC activation and disruption of the HSC-endothelial interaction via upregulation of multiple cytokines and enhanced the trans-endothelial migration of MVI+-HCC cells by remodeling the cytoskeleton by sustaining GTPase Rac1 activity. Importantly, systemic delivery of IQGAP3-targeting small-interfering RNA nanoparticles disrupted the infiltrative vessel co-optive growth pattern and reduced the MVI of HCC. CONCLUSIONS Our results revealed a plausible mechanism underlying IQGAP3-mediated microvascular invasion in HCC, and provided a potential target to develop therapeutic strategies to treat HCC with MVI.
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Affiliation(s)
- Miaoling Tang
- Department of Oncology, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shuxia Zhang
- Department of Oncology, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Meisongzhu Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Rongni Feng
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jinbin Lin
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xiaohong Chen
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yingru Xu
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ruyuan Yu
- Molecular Diagnosis and Gene Testing Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xinyi Liao
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ziwen Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xincheng Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Man Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Qiliang Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Suwen Chen
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Wanying Qian
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yuanji Liu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Libing Song
- State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jun Li
- Department of Oncology, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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7
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8
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Zhao J, Zhang X, Li Y, Yu J, Chen Z, Niu Y, Ran S, Wang S, Ye W, Luo Z, Li X, Hao Y, Zong J, Xia C, Xia J, Wu J. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front Immunol 2023; 14:1314123. [PMID: 38155961 PMCID: PMC10754533 DOI: 10.3389/fimmu.2023.1314123] [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: 10/11/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023] Open
Abstract
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
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Affiliation(s)
- Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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9
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Le TV, Truong NH, Holterman AXL. Autophagy modulates physiologic and adaptive response in the liver. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:304-320. [PMID: 39958781 PMCID: PMC11792069 DOI: 10.1016/j.livres.2023.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/20/2023] [Accepted: 11/14/2023] [Indexed: 01/03/2025]
Abstract
Autophagy is a physiological process that is ubiquitous and essential to the disposal or recycling of damaged cellular organelles and misfolded proteins to maintain organ homeostasis and survival. Its importance in the regulation of liver function in normal and pathological conditions is increasingly recognized. This review summarizes how autophagy regulates epithelial cell- and non-epithelial cell-specific function in the liver and how it differentially participates in hepatic homeostasis, hepatic injury response to stress-induced liver damage such as cholestasis, sepsis, non-alcoholic and alcohol-associated liver disease, viral hepatitis, hepatic fibrosis, hepatocellular and cholangiocellular carcinoma, and aging. Autophagy-based interventional studies for liver diseases that are currently registered in clinicatrials.gov are summarized. Given the broad and multidirectional autophagy response in the liver, a more refined understanding of the liver cell-specific autophagy activities in a context-dependent manner is necessary.
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Affiliation(s)
- Trinh Van Le
- Laboratory of Stem Cell Research and Application, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
- Vietnam National University, Ho Chi Minh City, Vietnam
| | - Nhung Hai Truong
- Faculty of Biology and Biotechnology, University of Science-VNUHCM, Ho Chi Minh City, Vietnam
| | - Ai Xuan L. Holterman
- Department of Pediatrics and Surgery, University of Illinois College of Medicine, Chicago and Peoria, IL, USA
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10
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Morales-Carrizales DA, Gopar-Cuevas Y, Loera-Arias MDJ, Saucedo-Cardenas O, Montes de Oca-Luna R, Garcia-Garcia A, Rodriguez-Rocha H. A neuroprotective dose of trehalose is harmless to metabolic organs: comprehensive histopathological analysis of liver, pancreas, and kidney. Daru 2023; 31:135-144. [PMID: 37393413 PMCID: PMC10624785 DOI: 10.1007/s40199-023-00468-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 06/18/2023] [Indexed: 07/03/2023] Open
Abstract
BACKGROUND Trehalose is a non-reducing disaccharide synthesized by lower organisms. It has recently received special attention because of its neuroprotective properties by stimulating autophagy in Parkinson's disease (PD) models. Therefore, evaluating whether trehalose affects metabolic organs is vital to determine its neurotherapeutic safety. METHODS We validated the trehalose neuroprotective dosage in a PD model induced with intraperitoneal paraquat administration twice weekly for 7 weeks. One week before paraquat administration, mice were treated with trehalose in the drinking water and continued along with paraquat treatment. Histological and morphometrical analyses were conducted on the organs involved in trehalose metabolism, including the liver, pancreas, and kidney. RESULTS Paraquat-induced dopaminergic neuronal loss was significantly decreased by trehalose. After trehalose treatment, the liver morphology, the mononucleated/binucleated hepatocytes percentage, and sinusoidal diameter remained unchanged in each liver lobes. Endocrine and exocrine pancreas's histology was not affected, nor was any fibrotic process observed. The islet of Langerhans's structure was preserved when analyzing the area, the largest and smallest diameter, and circularity. Renal morphology remained undamaged, and no changes were identified within the glomerular basement membrane. The renal corpuscle structure did not suffer alterations in the Bowman's space, area, diameter, circularity, perimeter, and cellularity. Besides, the renal tubular structures's luminal area and internal and external diameter were preserved. CONCLUSION Our study demonstrates that systemic trehalose administration preserved the typical histological architecture of the organs involved in its metabolism, supporting its safety as a potential neuroprotective agent.
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Affiliation(s)
- Diego Armando Morales-Carrizales
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico
| | - Yareth Gopar-Cuevas
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico
| | - Maria de Jesus Loera-Arias
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico
| | - Odila Saucedo-Cardenas
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico
| | - Roberto Montes de Oca-Luna
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico
| | - Aracely Garcia-Garcia
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico.
| | - Humberto Rodriguez-Rocha
- Departamento de Histologia, Universidad Autónoma de Nuevo Leon, Francisco I. Madero S/N, Mitras Centro, 64460, Monterrey, Nuevo Leon, Mexico.
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11
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Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [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] [Received: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
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Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
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12
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Găman MA, Cozma MA, Manan MR, Srichawla BS, Dhali A, Ali S, Nahian A, Elton AC, Simhachalam Kutikuppala LV, Suteja RC, Diebel S, Găman AM, Diaconu CC. Budd-Chiari syndrome in myeloproliferative neoplasms: A review of literature. World J Clin Oncol 2023; 14:99-116. [PMID: 37009527 PMCID: PMC10052333 DOI: 10.5306/wjco.v14.i3.99] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 02/10/2023] [Accepted: 03/01/2023] [Indexed: 03/19/2023] Open
Abstract
Myeloproliferative neoplasms (MPNs) are defined as clonal disorders of the hematopoietic stem cell in which an exaggerated production of terminally differentiated myeloid cells occurs. Classical, Philadelphia-negative MPNs, i.e., polycythemia vera, essential thrombocythemia and primary myelofibrosis, exhibit a propensity towards the development of thrombotic complications that can occur in unusual sites, e.g., portal, splanchnic or hepatic veins, the placenta or cerebral sinuses. The pathogenesis of thrombotic events in MPNs is complex and requires an intricate mechanism involving endothelial injury, stasis, elevated leukocyte adhesion, integrins, neutrophil extracellular traps, somatic mutations (e.g., the V617F point mutation in the JAK2 gene), microparticles, circulating endothelial cells, and other factors, to name a few. Herein, we review the available data on Budd-Chiari syndrome in Philadelphia-negative MPNs, with a particular focus on its epidemiology, pathogenesis, histopathology, risk factors, classification, clinical presentation, diagnosis, and management.
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Affiliation(s)
- Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
- Department of Hematology, Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest 022328, Romania
| | - Matei-Alexandru Cozma
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
| | | | - Bahadar S Srichawla
- Department of Neurology, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01655, United States
| | - Arkadeep Dhali
- Department of Internal Medicine, Nottingham University Hospitals NHS Trust, Nottingham NG7 2UH, United Kingdom
| | - Sajjad Ali
- Department of Medicine, Ziauddin University, Karachi 75600, Pakistan
| | - Ahmed Nahian
- California Baptist University-Lake Erie College of Osteopathic Medicine, Riverside, CA 92504, United States
| | - Andrew C Elton
- University of Minnesota Medical School, Minneapolis, MN 55455, United States
| | - L V Simhachalam Kutikuppala
- Department of General Surgery, Dr NTR University of Health Sciences, Andhra Pradesh, Vijayawada 520008, India
| | - Richard Christian Suteja
- Department of Undergraduate Medicine, Faculty of Medicine, Udayana University Denpasar, Bali 80232, Indonesia
| | - Sebastian Diebel
- Department of Family Medicine, Northern Ontario School of Medicine Timmins, Ontario 91762, Canada
| | - Amelia Maria Găman
- Department of Pathophysiology, University of Medicine and Pharmacy of Craiova, Romania & Clinic of Hematology, Filantropia City Hospital, Craiova 200143, Romania
| | - Camelia Cristina Diaconu
- Department of Internal Medicine, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Romania & Internal Medicine Clinic, Clinical Emergency Hospital of Bucharest, Bucharest 105402, Romania
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13
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Wang Y, Wang Q, Yang TW, Yin JM, Wei F, Liu H, Yang PX, Li J, Liu N, Zhu Y, Chen D. Analysis of Immune and Inflammatory Microenvironment Characteristics of Noncancer End-Stage Liver Disease. J Interferon Cytokine Res 2023; 43:86-97. [PMID: 36749162 DOI: 10.1089/jir.2022.0172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Chronic liver injury eventually progresses to cirrhosis and end-stage liver disease (ESLD), which are the leading causes of death in patients with liver disease worldwide. ESLD has a variety of etiologies and a complex pathogenesis. This study analyzed the characteristics of ESLD by studying the immune microenvironment and inflammatory microenvironment of ESLD caused by 4 noncancer diseases, including HBV-ALF, ALF, AILD, and AH. We collected transcriptome data from noncancer ESLD patients, collected liver tissue samples and blood samples from ESLD liver transplant patients, and analyzed the immune and inflammatory microenvironments in the liver and blood. The results showed that with the exception of HBV-induced ESLD, there were no significant differences in immune microenvironment scores among patients with ESLD caused by other noncancer diseases. Moreover, there were no significant differences in the inflammatory microenvironment in the liver and blood of patients with ESLD caused by the 4 noncancer diseases. Furthermore, we found that the cytokine, IL-15, could predict the prognosis of ESLD patients.
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Affiliation(s)
- Yang Wang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Qi Wang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China.,Beijing DiTan Hospital, Capital Medical University, Beijing, China.,Organ Transplant Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Tong Wang Yang
- Hunan Key Laboratory of Research and Development of Novel Pharmaceutical Preparations, Academician Workstation, Changsha Medical University, Changsha, China.,Organ Transplant Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ji Ming Yin
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Feili Wei
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Huan Liu
- Organ Transplant Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Peng Xiang Yang
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Jiaxi Li
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Ning Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yunxia Zhu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Dexi Chen
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
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14
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Nambiar K, Wang Q, Yan H, Wilson JM. Characterizing Complex Populations of Endogenous Adeno-Associated Viruses by Single-Genome Amplification. Hum Gene Ther 2022; 33:1164-1173. [PMID: 35906801 DOI: 10.1089/hum.2022.099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The isolation of adeno-associated virus (AAV) genomes from biomaterials at the molecular level has traditionally relied on polymerase chain reaction-based and cloning-based techniques. However, when applied to samples containing multiple species, traditional techniques for isolating viral genomes can amplify artificial recombinants and introduce polymerase misincorporation errors. In this study, we describe AAV single-genome amplification (AAV-SGA): a powerful technique to isolate, amplify, and sequence single AAV genomes from mammalian genomic DNA, which can then be used to construct vectors for gene therapy. We used AAV-SGA to precisely isolate 15 novel AAV genomes belonging to AAV clades A, D, and E and the Fringe outgroup. This technique also enables investigations of AAV population dynamics and recombination events to provide insights into virus-host interactions and virus biology. Using AAV-SGA, we identified regional heterogeneity within AAV populations from different lobes of the liver of a rhesus macaque and found evidence of frequent genomic recombination between AAV populations. This study highlights the strengths of AAV-SGA and demonstrates its capability to provide valuable insights into the biology and diversity of AAVs.
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Affiliation(s)
- Kalyani Nambiar
- Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Qiang Wang
- Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hanying Yan
- Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - James M Wilson
- Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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15
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Lv W, Zhou H, Aazmi A, Yu M, Xu X, Yang H, Huang YYS, Ma L. Constructing biomimetic liver models through biomaterials and vasculature engineering. Regen Biomater 2022; 9:rbac079. [PMID: 36338176 PMCID: PMC9629974 DOI: 10.1093/rb/rbac079] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/19/2022] [Accepted: 10/08/2022] [Indexed: 04/04/2024] Open
Abstract
The occurrence of various liver diseases can lead to organ failure of the liver, which is one of the leading causes of mortality worldwide. Liver tissue engineering see the potential for replacing liver transplantation and drug toxicity studies facing donor shortages. The basic elements in liver tissue engineering are cells and biomaterials. Both mature hepatocytes and differentiated stem cells can be used as the main source of cells to construct spheroids and organoids, achieving improved cell function. To mimic the extracellular matrix (ECM) environment, biomaterials need to be biocompatible and bioactive, which also help support cell proliferation and differentiation and allow ECM deposition and vascularized structures formation. In addition, advanced manufacturing approaches are required to construct the extracellular microenvironment, and it has been proved that the structured three-dimensional culture system can help to improve the activity of hepatocytes and the characterization of specific proteins. In summary, we review biomaterials for liver tissue engineering, including natural hydrogels and synthetic polymers, and advanced processing techniques for building vascularized microenvironments, including bioassembly, bioprinting and microfluidic methods. We then summarize the application fields including transplant and regeneration, disease models and drug cytotoxicity analysis. In the end, we put the challenges and prospects of vascularized liver tissue engineering.
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Affiliation(s)
- Weikang Lv
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | | | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
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16
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She S, Ren L, Chen P, Wang M, Chen D, Wang Y, Chen H. Functional Roles of Chemokine Receptor CCR2 and Its Ligands in Liver Disease. Front Immunol 2022; 13:812431. [PMID: 35281057 PMCID: PMC8913720 DOI: 10.3389/fimmu.2022.812431] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.
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Affiliation(s)
- Shaoping She
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Liying Ren
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Pu Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Mingyang Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Dongbo Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
| | - Ying Wang
- Department of Immunology, School of Basic Medical Sciences, and NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China
| | - Hongsong Chen
- Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University People’s Hospital, Beijing, China
- *Correspondence: Hongsong Chen,
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17
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Msomi NZ, Erukainure OL, Salau VF, Olofinsan KA, Islam MS. Xylitol improves antioxidant, purinergic and cholinergic dysfunction, and lipid metabolic homeostasis in hepatic injury in type 2 diabetic rats. J Food Biochem 2022; 46:e14040. [DOI: 10.1111/jfbc.14040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 11/17/2021] [Accepted: 11/19/2021] [Indexed: 11/28/2022]
Affiliation(s)
| | | | | | | | - Md. Shahidul Islam
- Department of Biochemistry University of KwaZulu‐Natal Durban South Africa
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18
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Deng X, Wu Y, Xu H, Yan J, Liu H, Zhang B. Recent research progress in galactose-based fluorescent probes for detection of biomarkers of liver diseases. Chem Commun (Camb) 2022; 58:12518-12527. [DOI: 10.1039/d2cc04180d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
This highlight illustrates the challenges and latest progress in galactose-based fluorescent probes for early diagnosis of liver diseases.
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Affiliation(s)
- Xiaojing Deng
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Yingxu Wu
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Hu Xu
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 16044, China
| | - Jiawei Yan
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
| | - Huanying Liu
- School of Mechanical and Power Engineering, Dalian Ocean University, Dalian 116023, China
| | - Boyu Zhang
- College of Medical Laboratory, Dalian Medical University, Dalian 116044, China
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19
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Navale P, Gonzalez RS. Mild changes of hepatic nodular regenerative hyperplasia may cause portal hypertension and be visible on reticulin but not hematoxylin and eosin staining. Virchows Arch 2021; 479:1145-1152. [PMID: 34435237 DOI: 10.1007/s00428-021-03195-2] [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: 05/19/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 01/05/2023]
Abstract
Nodular regenerative hyperplasia (NRH) can manifest as alternating parenchymal compression/expansion on hematoxylin and eosin (H&E) staining and as reticulin collapse/nodularity on reticulin staining. Histologic diagnosis can be challenging, especially when there is mild disease and on limited biopsy samples. We reviewed clinical and histologic parameters in a large series of NRH. We identified 60 liver specimens convincingly showing changes of NRH and reviewed them for clinical (age, sex, symptoms, lab values, portal hypertension [PHTN], NRH etiology) and histologic (inflammation, sinusoidal dilation, cholestasis, architectural change, portal vascular abnormalities, degree of changes on reticulin) parameters. The cases came from 28 women and 32 men (median age: 54 years). Most (55, 92%) were biopsies. Thirty patients were symptomatic. Forty-five cases showed mild NRH changes on reticulin; 24 of these (53%) showed them on H&E as well. Fifteen demonstrated well-developed changes on reticulin, which were always seen on H&E as well. Sinusoidal dilation was commonly observed in both of these subgroups (88% overall). Portal vascular abnormalities were seen in 33%. Well-developed NRH was diffuse more often than mild NRH (53% vs. 4%, P < 0.0001). Twenty-nine patients had clinically confirmed or likely PHTN. Of these, 21 showed mild and 8 showed well-developed NRH changes; only 3 had concomitant advanced fibrosis. Chemotherapy was the most frequent known cause of NRH; 30 patients lacked any definite etiology. NRH can be difficult to diagnose on biopsy, particularly since mild changes may be visible on reticulin but not H&E; even these patients can have PHTN. Additionally, NRH is often idiopathic, potentially lowering clinical and pathologic suspicion. Pathologists should have a low threshold for ordering reticulin stains, especially when a patient is known to have PHTN. Sinusoidal dilation, while nonspecific, commonly accompanies NRH.
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Affiliation(s)
- Pooja Navale
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA.
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20
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Shi L, Lu BL, Qiu Y, Huang L, Huang SY, Mao R, Lin JJ, Du JF, Feng ST, Li ZP, Sun CH, Li XH. Hepatic mosaic enhancement pattern correlates with increased inflammatory activity and adverse therapeutic outcomes in patients with Crohn's disease. Abdom Radiol (NY) 2021; 46:3149-3158. [PMID: 33646351 DOI: 10.1007/s00261-021-02979-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/25/2021] [Accepted: 02/09/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE This study aimed to evaluate the role of hepatic mosaic enhancement pattern (HMEP) on computed tomography images in the disease activity and therapeutic outcome of Crohn's Disease (CD). METHODS Twenty-five CD patients with HMEP comprised the HMEP group, and 25 CD patients without HMEP, who had a similar onset age, sex, and disease course with those in the HMEP group, comprised the non-HMEP group. No underlying liver/biliary disease was observed in any of the patients. Clinical characteristics, laboratory test results, Lémann index, and CD endoscopic index of severity (CDEIS) were compared between the groups using the Student t-, Mann-Whitney U, Chi square, or Fisher's exact tests. Patients received top-down, step-up, or traditional treatment during the follow-up period. After the 1-year follow-up, therapeutic outcomes (active inflammation [CDEIS > 3.5 if the endoscopic data were available, or C-reactive protein level > 5 mg/L if the endoscopic data were unavailable] or remission) were evaluated. RESULTS The occurrence rate of fistulas/abscesses was higher in the HMEP group (84%, 21/25) than in the non-HMEP group (48%, 12/25) with no statistical significance (P = 0.056). The HMEP group showed a higher C-reactive protein level (P = 0.001), erythrocyte sedimentation rate (P = 0.013), and blood platelet count (P = 0.005). There was no significant difference in therapeutic strategies between the groups (P = 0.509). The HMEP group showed a significantly lower remission ratio after anti-inflammatory treatment than the non-HMEP group (P = 0.045). CONCLUSIONS HMEP was correlated with increased inflammatory activity and adverse therapeutic outcomes in CD. This finding provided insights regarding novel markers of CD diagnosis and treatment.
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Affiliation(s)
- Li Shi
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
- Department of Radiology, The Third Affiliated Hospital of Guangzhou Medical University, 63 Duobao Road, Guangzhou, 510150, People's Republic of China
| | - Bao-Lan Lu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Li Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Si-Yun Huang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Jin-Jiang Lin
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Jin-Fang Du
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Shi-Ting Feng
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Zi-Ping Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China
| | - Can-Hui Sun
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
| | - Xue-Hua Li
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, 58 Zhongshan II Road, Guangzhou, 510080, People's Republic of China.
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21
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Wang XK, Peng ZG. Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:655557. [PMID: 33935770 PMCID: PMC8082362 DOI: 10.3389/fphar.2021.655557] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.
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Affiliation(s)
- Xue-Kai Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Biotechnology of Antibiotics, National Health and Family Planning Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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22
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Liu JY, Lv WJ, Jian JB, Xin XH, Zhao XY, Hu CH. High-resolution three-dimensional visualization of hepatic sinusoids in cirrhotic rats via serial histological sections. Histol Histopathol 2021; 36:577-586. [PMID: 33851410 DOI: 10.14670/hh-18-339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM As a specialized intraparenchymal vascular conduit, hepatic sinusoids play a key role in liver microcirculation. This study aimed to explore the three-dimensional (3D) morphological changes of cirrhotic sinusoids by serial histological sections. METHODS Cirrhosis was induced by tail vein injection of albumin in Wistar rats with a positive antibody. A total of 356 serial histological sections were prepared from liver tissue blocks of normal and cirrhotic rats. The optical microscope images were registered and reconstructed, and 3D reconstructions of the fine structures of fibrous tissues and sinusoids were subsequently visualized. RESULTS The fibrosis area of the cirrhotic sample was 6-16 times that of the normal sample (P<0.001). Cirrhosis led to obvious changes in the distribution and morphology of sinusoids, which were mainly manifested as dilation, increased quantity and disordered distribution. Compared with normal liver, cirrhotic liver has a significantly increased volume ratio, number and volume of sinusoids (1.63-, 0.53-, and 1.75-fold, respectively, P<0.001). Furthermore, the samples were further divided into three zones according to the oxygen supply, and there were significant differences in the morphology of the sinusoids in the normal and cirrhotic samples (P<0.05). In particular, morphological parameters of the cirrhotic sinusoids near the portal area were obviously greater than those in the normal liver (P<0.05). CONCLUSION 3D morphological structures of hepatic sinusoids were reconstructed, and the adaptive microstructure changes of cirrhotic sinusoids were accurately measured, which has an important implications for the study of hepatic microcirculation and pathological changes of cirrhosis.
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Affiliation(s)
- Jing-Yi Liu
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Wen-Juan Lv
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Jian-Bo Jian
- Department of Radiation Oncology, Tianjin Medical University General Hospital, Tianjin, China, China
| | - Xiao-Hong Xin
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China
| | - Xin-Yan Zhao
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. .,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis and National Clinical Research Center of Digestive Disease, Beijing, China
| | - Chun-Hong Hu
- School of Biomedical Engineering and Technology, Tianjin Medical University, Tianjin, China.
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23
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Comparison of Thiel preserved, fresh human, and animal liver tissue in terms of mechanical properties. Ann Anat 2021; 236:151717. [PMID: 33689839 DOI: 10.1016/j.aanat.2021.151717] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/26/2021] [Accepted: 02/09/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND In medical training and research fresh human tissue is often replaced by preserved human or fresh animal tissue, due to availability and ethical reasons. Newer preservation approaches, such as the Thiel method, promise more realistic mechanical properties than conventional formaldehyde fixation. Concerning animal substitute material, porcine and bovine tissue is often chosen, as it is easily obtainable and certain similarity to human tissue is assumed. However, it has not been thoroughly investigated how Thiel preservation changes non-linear and viscoelastic behaviour of soft organ tissues. Furthermore, differences in these properties between animal tissue and human tissue have not been previously corroborated. METHODS We conducted ramp and relaxation tensile tests on fresh human and Thiel preserved hepatic tissue, extracting strain-specific elastic moduli, and viscoelastic properties. The results for fresh human liver were then compared to corresponding results for Thiel preserved liver, as well as previously published results for porcine and bovine liver. RESULTS Our results showed that Thiel preservation seems to be associated with increased stiffness as well as decreased viscoelastic damping behaviour. Porcine liver was stiffer than human liver with similar viscoelastic properties. Bovine liver exhibited similar stiffness as human liver, however lower viscoelastic damping. CONCLUSIONS The differences between human and animal liver tissue, concerning their mechanical properties, can be explained by their characteristic histology. Changes in mechanical properties due to Thiel preservation might stem from altered protein cross-linking and dehydration. The results illustrate that appropriate materials for medical training systems must be selected based on which mechanical properties are relevant for the respective application.
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Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies. Int J Mol Sci 2021; 22:ijms22041864. [PMID: 33668478 PMCID: PMC7918617 DOI: 10.3390/ijms22041864] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular–pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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25
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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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26
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Fan J, He M, Wang CJ, Zhang M. Gadolinium Chloride Inhibits the Production of Liver Interleukin-27 and Mitigates Liver Injury in the CLP Mouse Model. Mediators Inflamm 2021; 2021:2605973. [PMID: 33564275 PMCID: PMC7867451 DOI: 10.1155/2021/2605973] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 11/28/2020] [Accepted: 12/17/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Liver macrophages play an important regulatory role in the inflammatory response of liver injury after severe infection. Interleukin- (IL-) 27 is an inflammatory cytokine that plays an important role in diseases caused by bacterial infection. However, the relationship between IL-27 and liver macrophages in liver injury after severe infection is not yet clear. METHODS A cecal ligation puncture (CLP) model was established in wild-type (WT) and IL-27 receptor- (WSX-1-) deficient (IL-27r-/-) mice, and recombinant IL-27 and gadolinium chloride (GdCl3) were injected into WT mice in the designated groups. The serum and liver IL-27, IL-6, tumor necrosis factor alpha (TNF-α), and IL-1β expression levels were evaluated by ELISA, quantitative PCR, or Western blotting; serum ALT and AST were detected by detection kits; and the severity of liver damage was evaluated by hematoxylin and eosin staining and the TUNEL assay of the liver tissue from the different groups. Liver macrophage polarization was evaluated by immunofluorescence. In addition, the polarization of peritoneal macrophage was evaluated by flow cytometry. RESULTS The serum and liver IL-27 expression levels were elevated in WT mice after CLP-induced severe infection, which were consistent with the changes in HE scores in the liver tissue. The levels of serum ALT, AST, liver IL-6, TNF-α, and IL-1β mRNA and liver pathological injury scores were further increased when pretreated with recombinant IL-27 in WT mice, but these levels were decreased in IL-27r-/- mice after CLP-induced severe infection compared to WT mice. In WT mice pretreated with GdCl3, liver pathological scores, serum ALT and AST, TUNEL-positive cell proportion from liver tissues, liver IL-27 expression, and the liver macrophages M1 polarization proportion decreased after CLP; however, the serum IL-27, IL-6, TNF-α, and IL-1β levels and the pathological lung and kidney scores were not significantly changed. When supplemented with exogenous IL-27, the liver pathological scores, serum ALT, AST, TUNEL-positive cell proportion of liver tissues, liver IL-27 expression, and the liver macrophage M1 polarization proportion increased. The in vitro, IL-27 expression increased in peritoneal macrophages when stimulated with LPS. Recombinant IL-27 together with LPS promoted the elevations in IL-6, TNF-α, and IL-1β levels in supernatant and the M1 polarization of peritoneal macrophages. CONCLUSION IL-27 is an important cytokine in the inflammatory response to liver injury after severe infection. The reduction of liver injury by gadolinium chloride in severe infection mice models may relate to the inhibition of liver IL-27 production. These changes may be mainly related to the decrease of liver macrophages M1 polarization. IL-27 may have a positive feedback on these macrophages.
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Affiliation(s)
- Jing Fan
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China
| | - Miao He
- Chongqing University Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing 400030, China
| | - Chuan-Jiang Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China
| | - Mu Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Yuzhong District, Chongqing 400016, China
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Wang Y, Brodin E, Nishii K, Frieboes HB, Mumenthaler SM, Sparks JL, Macklin P. Impact of tumor-parenchyma biomechanics on liver metastatic progression: a multi-model approach. Sci Rep 2021; 11:1710. [PMID: 33462259 PMCID: PMC7813881 DOI: 10.1038/s41598-020-78780-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 11/24/2020] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer and other cancers often metastasize to the liver in later stages of the disease, contributing significantly to patient death. While the biomechanical properties of the liver parenchyma (normal liver tissue) are known to affect tumor cell behavior in primary and metastatic tumors, the role of these properties in driving or inhibiting metastatic inception remains poorly understood, as are the longer-term multicellular dynamics. This study adopts a multi-model approach to study the dynamics of tumor-parenchyma biomechanical interactions during metastatic seeding and growth. We employ a detailed poroviscoelastic model of a liver lobule to study how micrometastases disrupt flow and pressure on short time scales. Results from short-time simulations in detailed single hepatic lobules motivate constitutive relations and biological hypotheses for a minimal agent-based model of metastatic growth in centimeter-scale tissue over months-long time scales. After a parameter space investigation, we find that the balance of basic tumor-parenchyma biomechanical interactions on shorter time scales (adhesion, repulsion, and elastic tissue deformation over minutes) and longer time scales (plastic tissue relaxation over hours) can explain a broad range of behaviors of micrometastases, without the need for complex molecular-scale signaling. These interactions may arrest the growth of micrometastases in a dormant state and prevent newly arriving cancer cells from establishing successful metastatic foci. Moreover, the simulations indicate ways in which dormant tumors could "reawaken" after changes in parenchymal tissue mechanical properties, as may arise during aging or following acute liver illness or injury. We conclude that the proposed modeling approach yields insight into the role of tumor-parenchyma biomechanics in promoting liver metastatic growth, and advances the longer term goal of identifying conditions to clinically arrest and reverse the course of late-stage cancer.
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Affiliation(s)
- Yafei Wang
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA
| | - Erik Brodin
- Department of Chemical, Paper and Biomedical Engineering, Miami University, Oxford, OH, USA
| | - Kenichiro Nishii
- Department of Chemical, Paper and Biomedical Engineering, Miami University, Oxford, OH, USA
| | - Hermann B Frieboes
- Department of Bioengineering, University of Louisville, Louisville, KY, USA
- James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
- Center for Predictive Medicine, University of Louisville, Louisville, KY, USA
| | - Shannon M Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, University of Southern California, Los Angeles, CA, USA
| | - Jessica L Sparks
- Department of Chemical, Paper and Biomedical Engineering, Miami University, Oxford, OH, USA.
| | - Paul Macklin
- Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA.
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28
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Ronca V, Mancuso C, Milani C, Carbone M, Oo YH, Invernizzi P. Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis. J Leukoc Biol 2020; 108:659-671. [PMID: 32349179 DOI: 10.1002/jlb.5mr0320-200r] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 03/09/2020] [Accepted: 03/19/2020] [Indexed: 12/13/2022] Open
Abstract
Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by the destruction of the small and medium bile ducts. Its pathogenesis is still unknown. Despite the genome wide association study findings, the therapies targeting the cytokines pathway, tested so far, have failed. The concept of the biliary epithelium as a key player of the PBC pathogenesis has emerged over the last few years. It is now well accepted that the biliary epithelial cells (BECs) actively participate to the genesis of the damage. The chronic stimulation of BECs via microbes and bile changes the cell phenotype toward an active state, which, across the production of proinflammatory mediators, can recruit, retain, and activate immune cells. The consequent immune system activation can in turn damage BECs. Thus, the crosstalk between both innate and adaptive immune cells and the biliary epithelium creates a paracrine loop responsible for the disease progression. In this review, we summarize the evidence provided in literature about the role of BECs and the immune system in the pathogenesis of PBC. We also dissect the relationship between the immune system and the BECs, focusing on the unanswered questions and the future potential directions of the translational research and the cellular therapy in this area.
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Affiliation(s)
- Vincenzo Ronca
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Clara Mancuso
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Chiara Milani
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Marco Carbone
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
| | - Ye Htun Oo
- National Institute of Health Research Liver Biomedical Research Centre Birmingham, Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Transplant and Hepatobiliary Unit, Queen Elizabeth Hospital, University Hospital of Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology and Centre for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan Bicocca, Milan, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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Torbenson M, Desmet V, Denk H, Callea F, Burt AD, Hübscher SG, Terracciano L, Dienes HP, Goodman ZD, Bedossa P, Wanless IR, Roberts EA, Brunt EM, Clouston AD, Gouw ASH, Kleiner D, Schirmacher P, Tiniakos D. Fifty years of impact on liver pathology: a history of the Gnomes. Virchows Arch 2020; 478:191-200. [PMID: 32607686 PMCID: PMC7969554 DOI: 10.1007/s00428-020-02879-5] [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: 04/24/2020] [Revised: 06/14/2020] [Accepted: 06/17/2020] [Indexed: 12/01/2022]
Abstract
Professional societies play a major role in medicine and science. The societies tend to be large with well-developed administrative structures. An additional model, however, is based on small groups of experts who meet regularly in an egalitarian model in order to discuss disease-specific scientific and medical problems. In order to illustrate the effectiveness of this model, the history and practices are examined of a long-standing successful example, the International Liver Pathology Group, better known as the Gnomes. The history shows that groups such as the Gnomes offer a number of important benefits not available in larger societies and nurturing such groups advances science and medicine in meaningful ways. The success of the Gnomes' approach provides a road map for future small scientific groups.
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Affiliation(s)
- Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Valeer Desmet
- Histology and Pathology, Faculty of Medicine, K.U. Leuven, Leuven, Belgium
| | - Helmut Denk
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | | | - Alastair D Burt
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.,Faculty of Health and Medical Sciences, University of Adelaide School of Medicine, Adelaide, South Australia, 5005, Australia
| | - Stefan G Hübscher
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.,Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham, Birmingham, B15 2WB, UK
| | - Luigi Terracciano
- Institute of Pathology, University of Basel, 4003, Basel, Switzerland
| | - Hans-Peter Dienes
- Institute of Pathology, Meduniwien, Medical University of Vienna, 1090, Wien, Austria
| | - Zachary D Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, 22042, USA
| | - Pierre Bedossa
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.,LiverPat, Paris, France
| | - Ian R Wanless
- Department of Pathology, Dalhousie University, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, B3H 1V8, Canada
| | - Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, M5G1X8, Canada
| | - Elizabeth M Brunt
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich Rd, Woolloongabba, 4109, Australia
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, 9700 RB, Groningen, The Netherlands
| | | | - Peter Schirmacher
- Heidelberg University, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany
| | - Dina Tiniakos
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. .,Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.
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Leth Jepsen M, Willumsen A, Mazzoni C, Boisen A, Hagner Nielsen L, Dufva M. 3D Printed Stackable Titer Plate Inserts Supporting Three Interconnected Tissue Models for Drug Transport Studies. ACTA ACUST UNITED AC 2020; 4:e1900289. [DOI: 10.1002/adbi.201900289] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 03/17/2020] [Indexed: 01/06/2023]
Affiliation(s)
- Morten Leth Jepsen
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
| | - Andreas Willumsen
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
| | - Chiara Mazzoni
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
| | - Anja Boisen
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
| | - Line Hagner Nielsen
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
| | - Martin Dufva
- The Danish National Research Foundation and Villum Foundation’s Center for Intelligent Drug Delivery and Sensing Using Microcontainers and Nanomechanics (IDUN)Department of Health TechnologyTechnical University of Denmark Ørsteds Plads 345C Kgs. Lyngby 2800 Denmark
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Abstract
Brain metastases are associated with poor prognosis irrespective of the primary tumor they originate from. Current treatments for brain metastases are palliative, and patients with symptomatic brain metastasis have a one-year survival of <20%. Lung cancer, breast cancer, and melanoma have higher incidences of brain metastases compared with other types of cancers. However, it is not very clear why some cancers metastasize to the brain more frequently than others. Studies thus far suggest that brain-specific tropism of certain types of cancers is defined by a winning combination of the following factors: unique genetic subtypes of primary tumors or its subclones enabling detachment, dissemination, blood-brain barrier penetration, plus proliferation and survival in hypoxic low-glucose microenvironment; specific transcriptomic and epigenetic changes of colony-forming metastatic cells, allowing their outgrowth; favorable metastasis-permissive microenvironment of the brain created by interactions of cancer cells and cells in the brain through triggering inflammation, recruiting myeloid-derived suppressor cells, and promoting metabolic adaptation; immunosuppression resulting in the failure of adaptive immune response to recognize or kill cancer cells in the brain. Here, we briefly review recent advances in understanding brain metastasis organotropism and outline directions for future research.
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Affiliation(s)
- Arseniy E Yuzhalin
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Dihua Yu
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Luo L, Chen L, Ke K, Zhao B, Wang L, Zhang C, Wang F, Liao N, Zheng X, Liu X, Wang Y, Liu J. High expression levels of CLEC4M indicate poor prognosis in patients with hepatocellular carcinoma. Oncol Lett 2020; 19:1711-1720. [PMID: 32194663 PMCID: PMC7038977 DOI: 10.3892/ol.2020.11294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 11/12/2019] [Indexed: 01/27/2023] Open
Abstract
The identification of novel and accurate biomarkers is important to improve the prognosis of patients with hepatocellular carcinoma (HCC). C-Type lectin domain family 4 member M (CLEC4M) is involved in the progression of numerous cancer types. However, the clinical significance of CLEC4M in HCC is yet to be elucidated. The aim of the present study is to evaluate the involvement of CLEC4M in HCC progression. The expression level of CLEC4M was determined in tumor, and their corresponding adjacent non-tumor tissues derived from 88 patients with HCC, using immunohistochemistry, western blot and reverse transcription-quantitative PCR. The correlation between CLEC4M expression and certain clinicopathological characteristics was retrospectively analyzed. The results suggested that CLEC4M was specifically labeled in sinusoidal endothelial cells, in both HCC and non-tumor tissues. Moreover, the expression of CLEC4M in tumor tissues was significantly lower than that in non-tumor tissues (P<0.0001), which indicated its potential as a biomarker of the development of HCC. Subsequently, correlation analysis suggested that the relatively higher CLEC4M expression in HCC tissues was significantly associated with increased microvascular invasion (P=0.008), larger tumor size (P=0.018), absence of tumor encapsulation (P<0.0001) and lower tumor differentiation (P=0.019). Notably, patients with high CLEC4M expression levels in their tumor tissues experienced more frequent recurrence and shorter overall survival (OS) times compared with the low-expression group. Furthermore, CLEC4M expression in tumor tissues was identified as an independent and significant risk factor for recurrence-free survival and OS. The results of the present study suggest that CLEC4M may be a valuable biomarker for the prognosis of the patients with HCC, postoperatively.
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Affiliation(s)
- Liuping Luo
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Lihong Chen
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Kun Ke
- The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Bixing Zhao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Lili Wang
- Department of Diagnostic Radiology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Cuilin Zhang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Fei Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Naishun Liao
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xiaoyuan Zheng
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Yingchao Wang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
| | - Jingfeng Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian 350025, P.R. China
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Cheng D, Morsch M, Shami GJ, Chung RS, Braet F. Observation and characterisation of macrophages in zebrafish liver. Micron 2020; 132:102851. [PMID: 32092694 DOI: 10.1016/j.micron.2020.102851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 01/22/2023]
Abstract
Kupffer cells are liver-resident macrophages that play an important role in mediating immune-related functions in mammals and humans. They are well-known for their capacity to phagocytose large amounts of waste complexes, cell debris, microbial particles and even malignant cells. Location, appearance and functional aspects are important features used to identify these characteristic cells of the liver sinusoid. To-date, there is limited information on the occurrence of macrophages in zebrafish liver. Therefore, we aimed to characterise the ultrastructural and functional aspects of liver-associated macrophages in the zebrafish model by taking advantage of the latest advances in zebrafish genetics and multimodal correlative imaging. Herein, we report on the occurrence of macrophages within the zebrafish liver exhibiting conventional ultrastructural features (e.g. presence of pseudopodia, extensive lysosomal apparatus, a phagolysosome and making up ∼3% of the liver volume). Intriguingly, these cells were not located within the sinusoidal vascular bed of hepatic tissue but instead resided between hepatocytes and lacked phagocytic function. While our results demonstrated the presence and structural similarities with liver macrophages from other experimental models, their functional characteristics were distinctly different from Kupffer cells that have been described in rodents and humans. These findings illustrate that the innate immune system of the zebrafish liver has some distinctly different characteristics compared to other animal experimental models. This conclusion underpins our call for future studies in order to have a better understanding of the physiological role of macrophages residing between the parenchymal cells of the zebrafish liver.
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Affiliation(s)
- Delfine Cheng
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia.
| | - Marco Morsch
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
| | - Gerald J Shami
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia.
| | - Roger S Chung
- Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW 2109, Australia.
| | - Filip Braet
- School of Medical Sciences (Discipline of Anatomy and Histology) - The Bosch Institute, The University of Sydney, NSW 2006, Australia; Australian Centre for Microscopy & Microanalysis, The University of Sydney, NSW 2006, Australia; Charles Perkins Centre (Cellular Imaging Facility), The University of Sydney, NSW 2006, Australia.
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6-Gingerol ameliorates sepsis-induced liver injury through the Nrf2 pathway. Int Immunopharmacol 2020; 80:106196. [PMID: 31978803 DOI: 10.1016/j.intimp.2020.106196] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 01/05/2020] [Accepted: 01/05/2020] [Indexed: 12/17/2022]
Abstract
Sepsis-induced liver injury is very common in intensive care units. Here, we investigated the effects of 6-gingerol on sepsis-induced liver injury and the role of the Nrf2 pathway in this process. 6-Gingerol is the principal ingredient of ginger that exerts anti-inflammatory and antioxidant effects. Using cecal ligation and puncture (CLP) to induce polymicrobial sepsis and related liver injury, we found that mice pre-treated with 6-Gingerol showed less incidences of severe liver inflammation and death than untreated CLP groups. 6-Gingerol administration also inhibited the expression of pyroptosis-related proteins, including NOD-like receptor protein 3 (NLRP3), IL-1β, and caspase-1. Consistent with these findings, 6-gingerol reduced the effects of pyroptosis induced by lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP) in RAW 264.7 cells, as evidenced by IL-1β and caspase-1 protein levels in the supernatant and propidium iodide (PI) staining. 6-Gingerol was shown to activate the Nrf2 pathway in vivo and in vitro. Notably, Nrf2 siRNA transfection nullified the inhibitory effects of 6-gingerol on pyroptosis in vitro. In summary, these findings suggested that 6-gingerol alleviated sepsis-induced liver injury by inhibiting pyroptosis through the Nrf2 pathway.
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Herron LA, Hansen CS, Abaci HE. Engineering tissue-specific blood vessels. Bioeng Transl Med 2019; 4:e10139. [PMID: 31572797 PMCID: PMC6764806 DOI: 10.1002/btm2.10139] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 06/15/2019] [Accepted: 06/17/2019] [Indexed: 12/11/2022] Open
Abstract
Vascular diversity among organs has recently become widely recognized. Several studies using mouse and human fetal tissues revealed distinct characteristics of organ-specific vasculature in molecular and functional levels. Thorough understanding of vascular heterogeneities in human adult tissues is significant for developing novel strategies for targeted drug delivery and tissue regeneration. Recent advancements in microfabrication techniques, biomaterials, and differentiation protocols allowed for incorporation of microvasculature into engineered organs. Such vascularized organ models represent physiologically relevant platforms that may offer innovative tools for dissecting the effects of the organ microenvironment on vascular development and expand our present knowledge on organ-specific human vasculature. In this article, we provide an overview of the current structural and molecular evidence on microvascular diversity, bioengineering methods used to recapitulate the microenvironmental cues, and recent vascularized three-dimensional organ models from the perspective of tissue-specific vasculature.
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Affiliation(s)
- Lauren A. Herron
- Department of DermatologyColumbia University Irving Medical CenterNew YorkNY10032
| | - Corey S. Hansen
- Department of DermatologyColumbia University Irving Medical CenterNew YorkNY10032
| | - Hasan E. Abaci
- Department of DermatologyColumbia University Irving Medical CenterNew YorkNY10032
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Kostallari E, Shah VH. Pericytes in the Liver. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:153-167. [PMID: 30937868 DOI: 10.1007/978-3-030-11093-2_9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver pericytes, commonly named hepatic stellate cells (HSCs), reside in the space between liver sinusoidal endothelial cells (LSECs) and hepatocytes. They display important roles in health and disease. HSCs ensure the storage of the majority of vitamin A in a healthy body, and they represent the major source of fibrotic tissue in liver disease. Surrounding cells, such as LSECs, hepatocytes, and Kupffer cells, present a significant role in modulating HSC behavior. Therapeutic strategies against liver disease are being currently developed, where HSCs represent an ideal target. In this chapter, we will discuss HSC quiescence and activation in the context of healthy liver and diseases, such as fibrosis, steatohepatitis, and hepatocellular carcinoma.
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Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Albumin uptake and distribution in the zebrafish liver as observed via correlative imaging. Exp Cell Res 2018; 374:162-171. [PMID: 30496757 DOI: 10.1016/j.yexcr.2018.11.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/20/2018] [Accepted: 11/23/2018] [Indexed: 12/20/2022]
Abstract
Although liver transport routes have been extensively studied in rodents, live imaging under in situ and in vivo conditions of large volumes is still proven to be difficult. In this study, we took advantage of the optical transparency of zebrafish and their small size to explore their usefulness for correlative imaging studies and liver transport experimentations. First, we assessed the micro-architecture of the zebrafish liver and compared its fine structure to the rodent and humans' literature. Next, we investigated the transport routes and cellular distribution of albumin using combined and correlative microscopy approaches. These methods permitted us to track the injected proteins at different time points through the process of liver uptake and clearance of albumin. We demonstrate strong structural and functional resemblance between the zebrafish liver and its rodents and humans' counterparts. In as short as 5 min post-injection, albumin rapidly accumulated within the LSECs. Furthermore, albumin entered the space of Disse where it initially accumulated then subsequently was taken up by the hepatocytes. We propose the zebrafish as a viable alternative experimental model for hepatic transport studies, allowing swift multimodal imaging and direct quantification on the hepatic distribution of supramolecular complexes of interest.
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Piobbico D, Bartoli D, Pieroni S, De Luca A, Castelli M, Romani L, Servillo G, Della-Fazia MA. Role of IL-17RA in the proliferative priming of hepatocytes in liver regeneration. Cell Cycle 2018; 17:2423-2435. [PMID: 30395772 PMCID: PMC6342078 DOI: 10.1080/15384101.2018.1542893] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 10/16/2018] [Accepted: 10/19/2018] [Indexed: 12/20/2022] Open
Abstract
A tight link has been established between inflammation and cancer. Liver regeneration is a widely used model to study the correlation between inflammation and proliferation. IL-6 is essentially involved in liver regeneration and in cancer. Recently, IL-17A has been shown to regulate not only inflammation, but also cell proliferation. Here, we analyze the role played by IL-17A signaling in liver regeneration by comparing cell proliferation in Wild Type and IL-17RA-/- mice. Partial hepatectomy experiments performed in IL-17RA-/- mice showed a delay in expression of early-genes to prime the residual hepatocyte to proliferate, with subsequent delay in G1/S-phase transition. We demonstrated that IL-17RA regulates, by recruitment of non-parenchymal cell, the expression of IL-6, which in turn triggers the proliferation of residual hepatocytes. Our data indicate an important role played by IL-17RA in liver proliferation via IL-6.
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Affiliation(s)
- Danilo Piobbico
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Daniela Bartoli
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Stefania Pieroni
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Antonella De Luca
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Marilena Castelli
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Luigina Romani
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
| | - Giuseppe Servillo
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
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Abstract
Hepatic sinusoidal dilatation refers to the enlargement of the hepatic capillaries. Most of the time this condition is caused by hepatic venous outflow obstruction, which results in vascular stasis and congestion of hepatic parenchyma. In this setting, hepatic sinusoidal dilatation can be related to pericardial disease, heart failure, compression or thrombosis of the hepatic veins or inferior vena cava (i.e., Budd-Chiari syndrome) or central veins/sinusoids involvement (i.e., sinusoidal obstruction syndrome). Nevertheless, some extrahepatic inflammatory conditions (such as pyelonephritis, cholecystitis, pneumonia, pancreatitis, intestinal bowel disease, and others) may be associated with hepatic sinusoidal dilatation without concurrent venous outflow obstruction. On contrast-enhanced cross-sectional imaging, hepatic sinusoidal dilatation is typically characterized by a mottled, reticular enhancement of the liver, usually referred to as "mosaic" pattern. Other hepatic and extrahepatic imaging features, such us the dilatation of the hepatic veins or the presence of ascites, can help in identifying the cause of sinusoidal dilatation.
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40
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Pathology of idiopathic non-cirrhotic portal hypertension. Virchows Arch 2018; 473:23-31. [DOI: 10.1007/s00428-018-2355-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 03/29/2018] [Accepted: 04/02/2018] [Indexed: 12/15/2022]
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Extrahepatic angiogenesis hinders recovery of portal hypertension and collaterals in rats with cirrhosis resolution. Clin Sci (Lond) 2018; 132:669-683. [PMID: 29449343 DOI: 10.1042/cs20171370] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 02/09/2018] [Accepted: 02/15/2018] [Indexed: 12/20/2022]
Abstract
Liver cirrhosis is characterized by portal hypertension. However, the alteration of portal hypertension-related derangements during cirrhosis resolution is not well known. The present study aimed to establish animal models with cirrhosis resolution and to investigate the relevant changes during this process. Male Sprague-Dawley rats were applied. In reverse thioacetamide (rTAA) model, rats were randomly allocated into four groups with control, thioacetamide (TAA) cirrhosis and rTAA groups that discontinued TAA for 4 or 8 weeks after cirrhosis induction. In reverse bile duct ligation (rBDL) model, rats received choledochoduodenal shunt surgery upon the establishment of cirrhosis and 4, 8, or 16 weeks were allowed after the surgery. At the end, portal hypertension-related parameters were evaluated. Cirrhosis resolution was observed in rTAA groups. Portal pressure (PP) decreased after cirrhosis resolution but remained higher than control group (control, TAA, rTAA4, rTAA8 (mmHg): 5.4 ± 0.3, 12.9 ± 0.3, 8.6 ± 0.4, 7.6 ± 0.6). Further survey found the increased splanchnic blood flow did not reduce during cirrhosis resolution. The extrahepatic pathological angiogenesis was not ameliorated (% of mesenteric window area: 1.2 ± 0.3, 7.3 ± 1.1, 8.3 ± 1.0, 11.3 ± 2.7). In collateral system, the shunting degree reduced while the vessels structure remained. The vascular contractility of all systems and nitric oxide (NO) production were normalized. In rBDL series, PP decreased in rBDL16 groups but the extrahepatic angiogenesis persisted. In conclusion, cirrhosis resolution attenuates but not completely normalizes portal hypertension because of persistently high splanchnic inflow and angiogenesis. In clinical setting, vascular complications such as varices could persist after cirrhosis resolution and further investigation to define the follow-up and treatment strategies is anticipated.
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Plumbagin Alleviates Capillarization of Hepatic Sinusoids In Vitro by Downregulating ET-1, VEGF, LN, and Type IV Collagen. BIOMED RESEARCH INTERNATIONAL 2017; 2017:5603216. [PMID: 28770223 PMCID: PMC5523349 DOI: 10.1155/2017/5603216] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/28/2017] [Accepted: 06/05/2017] [Indexed: 12/19/2022]
Abstract
Critical roles for liver sinusoidal endothelial cells (LSECs) in liver fibrosis have been demonstrated, while little is known regarding the underlying molecular mechanisms of drugs delivered to the LSECs. Our previous study revealed that plumbagin plays an antifibrotic role in liver fibrosis. In this study, we investigated whether plumbagin alleviates capillarization of hepatic sinusoids by downregulating endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), laminin (LN), and type IV collagen on leptin-stimulated LSECs. We found that normal LSECs had mostly open fenestrae and no organized basement membrane. Leptin-stimulated LSECs showed the formation of a continuous basement membrane with few open fenestrae, which were the features of capillarization. Expression of ET-1, VEGF, LN, and type IV collagen was enhanced in leptin-stimulated LSECs. Plumbagin was used to treat leptin-stimulated LSECs. The sizes and numbers of open fenestrae were markedly decreased, and no basement membrane production was found after plumbagin administration. Plumbagin decreased the levels of ET-1, VEGF, LN, and type IV collagen in leptin-stimulated LSECs. Plumbagin promoted downregulation of ET-1, VEGF, LN, and type IV collagen mRNA. Altogether, our data reveal that plumbagin reverses capillarization of hepatic sinusoids by downregulation of ET-1, VEGF, LN, and type IV collagen.
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Anavi S, Madar Z, Tirosh O. Non-alcoholic fatty liver disease, to struggle with the strangle: Oxygen availability in fatty livers. Redox Biol 2017; 13:386-392. [PMID: 28667907 PMCID: PMC5493836 DOI: 10.1016/j.redox.2017.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2017] [Revised: 06/18/2017] [Accepted: 06/20/2017] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver diseases (NAFLD) is one of the most common chronic liver disease in Western countries. Oxygen is a central component of the cellular microenvironment, which participate in the regulation of cell survival, differentiation, functions and energy metabolism. Accordingly, sufficient oxygen supply is an important factor for tissue durability, mainly in highly metabolic tissues, such as the liver. Accumulating evidence from the past few decades provides strong support for the existence of interruptions in oxygen availability in fatty livers. This outcome may be the consequence of both, impaired systemic microcirculation and cellular membrane modifications which occur under steatotic conditions. This review summarizes current knowledge regarding the main factors which can affect oxygen supply in fatty liver.
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Affiliation(s)
- Sarit Anavi
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel; Peres Academic Center, Rehovot, Israel
| | - Zecharia Madar
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel
| | - Oren Tirosh
- Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Israel.
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Toriyabe N, Sakurai Y, Kato A, Yamamoto S, Tange K, Nakai Y, Akita H, Harahsima H. The Delivery of Small Interfering RNA to Hepatic Stellate Cells Using a Lipid Nanoparticle Composed of a Vitamin A-Scaffold Lipid-Like Material. J Pharm Sci 2017; 106:2046-2052. [PMID: 28456722 DOI: 10.1016/j.xphs.2017.04.042] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Revised: 02/23/2017] [Accepted: 04/19/2017] [Indexed: 01/22/2023]
Abstract
Hepatic stellate cells (HSCs) are responsible for hepatic fibrosis and liver cirrhosis via their ability to produce extracellular matrices such as collagens and elastin. However, a strategy for delivering cargoes to HSCs has not been established yet. We herein report on attempts to deliver small interfering RNA (siRNA) to HSCs using several types of SS-cleavable proton-activated lipid-like materials (ssPalms) that contained myristic acid (ssPalmM) or hydrophobic vitamin A (ssPalmA) and E (ssPalmE) as hydrophobic scaffolds. We initially verified that hepatic fibrosis could induce the treatment with tetrachloromethane in terms of collagen fibrils and the expression of marker genes, type I collagen α-1, transforming growth factor β, heat shock protein 47, and α-smooth muscle actin. The siRNA silencing efficiency of the 3 LNPs was then compared using fibrosis-induced mice. Of the materials tested, LNPssPalmA showed the highest efficiency, with an effective (ED)50 of approximately 0.25 mg siRNA/kg. The LNPssPalmA showed a significant inhibitory effect on collagen production at a dose of 3.0 mg siRNA/kg with no evidence of any severe adverse effects. In conclusion, LNPssPalmA holds considerable potential for use in the treatment of HSCs-mediated diseases.
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Affiliation(s)
- Naoyuki Toriyabe
- Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Yu Sakurai
- Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Akari Kato
- Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Shoshiro Yamamoto
- Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan
| | - Kota Tange
- NOF Corporation, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan
| | - Yuta Nakai
- NOF Corporation, 3-3 Chidori-cho, Kawasaki-ku, Kawasaki, Kanagawa 210-0865, Japan
| | - Hidetaka Akita
- Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba City, Chiba 260-8675, Japan
| | - Hideyoshi Harahsima
- Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
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Zhao ZM, Liu HL, Sun X, Guo T, Shen L, Tao YY, Liu CH. Levistilide A inhibits angiogenesis in liver fibrosis via vascular endothelial growth factor signaling pathway. Exp Biol Med (Maywood) 2017; 242:974-985. [PMID: 28440736 DOI: 10.1177/1535370217701005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Levistilide A (C24H28O4, molecular weight = 380.48) derived from Angelica sinensis (Danggui) has been reported to inhibit hepatic stellate cell proliferation. This study investigated the effects of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. LX-2 cells were activated by TGF-β1, and the human hepatic sinusoidal endothelial cells (HHSECs) were induced by endothelial cell growth supplement. Cell viability was detected using a methylthiazoldiphenyl-tetrazolium bromide assay; F-actin was visualized through the fluorescence probe method; cell proliferation was examined using the EdU kit; antiangiogenesis activity was assessed using the tube formation assay and transgenic zebrafish model. To verify the results in vivo, rats were subcutaneously injected with CCl4 twice a week for six weeks to duplicate the liver fibrosis model and then treated with 10 mL/kg of normal saline, 4 mg/kg of sorafenib, and 3 and 6 mg/kg of levistilide A for three weeks from the fourth week. Collagen deposition was detected through Sirius Red staining; liver microvasculature was examined through vWF labeling and X-ray 2D imaging; sinusoidal fenestrations were observed through scanning electron microscopy; collagen I, α-SMA, CD31, vascular endothelial growth factor (VEGF), and VEGF-R2 were detected through Western blotting. Our results indicated that levistilide A attenuated LX-2 cell activation and HHSEC proliferation. The ability of HHSECs to form tubelike structures in Matrigel was inhibited, and the number of functional vessels in transgenic zebrafish decreased. In in vivo experiments, levistilide A reduced collagen deposition and the number of new microvessels; ameliorated sinusoid capillarization; and downregulated the expression of CD31, VEGF, and VEGF-R2. These findings suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the VEGF signaling pathway. Impact statement Levistilide A has been reported to inhibit hepatic stellate cell (HSC) proliferation. In this study, we further investigated the mechanisms of levistilide A on liver fibrosis relating to angiogenesis, particularly on the characteristic change in liver sinusoidal endothelial cells. The cell models of HSC and liver sinusoidal endothelial cell and CCl4 induced liver fibrosis model were used. These results suggest that levistilide A can inhibit liver fibrosis through antiangiogenesis by alleviating sinusoid capillarization via the vascular endothelial growth factor signaling pathway. The effect of levistilide A on liver fibrosis was confirmed, and its detailed mechanism was also discussed. These findings suggest that levistilide A may be a great potential drug for treating liver fibrosis through antiangiogenesis, and this effect will be verified in other fibrotic animal model studies or by clinical trials.
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Affiliation(s)
- Zhi-Min Zhao
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,2 Shanghai Key Lab of Liver Diseases of TCM, Shanghai 201203, China
| | - Hong-Liang Liu
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xin Sun
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Guo
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Shen
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan-Yan Tao
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng-Hai Liu
- 1 Institute of Liver Diseases, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,2 Shanghai Key Lab of Liver Diseases of TCM, Shanghai 201203, China.,3 E-Institute of TCM Internal Medicine, Shanghai Municipal Education Commission, Shanghai 201203, China
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Feng S, Demetris AJ, Spain KM, Kanaparthi S, Burrell BE, Ekong UD, Alonso EM, Rosenthal P, Turka LA, Ikle D, Tchao NK. Five-year histological and serological follow-up of operationally tolerant pediatric liver transplant recipients enrolled in WISP-R. Hepatology 2017; 65:647-660. [PMID: 27302659 PMCID: PMC5159322 DOI: 10.1002/hep.28681] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 05/15/2016] [Accepted: 05/24/2016] [Indexed: 12/13/2022]
Abstract
UNLABELLED Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP-R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor-specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth-muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q. CONCLUSION Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo-immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody-mediated damage. (Hepatology 2017;65:647-660).
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Affiliation(s)
- Sandy Feng
- Department of Surgery, University of California San Francisco, San Francisco, CA
| | | | | | | | | | - Udeme D. Ekong
- Department of Pediatrics, Yale School of Medicine, New Haven, CO
| | - Estella M. Alonso
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Philip Rosenthal
- Department of Surgery, University of California San Francisco, San Francisco, CA,Department of Pediatrics, University of California San Francisco, San Francisco, CA
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Abstract
Sepsis and septic shock are characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection. The liver has a central role during sepsis, and is essential to the regulation of immune defence during systemic infections by mechanisms such as bacterial clearance, acute-phase protein or cytokine production and metabolic adaptation to inflammation. However, the liver is also a target for sepsis-related injury, including hypoxic hepatitis due to ischaemia and shock, cholestasis due to altered bile metabolism, hepatocellular injury due to drug toxicity or overwhelming inflammation, as well as distinct pathologies such as secondary sclerosing cholangitis in critically ill patients. Hence, hepatic dysfunction substantially impairs the prognosis of sepsis and serves as a powerful independent predictor of mortality in the intensive care unit. Sepsis is particularly problematic in patients with liver cirrhosis (who experience increased bacterial translocation from the gut and impaired microbial defence) as it can trigger acute-on-chronic liver failure - a syndrome with high short-term mortality. Here, we review the importance of the liver as a guardian, modifier and target of sepsis, the factors that contribute to sepsis in patients with liver cirrhosis and new therapeutic strategies.
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Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D, Rautou PE. Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol 2017; 66:212-227. [PMID: 27423426 DOI: 10.1016/j.jhep.2016.07.009] [Citation(s) in RCA: 688] [Impact Index Per Article: 86.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 07/05/2016] [Accepted: 07/07/2016] [Indexed: 12/13/2022]
Abstract
Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the association of 'fenestrae', absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.
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Affiliation(s)
- Johanne Poisson
- INSERM, UMR-970, Paris Cardiovascular Research Center - PARCC, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Sara Lemoinne
- INSERM, UMRS 938, Centre de Recherche Saint-Antoine, Université Pierre et Marie Curie Paris 6, Paris, France; Service d'hépatologie, Hôpital Saint-Antoine, APHP, Paris, France
| | - Chantal Boulanger
- INSERM, UMR-970, Paris Cardiovascular Research Center - PARCC, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - François Durand
- Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Clichy, France; INSERM, UMR-1149, Centre de Recherche sur l'inflammation, Paris-Clichy, France; Université Denis Diderot-Paris 7, Sorbonne Paris Cité, 75018 Paris, France
| | - Richard Moreau
- Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Clichy, France; INSERM, UMR-1149, Centre de Recherche sur l'inflammation, Paris-Clichy, France; Université Denis Diderot-Paris 7, Sorbonne Paris Cité, 75018 Paris, France
| | - Dominique Valla
- Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Clichy, France; INSERM, UMR-1149, Centre de Recherche sur l'inflammation, Paris-Clichy, France; Université Denis Diderot-Paris 7, Sorbonne Paris Cité, 75018 Paris, France
| | - Pierre-Emmanuel Rautou
- INSERM, UMR-970, Paris Cardiovascular Research Center - PARCC, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Service d'hépatologie, DHU Unity Hôpital Beaujon, APHP, Clichy, France; INSERM, UMR-1149, Centre de Recherche sur l'inflammation, Paris-Clichy, France; Université Denis Diderot-Paris 7, Sorbonne Paris Cité, 75018 Paris, France.
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Furlan A, Minervini MI, Borhani AA, Dioguardi Burgio M, Tublin ME, Brancatelli G. Hepatic Sinusoidal Dilatation: A Review of Causes With Imaging-Pathologic Correlation. Semin Ultrasound CT MR 2016; 37:525-532. [DOI: 10.1053/j.sult.2016.08.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Gonzalez RS, Gilger MA, Huh WJ, Washington MK. The Spectrum of Histologic Findings in Hepatic Outflow Obstruction. Arch Pathol Lab Med 2016; 141:98-103. [PMID: 27681331 DOI: 10.5858/arpa.2015-0388-oa] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -Cardiac hepatopathy and Budd-Chiari syndrome are 2 forms of hepatic venous outflow obstruction with different pathophysiology but overlapping histologic findings, including sinusoidal dilation and centrilobular necrosis. OBJECTIVE -To determine whether a constellation of morphologic findings could help distinguish between the 2 and could suggest the diagnoses in previously undiagnosed patients. DESIGN -We identified 26 specimens with a diagnosis of cardiac hepatopathy and 23 with a diagnosis of Budd-Chiari syndrome. Slides stained with hematoxylin and eosin and with trichrome were evaluated for several distinctive histologic findings. RESULTS -Features common to both forms of hepatic outflow obstruction included sinusoidal dilation and portal tract changes of fibrosis, chronic inflammation, and bile ductular reaction. Histologic findings significantly more common in cardiac hepatopathy included pericellular/sinusoidal fibrosis and fibrosis around the central vein. Only centrilobular hepatocyte dropout/necrosis was significantly more common in Budd-Chiari, regardless of duration. CONCLUSIONS -The finding of pericellular/sinusoidal fibrosis in cardiac hepatopathy compared with Budd-Chiari is not unexpected, given the chronic nature of most cardiac hepatopathy. Portal tract changes are common in both forms of hepatic outflow obstruction and should not deter one from making the diagnosis of hepatic outflow obstruction. Fibrosis along sinusoids and around the central vein may be suggestive of cardiac hepatopathy in biopsies from patients without a prior diagnosis.
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Affiliation(s)
| | | | | | - Mary Kay Washington
- From the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York (Dr Gonzalez); and the Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Drs Gilger, Huh, and Washington). Dr Gilger is currently at Colorado GI Pathology/Centennial Pathologists, Centennial
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