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1
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Schwabe RF, Brenner DA. Hepatic stellate cells: balancing homeostasis, hepatoprotection and fibrogenesis in health and disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-025-01068-6. [PMID: 40404839 DOI: 10.1038/s41575-025-01068-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2025] [Indexed: 05/24/2025]
Abstract
In the past decades, the pathogenic role of hepatic stellate cells (HSCs) in the development of liver fibrosis and its complications has been deeply characterized, rendering HSCs a primary target for antifibrotic therapies. By contrast, the beneficial roles of HSCs in liver homeostasis and liver disease are only beginning to emerge, revealing critical regulatory and fibrosis-independent functions in hepatic zonation, metabolism, injury, regeneration and non-parenchymal cell identity. Here, we review how HSC mediators, such as R-spondin 3, hepatocyte growth factor and bone morphogenetic proteins, regulate critical and homeostatic liver functions in health and disease via cognate receptors in hepatocytes, Kupffer cells and endothelial cells. We highlight how the balance shifts from protective towards fibropathogenic HSC mediators during the progression of chronic liver disease (CLD) and the impact of this shifted balance on patient outcomes. Notably, the protective roles of HSCs are not accounted for in current therapeutic concepts for CLD. We discuss the concept that reverting the HSC balance from fibrogenesis towards hepatoprotection might represent a novel holistic treatment approach to inhibit fibrogenesis and restore epithelial health in CLD simultaneously.
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Affiliation(s)
- Robert F Schwabe
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, NY, USA.
- Columbia University Digestive and Liver Disease Research Center, New York, NY, USA.
- Herbert Irving Comprehensive Cancer Center, New York, NY, USA.
- Institute of Human Nutrition, New York, NY, USA.
| | - David A Brenner
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Division of Gastroenterology and Hepatology, Department of Medicine, UC San Diego, La Jolla, CA, USA
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2
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Graham CT, Gordon S, Kubes P. A historical perspective of Kupffer cells in the context of infection. Cell Tissue Res 2025; 400:121-136. [PMID: 39392500 DOI: 10.1007/s00441-024-03924-4] [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: 06/28/2024] [Accepted: 10/02/2024] [Indexed: 10/12/2024]
Abstract
The Kupffer cell was first discovered by Karl Wilhelm von Kupffer in 1876, labeling them as "Sternzellen." Since their discovery as the primary macrophages of the liver, researchers have gradually gained an in-depth understanding of the identity, functions, and influential role of Kupffer cells, particularly in infection. It is becoming clear that Kupffer cells perform important tissue-specific functions in homeostasis and disease. Stationary in the sinusoids of the liver, Kupffer cells have a high phagocytic capacity and are adept in clearing the bloodstream of foreign material, toxins, and pathogens. Thus, they are indispensable to host defense and prevent the dissemination of bacteria during infections. To highlight the importance of this cell, this review will explore the history of the Kupffer cell in the context of infection beginning with its discovery to the present day.
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Affiliation(s)
- Carolyn T Graham
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.
| | - Siamon Gordon
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road Guishan Dist., Taoyuan, Taiwan
| | - Paul Kubes
- Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada
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3
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Yuasa H, Matsubara T, Urushima H, Daikoku A, Ikenaga H, Kadono C, Kinoshita M, Kimura K, Ishizawa T, Ohta K, Kawada N, Ikeda K. Cdc42 is crucial for the early regulation of hepatic stellate cell activation. Am J Physiol Cell Physiol 2025; 328:C757-C775. [PMID: 39871537 DOI: 10.1152/ajpcell.00987.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 12/28/2024] [Accepted: 01/16/2025] [Indexed: 01/29/2025]
Abstract
The activation of hepatic stellate cells (HSCs) from a quiescent state is a cause of liver fibrosis and a therapeutic target. HSCs are resident mesenchymal cells located in the space of Disse, exhibiting specialized morphological characteristics such as a stellate shape, large lipid droplets, and direct adhesions to hepatocytes via microprojections called HSC spines. Morphological alterations in HSCs play a crucial role in initiating their activation. However, the mechanisms regulating these changes remain unexplored. In this study, we analyzed the morphological alterations associated with HSC activation in vivo using carbon tetrachloride treatment and identified the key factors regulating these changes in vitro. Following carbon tetrachloride treatment, HSCs exhibited shortened cell processes and HSC spines, adopting an oval shape. Subsequently, the HSCs underwent further morphological changes into two activated forms: flattened and complex shapes. In vitro, activation of cell division cycle 42 (Cdc42) maintained the morphological characteristics of quiescent HSCs. Cdc42 activation in HSC cell lines inhibited the expression of markers associated with activated HSCs. Cdc42 inhibitor treatment in vivo prevented quiescent HSCs from maintaining their morphological characteristics and hindered activated HSCs from reverting to the quiescent state. In addition, HSCs around fibrotic areas in the human liver exhibited morphological alterations indicative of early activation. These findings demonstrate that Cdc42 is a crucial regulator of morphological and molecular alterations associated with HSC activation, identifying it as a novel target for the development of therapeutic agents against liver fibrosis.NEW & NOTEWORTHY The activation of hepatic stellate cells from a quiescent state is a cause and a therapeutic target for liver fibrosis. Morphological alterations in the hepatic stellate cells play a critical role in initiating their activation. However, the mechanisms that regulate these alterations remain unexplored. Our results indicate that cell division cycle 42 is a crucial regulator of hepatic stellate cell activation and a novel target for the development of therapeutic agents against liver fibrosis.
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Affiliation(s)
- Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Research Institute for Light-induced Acceleration System, Osaka Metropolitan University, Sakai, Japan
| | - Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Chiho Kadono
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masahiko Kinoshita
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kenjiro Kimura
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Takeaki Ishizawa
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Keisuke Ohta
- Division Microscopic and Development Anatomy, Department of Anatomy, School of Medicine, Kurume University, Kurume, Japan
- Advanced Imaging Research Center, School of Medicine, Kurume University, Kurume, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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4
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Nakashima H, Kearney BM, Kinoshita M. The Liver X Receptor Promotes Immune Homeostasis via Controlled Activation of the Innate Immune System in the Liver. Biomolecules 2024; 15:25. [PMID: 39858420 PMCID: PMC11764419 DOI: 10.3390/biom15010025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 12/24/2024] [Accepted: 12/25/2024] [Indexed: 01/27/2025] Open
Abstract
The liver is an indispensable metabolic organ, responsible for accumulating and transporting various nutritional compounds in hepatocytes. However, the transport of these materials from the liver is an energetically intensive task because they contain a considerable number of hydrophobic components, including free cholesterol, and require specialized transfer proteins to shuttle these substances through an aqueous phase. Liver X receptors (LXRs) induce the expression of cholesterol transporters in macrophages to transport free cholesterol derived from apoptotic cells into extracellular space via high-density lipoproteins. Additionally, LXRs control innate immune cells through two major mechanisms: upregulating the phagocytic activity of macrophages and suppressing inflammatory reactions to prevent aggressive activation of immune cells. Therefore, the primary role of LXRs is to accelerate efferocytosis without provoking inflammation and facilitate the transfer of free cholesterol from the intracellular space. This mechanism makes the innate immune system a substantial contributor to systemic metabolic control. Concomitantly, LXRs are important factors in regulating systemic defense mechanisms through the efficient regulation of immune cells. LXR activation, therefore, has great potential for clinical applications in the treatment of metabolic, infectious, and autoimmune diseases. In this review, we discuss the current understanding of the link between LXRs and innate immune cells in the liver, along with prospects for clinical applications of LXR agonists.
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Affiliation(s)
- Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Saitama 359-8513, Japan; (B.M.K.); (M.K.)
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5
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De Ponti FF, Liu Z, Scott CL. Understanding the complex macrophage landscape in MASLD. JHEP Rep 2024; 6:101196. [PMID: 39524202 PMCID: PMC11550213 DOI: 10.1016/j.jhepr.2024.101196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/07/2024] [Accepted: 08/14/2024] [Indexed: 11/16/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a spectrum of disease states ranging from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), which can eventually lead to the development of cirrhosis and hepatocellular carcinoma. Macrophages have long been implicated in driving the progression from steatosis to end-stage disease, yet we still know relatively little about the precise involvement of these cells in MASLD progression and/or regression. Rather, there are a considerable number of conflicting reports regarding the precise roles of these cells. This confusion stems from the fact that, until recently, macrophages in the liver were considered a homogenous population. However, thanks to recent technological advances including multi-parameter flow cytometry, single-cell RNA sequencing and spatial proteogenomics, we now know that this is not the case. Rather hepatic macrophages, even in the healthy liver, are heterogenous, existing in multiple subsets with distinct transcriptional profiles and hence likely functions. This heterogeneity is even more prominent in MASLD, where the macrophage pool consists of multiple different subsets of resident and recruited cells. To probe the unique functions of these cells and determine if targeting macrophages may be a viable therapeutic strategy in MASLD, we first need to unravel this complexity and decipher which populations and/or activation states are present and what functions each of these may play in driving MASLD progression. In this review, we summarise recent advances in the field, highlighting what is currently known about the hepatic macrophage landscape in MASLD and the questions that remain to be tackled.
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Affiliation(s)
- Federico F. De Ponti
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium
| | - Zhuangzhuang Liu
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium
| | - Charlotte L. Scott
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Belgium
- Department of Chemical Sciences, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Ireland
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6
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Arteel GE. When is a Kupffer cell not a Kupffer cell? Novel insight into macrophage fate and function in hepatic fibrosis. J Leukoc Biol 2024; 115:415-416. [PMID: 38285520 PMCID: PMC12020053 DOI: 10.1093/jleuko/qiae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/31/2024] Open
Affiliation(s)
- Gavin E. Arteel
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, 3708 Fifth Ave, Pittsburgh, PA 15213, United States
- Pittsburgh Liver Research Center, University of Pittsburgh, Biomedical Science Tower, South 414, 200 Lothrop Street, Pittsburgh, PA 15213, United States
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7
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Liu Z, Louwe PA, Scott CL. Studying Macrophages in the Murine Steatotic Liver Using Flow Cytometry and Confocal Microscopy. Methods Mol Biol 2024; 2713:207-230. [PMID: 37639126 DOI: 10.1007/978-1-0716-3437-0_15] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Abstract
The study of macrophage functions in the context of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction associated steatohepatitis (MASH) has been hampered by the fact that until recently all macrophages in the liver were thought to be Kupffer cells, the resident macrophages of the liver. With the advent of single-cell technologies, it is now clear that the steatotic liver harbors many distinct populations of macrophages, likely each with their own unique functions as well as subsets of monocytes and dendritic cells which can be difficult to discriminate from one another. Here, we detail the protocols we utilize to (i) induce MASLD/MASH in mice, (ii) isolate cells from the steatotic liver, and (iii) describe reliable gating strategies, which can be used to identify the different subsets of myeloid cells. Finally, we also discuss the issue of increased autofluorescence in the steatotic liver and the techniques we use to minimize this both for flow cytometry and confocal microscopy analyses.
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Affiliation(s)
- Zhuangzhuang Liu
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
| | - Pieter A Louwe
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Ghent, Belgium
| | - Charlotte L Scott
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
- Department of Biomedical Molecular Biology, Faculty of Science, Ghent University, Ghent, Belgium.
- Department of Chemical Sciences, Bernal Institute, University of Limerick, Castletroy, Co. Limerick, Ireland.
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8
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Apte M. A journey to and with the stars: The pancreatic stellate cell story. Pancreatology 2023; 23:893-899. [PMID: 37973449 DOI: 10.1016/j.pan.2023.10.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Accepted: 10/30/2023] [Indexed: 11/19/2023]
Abstract
The George E Palade Prize is the highest honour awarded by the International Association of Pancreatology, that recognises an individual who has made outstanding contributions to the understanding of the pancreas and pancreatic diseases. The 2023 Palade Prize was awarded to Professor Minoti Apte, University of New South Wales Sydney on September 16, 2023 during the Joint Meeting of the International Association of Pancreatology and the Indian Pancreas Club, held in Delhi, India. This paper summarises her Palade lecture wherein she reflects on her journey as a medical graduate, an academic and a researcher, with a particular focus on her team's pioneering work on pancreatic stellate cell biology and the role of these cells in health and disease. While there has been much progress in this field with the efforts of researchers worldwide, there is much still to be learned; thus it is a topic with ample scope for innovative research with the potential to translate into better outcomes for patients with pancreatic disease.
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Affiliation(s)
- Minoti Apte
- Pancreatic Research Group, South Western Sydney Clinical Campuses, School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales Sydney and Ingham Institute for Applied Medical Research, Liverpool, Sydney, Australia.
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9
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Chen G, Hu X, Huang Y, Xiang X, Pan S, Chen R, Xu X. Role of the immune system in liver transplantation and its implications for therapeutic interventions. MedComm (Beijing) 2023; 4:e444. [PMID: 38098611 PMCID: PMC10719430 DOI: 10.1002/mco2.444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/17/2023] Open
Abstract
Liver transplantation (LT) stands as the gold standard for treating end-stage liver disease and hepatocellular carcinoma, yet postoperative complications continue to impact survival rates. The liver's unique immune system, governed by a microenvironment of diverse immune cells, is disrupted during processes like ischemia-reperfusion injury posttransplantation, leading to immune imbalance, inflammation, and subsequent complications. In the posttransplantation period, immune cells within the liver collaboratively foster a tolerant environment, crucial for immune tolerance and liver regeneration. While clinical trials exploring cell therapy for LT complications exist, a comprehensive summary is lacking. This review provides an insight into the intricacies of the liver's immune microenvironment, with a specific focus on macrophages and T cells as primary immune players. Delving into the immunological dynamics at different stages of LT, we explore the disruptions after LT and subsequent immune responses. Focusing on immune cell targeting for treating liver transplant complications, we provide a comprehensive summary of ongoing clinical trials in this domain, especially cell therapies. Furthermore, we offer innovative treatment strategies that leverage the opportunities and prospects identified in the therapeutic landscape. This review seeks to advance our understanding of LT immunology and steer the development of precise therapies for postoperative complications.
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Affiliation(s)
- Guanrong Chen
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xin Hu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Yingchen Huang
- The Fourth School of Clinical MedicineZhejiang Chinese Medical UniversityHangzhouChina
| | - Xiaonan Xiang
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Sheng Pan
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
| | - Ronggao Chen
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Xiao Xu
- Zhejiang University School of MedicineHangzhouChina
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang ProvinceHangzhouChina
- Zhejiang Chinese Medical UniversityHangzhouChina
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10
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Nakashima H, Kearney BM, Kato A, Miyazaki H, Ito S, Nakashima M, Kinoshita M. Novel phenotypical and functional sub-classification of liver macrophages highlights changes in population dynamics in experimental mouse models. Cytometry A 2023; 103:902-914. [PMID: 37606087 DOI: 10.1002/cyto.a.24783] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/11/2023] [Accepted: 07/28/2023] [Indexed: 08/23/2023]
Abstract
Liver macrophages are critical components of systemic immune system defense mechanisms. F4/80high Kupffer cells (KCs) are the predominant liver-resident macrophages and the first immune cells to contact pathogens entering the liver. F4/80low monocyte-derived macrophages (MoMφs) are essential macrophages that modulate liver immune functions. Here we report a novel method of identifying subpopulations of these two populations using traditional flow cytometry and examine each subpopulation for its putative roles in the pathogenesis of an experimental non-alcoholic steatohepatitis model. Using male C57BL/6 mice, we isolated and analyzed liver non-parenchymal cells by flow cytometry. We identified F4/80high and F4/80low macrophage populations and characterized subpopulations using uniform manifold approximation and projection. We identified three subpopulations in F4/80high macrophages: CD163(+) KCs, CD163(-) KCs, and liver capsular macrophages. CD163(+) KCs had higher phagocytic and bactericidal activities and more complex cellular structures than CD163(-) KCs. We also identified four subpopulations of F4/80low MoMφs based on Ly6C and MHC class II expression: infiltrating monocytes, pro-inflammatory MoMφs, Ly6C(-) monocytes, and conventional dendritic cells. CCR2 knock-out mice expressed lower levels of these monocyte-derived cells, and the count varied by subpopulation. In high-fat- and cholesterol-diet-fed mice, only one subpopulation, pro-inflammatory MoMφs, significantly increased in count. This indicates that changes to this subpopulation is the first step in the progression to non-alcoholic steatohepatitis. The community can use our novel subpopulation and gating strategy to better understand complex immunological mechanisms in various liver disorders through detailed analysis of these subpopulations.
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Affiliation(s)
- Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
| | - Bradley M Kearney
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
| | - Azusa Kato
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
| | - Hiromi Miyazaki
- Division of Biomedical Engineering, National Defense Medical College Research Institute, Saitama, Japan
| | - Seigo Ito
- Department of Internal Medicine, Self-Defense Force Iruma Hospital, Saitama, Japan
| | - Masahiro Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Saitama, Japan
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11
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Ma L, Wu Q, Tam PKH. The Current Proceedings of PSC-Based Liver Fibrosis Therapy. Stem Cell Rev Rep 2023; 19:2155-2165. [PMID: 37490204 DOI: 10.1007/s12015-023-10592-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2023] [Indexed: 07/26/2023]
Abstract
Liver fibrosis was initially considered to be an irreversible process which will eventually lead to the occurrence of liver cancer. So far there has been no effective therapeutic approach to treat liver fibrosis although scientists have put tremendous efforts into the underlying mechanisms of this disease. Therefore, in-depth research on novel and safe treatments of liver fibrosis is of great significance to human health. Pluripotent stem cells (PSCs) play important roles in the study of liver fibrosis due to their unique features in self-renewal ability, pluripotency, and paracrine function. This article mainly reviews the applications of PSCs in the study of liver fibrosis in recent years. We discuss the role of PSC-derived liver organoids in the study of liver fibrosis, and the latest research advances on the differentiation of PSCs into hepatocytes or macrophages. We also highlight the importance of exosomes of PSCs for the treatment of liver fibrosis.
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Affiliation(s)
- Li Ma
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, China
| | - Qiang Wu
- The State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, China.
| | - Paul Kwong-Hang Tam
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China.
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12
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Ng LG, Liu Z, Kwok I, Ginhoux F. Origin and Heterogeneity of Tissue Myeloid Cells: A Focus on GMP-Derived Monocytes and Neutrophils. Annu Rev Immunol 2023; 41:375-404. [PMID: 37126421 DOI: 10.1146/annurev-immunol-081022-113627] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
Myeloid cells are a significant proportion of leukocytes within tissues, comprising granulocytes, monocytes, dendritic cells, and macrophages. With the identification of various myeloid cells that perform separate but complementary functions during homeostasis and disease, our understanding of tissue myeloid cells has evolved significantly. Exciting findings from transcriptomics profiling and fate-mapping mouse models have facilitated the identification of their developmental origins, maturation, and tissue-specific specializations. This review highlights the current understanding of tissue myeloid cells and the contributing factors of functional heterogeneity to better comprehend the complex and dynamic immune interactions within the healthy or inflamed tissue. Specifically, we discuss the new understanding of the contributions of granulocyte-monocyte progenitor-derived phagocytes to tissue myeloid cell heterogeneity as well as the impact of niche-specific factors on monocyte and neutrophil phenotype and function. Lastly, we explore the developing paradigm of myeloid cell heterogeneity during inflammation and disease.
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Affiliation(s)
- Lai Guan Ng
- Shanghai Immune Therapy Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China;
- Singapore Immunology Network (SIgN), A*STAR (Agency for Science, Technology and Research), Biopolis, Singapore; ,
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Zhaoyuan Liu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Immanuel Kwok
- Singapore Immunology Network (SIgN), ASTAR (Agency for Science, Technology and Research), Biopolis, Singapore; ,
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), ASTAR (Agency for Science, Technology and Research), Biopolis, Singapore; ,
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institut Gustave Roussy, INSERM U1015, Villejuif, France
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore
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13
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Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
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Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
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14
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Guilliams M, Scott CL. Liver macrophages in health and disease. Immunity 2022; 55:1515-1529. [PMID: 36103850 DOI: 10.1016/j.immuni.2022.08.002] [Citation(s) in RCA: 192] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 12/30/2022]
Abstract
Single-cell and spatial transcriptomic technologies have revealed an underappreciated heterogeneity of liver macrophages. This has led us to rethink the involvement of macrophages in liver homeostasis and disease. Identification of conserved gene signatures within these cells across species and diseases is enabling the correct identification of specific macrophage subsets and the generation of more specific tools to track and study the functions of these cells. Here, we discuss what is currently known about the definitions of these different macrophage populations, the markers that can be used to identify them, how they are wired within the liver, and their functional specializations in health and disease.
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Affiliation(s)
- Martin Guilliams
- Laboratory of Myeloid Cell Biology in Tissue Homeostasis and Regeneration, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium.
| | - Charlotte L Scott
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium; Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Technologiepark-Zwijnaarde 71, Ghent 9052, Belgium; Department of Chemical Sciences, Bernal Institute, University of Limerick, Castletroy, County Limerick, Ireland.
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15
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Lebeau G, Ah-Pine F, Daniel M, Bedoui Y, Vagner D, Frumence E, Gasque P. Perivascular Mesenchymal Stem/Stromal Cells, an Immune Privileged Niche for Viruses? Int J Mol Sci 2022; 23:ijms23148038. [PMID: 35887383 PMCID: PMC9317325 DOI: 10.3390/ijms23148038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 07/16/2022] [Accepted: 07/20/2022] [Indexed: 11/16/2022] Open
Abstract
Mesenchymal stem cells (MSCs) play a critical role in response to stress such as infection. They initiate the removal of cell debris, exert major immunoregulatory activities, control pathogens, and lead to a remodeling/scarring phase. Thus, host-derived ‘danger’ factors released from damaged/infected cells (called alarmins, e.g., HMGB1, ATP, DNA) as well as pathogen-associated molecular patterns (LPS, single strand RNA) can activate MSCs located in the parenchyma and around vessels to upregulate the expression of growth factors and chemoattractant molecules that influence immune cell recruitment and stem cell mobilization. MSC, in an ultimate contribution to tissue repair, may also directly trans- or de-differentiate into specific cellular phenotypes such as osteoblasts, chondrocytes, lipofibroblasts, myofibroblasts, Schwann cells, and they may somehow recapitulate their neural crest embryonic origin. Failure to terminate such repair processes induces pathological scarring, termed fibrosis, or vascular calcification. Interestingly, many viruses and particularly those associated to chronic infection and inflammation may hijack and polarize MSC’s immune regulatory activities. Several reports argue that MSC may constitute immune privileged sanctuaries for viruses and contributing to long-lasting effects posing infectious challenges, such as viruses rebounding in immunocompromised patients or following regenerative medicine therapies using MSC. We will herein review the capacity of several viruses not only to infect but also to polarize directly or indirectly the functions of MSC (immunoregulation, differentiation potential, and tissue repair) in clinical settings.
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Affiliation(s)
- Grégorie Lebeau
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Franck Ah-Pine
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Service Anatomo-Pathologie, CHU de la Réunion, 97400 Saint-Denis, France
| | - Matthieu Daniel
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Yosra Bedoui
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Damien Vagner
- Service de Médecine Interne, CHU de la Réunion, 97400 Saint-Denis, France;
| | - Etienne Frumence
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
| | - Philippe Gasque
- Unité de Recherche en Pharmaco-Immunologie (UR-EPI), Université et CHU de La Réunion, 97400 Saint-Denis, France; (G.L.); (F.A.-P.); (M.D.); (Y.B.); (E.F.)
- Laboratoire d’Immunologie Clinique et Expérimentale de la ZOI (LICE-OI), Pôle de Biologie, CHU de La Réunion, 97400 Saint-Denis, France
- Correspondence:
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16
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Fibrogenic Pathways in Metabolic Dysfunction Associated Fatty Liver Disease (MAFLD). Int J Mol Sci 2022; 23:ijms23136996. [PMID: 35805998 PMCID: PMC9266719 DOI: 10.3390/ijms23136996] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 06/07/2022] [Accepted: 06/15/2022] [Indexed: 02/04/2023] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD), recently also re-defined as metabolic dysfunction associated fatty liver disease (MAFLD), is rapidly increasing, affecting ~25% of the world population. MALFD/NAFLD represents a spectrum of liver pathologies including the more benign hepatic steatosis and the more advanced non-alcoholic steatohepatitis (NASH). NASH is associated with enhanced risk for liver fibrosis and progression to cirrhosis and hepatocellular carcinoma. Hepatic stellate cells (HSC) activation underlies NASH-related fibrosis. Here, we discuss the profibrogenic pathways, which lead to HSC activation and fibrogenesis, with a particular focus on the intercellular hepatocyte–HSC and macrophage–HSC crosstalk.
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17
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Lendahl U, Muhl L, Betsholtz C. Identification, discrimination and heterogeneity of fibroblasts. Nat Commun 2022; 13:3409. [PMID: 35701396 PMCID: PMC9192344 DOI: 10.1038/s41467-022-30633-9] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 05/04/2022] [Indexed: 12/14/2022] Open
Abstract
Fibroblasts, the principal cell type of connective tissue, secrete extracellular matrix components during tissue development, homeostasis, repair and disease. Despite this crucial role, the identification and distinction of fibroblasts from other cell types are challenging and laden with caveats. Rapid progress in single-cell transcriptomics now yields detailed molecular portraits of fibroblasts and other cell types in our bodies, which complement and enrich classical histological and immunological descriptions, improve cell class definitions and guide further studies on the functional heterogeneity of cell subtypes and states, origins and fates in physiological and pathological processes. In this review, we summarize and discuss recent advances in the understanding of fibroblast identification and heterogeneity and how they discriminate from other cell types. In this review, the authors look at how recent progress in single-cell transcriptomics complement and enrich the classical, largely morphological, portraits of fibroblasts. The detailed molecular information now available provides new insights into fibroblast identity, heterogeneity and function.
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Affiliation(s)
- Urban Lendahl
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77, Stockholm, Sweden.,Department of Neurobiology, Care sciences and Society, Karolinska Institutet, SE-14183, Huddinge, Sweden
| | - Lars Muhl
- Department of Medicine, Huddinge, Karolinska Institutet, Blickagången 16, SE-141 57, Huddinge, Sweden
| | - Christer Betsholtz
- Department of Medicine, Huddinge, Karolinska Institutet, Blickagången 16, SE-141 57, Huddinge, Sweden. .,Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Dag Hammarskjölds väg 20, SE-751 85, Uppsala, Sweden.
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18
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Abstract
Hepatic macrophages are key immune cells associated with the broad ranges of liver diseases including steatosis, inflammation and fibrosis. Hepatic macrophages interact with other immune cells and orchestrate hepatic immune circumstances. Recently, the heterogenous populations of hepatic macrophages have been discovered termed residential Kupffer cells and monocyte-derived macrophages, and identified their distinct population dynamics during the progression of various liver diseases. Liver injury lead to Kupffer cells activation with induction of inflammatory cytokines and chemokines, which triggers recruitment of inflammatory monocyte-derived macrophages. To understand liver pathology, the functions of different subtypes of liver macrophages should be regarded with different perspectives. In this review, we summarize recent advances in the roles of hepatic macrophages under liver damages and suggest hepatic macrophages as promising therapeutic targets for treating liver diseases.
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Affiliation(s)
- Kyeong-Jin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
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19
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Lee KJ, Kim MY, Han YH. Roles of heterogenous hepatic macrophages in the progression of liver diseases. BMB Rep 2022; 55:166-174. [PMID: 35321784 PMCID: PMC9058466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/02/2022] [Accepted: 03/05/2022] [Indexed: 02/21/2025] Open
Abstract
Hepatic macrophages are key immune cells associated with the broad ranges of liver diseases including steatosis, inflammation and fibrosis. Hepatic macrophages interact with other immune cells and orchestrate hepatic immune circumstances. Recently, the heterogenous populations of hepatic macrophages have been discovered termed residential Kupffer cells and monocyte-derived macrophages, and identified their distinct population dynamics during the progression of various liver diseases. Liver injury lead to Kupffer cells activation with induction of inflammatory cytokines and chemokines, which triggers recruitment of inflammatory monocyte-derived macrophages. To understand liver pathology, the functions of different subtypes of liver macrophages should be regarded with different perspectives. In this review, we summarize recent advances in the roles of hepatic macrophages under liver damages and suggest hepatic macrophages as promising therapeutic targets for treating liver diseases. [BMB Reports 2022; 55(4): 166-174].
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Affiliation(s)
- Kyeong-Jin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Mi-Yeon Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Korea
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20
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Kamm DR, McCommis KS. Hepatic stellate cells in physiology and pathology. J Physiol 2022; 600:1825-1837. [PMID: 35307840 PMCID: PMC9012702 DOI: 10.1113/jp281061] [Citation(s) in RCA: 133] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 02/04/2022] [Indexed: 11/08/2022] Open
Abstract
Hepatic stellate cells (HSCs) comprise a minor cell population in the liver but serve numerous critical functions in the normal liver and in response to injury. HSCs are primarily known for their activation upon liver injury and for producing the collagen-rich extracellular matrix in liver fibrosis. In the absence of liver injury, HSCs reside in a quiescent state, in which their main function appears to be the storage of retinoids or vitamin A-containing metabolites. Less appreciated functions of HSCs include amplifying the hepatic inflammatory response and expressing growth factors that are critical for liver development and both the initiation and termination of liver regeneration. Recent single-cell RNA sequencing studies have corroborated earlier studies indictaing that HSC activation involves a diverse array of phenotypic alterations and identified unique HSC populations. This review serves to highlight these many functions of HSCs, and to briefly describe the recent genetic tools that will help to thoroughly investigate the role of HSCs in hepatic physiology and pathology.
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Affiliation(s)
- Dakota R. Kamm
- Department of Biochemistry & Molecular Biology Saint Louis University School of Medicine St. Louis MO
| | - Kyle S. McCommis
- Department of Biochemistry & Molecular Biology Saint Louis University School of Medicine St. Louis MO
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21
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Papachristoforou E, Ramachandran P. Macrophages as key regulators of liver health and disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 368:143-212. [PMID: 35636927 DOI: 10.1016/bs.ircmb.2022.04.006] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Macrophages are a heterogeneous population of innate immune cells and key cellular components of the liver. Hepatic macrophages consist of embryologically-derived resident Kupffer cells (KC), recruited monocyte-derived macrophages (MDM) and capsular macrophages. Both the diversity and plasticity of hepatic macrophage subsets explain their different functions in the maintenance of hepatic homeostasis and in injury processes in acute and chronic liver diseases. In this review, we assess the evidence for macrophage involvement in regulating both liver health and injury responses in liver diseases including acute liver injury (ALI), chronic liver disease (CLD) (including liver fibrosis) and hepatocellular carcinoma (HCC). In healthy livers, KC display critical functions such as phagocytosis, danger signal recognition, cytokine release, antigen processing and the ability to orchestrate immune responses and maintain immunological tolerance. However, in most liver diseases there is a striking hepatic MDM expansion, which orchestrate both disease progression and regression. Single-cell approaches have transformed our understanding of liver macrophage heterogeneity, dynamics, and functions in both human samples and preclinical models. We will further discuss the new insights provided by these approaches and how they are enabling high-fidelity work to specifically identify pathogenic macrophage subpopulations. Given the important role of macrophages in regulating injury responses in a broad range of settings, there is now a huge interest in developing new therapeutic strategies aimed at targeting macrophages. Therefore, we also review the current approaches being used to modulate macrophage function in liver diseases and discuss the therapeutic potential of targeting macrophage subpopulations as a novel treatment strategy for patients with liver disorders.
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Affiliation(s)
- Eleni Papachristoforou
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom
| | - Prakash Ramachandran
- University of Edinburgh Centre for Inflammation Research, The Queen's Medical Research Institute, Edinburgh BioQuarter, Edinburgh, United Kingdom.
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22
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Hrabák P, Kalousová M, Krechler T, Zima T. Pancreatic stellate cells - rising stars in pancreatic pathologies. Physiol Res 2021. [DOI: 10.33549//physiolres.934783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Pluripotent pancreatic stellate cells (PSCs) receive growing interest in past decades. Two types of PSCs are recognized –vitamin A accumulating quiescent PSCs and activated PSCs- the main producents of extracellular matrix in pancreatic tissue. PSCs plays important role in pathogenesis of pancreatic fibrosis in pancreatic cancer and chronic pancreatitis. PSCs are intensively studied as potential therapeutical target because of their important role in developing desmoplastic stroma in pancreatic cancer. There also exists evidence that PSC are involved in other pathologies like type-2 diabetes mellitus. This article brings brief characteristics of PSCs and recent advances in research of these cells.
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Affiliation(s)
| | - M Kalousová
- 2Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.
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23
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Delgado ME, Cárdenas BI, Farran N, Fernandez M. Metabolic Reprogramming of Liver Fibrosis. Cells 2021; 10:3604. [PMID: 34944111 PMCID: PMC8700241 DOI: 10.3390/cells10123604] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/13/2021] [Accepted: 12/17/2021] [Indexed: 12/12/2022] Open
Abstract
Liver fibrosis is an excessive and imbalanced deposition of fibrous extracellular matrix (ECM) that is associated with the hepatic wound-healing response. It is also the common mechanism that contributes to the impairment of the liver function that is observed in many chronic liver diseases (CLD). Despite the efforts, no effective therapy against fibrosis exists yet. Worryingly, due to the growing obesity pandemic, fibrosis incidence is on the rise. Here, we aim to summarize the main components and mechanisms involved in the progression of liver fibrosis, with special focus on the metabolic regulation of key effectors of fibrogenesis, hepatic stellate cells (HSCs), and their role in the disease progression. Hepatic cells that undergo metabolic reprogramming require a tightly controlled, fine-tuned cellular response, allowing them to meet their energetic demands without affecting cellular integrity. Here, we aim to discuss the role of ribonucleic acid (RNA)-binding proteins (RBPs), whose dynamic nature being context- and stimuli-dependent make them very suitable for the fibrotic situation. Thus, we will not only summarize the up-to-date literature on the metabolic regulation of HSCs in liver fibrosis, but also on the RBP-dependent post-transcriptional regulation of this metabolic switch that results in such important consequences for the progression of fibrosis and CLD.
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Affiliation(s)
- M. Eugenia Delgado
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
| | | | | | - Mercedes Fernandez
- IDIBAPS Biomedical Research Institute, University of Barcelona, 08036 Barcelona, Spain; (B.I.C.); (N.F.)
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24
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Manoukian P, Bijlsma M, van Laarhoven H. The Cellular Origins of Cancer-Associated Fibroblasts and Their Opposing Contributions to Pancreatic Cancer Growth. Front Cell Dev Biol 2021; 9:743907. [PMID: 34646829 PMCID: PMC8502878 DOI: 10.3389/fcell.2021.743907] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 08/30/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic tumors are known to harbor an abundant and highly desmoplastic stroma. Among the various cell types that reside within tumor stroma, cancer-associated fibroblasts (CAFs) have gained a lot of attention in the cancer field due to their contributions to carcinogenesis and tumor architecture. These cells are not a homogeneous population, but have been shown to have different origins, phenotypes, and contributions. In pancreatic tumors, CAFs generally emerge through the activation and/or recruitment of various cell types, most notably resident fibroblasts, pancreatic stellate cells (PSCs), and tumor-infiltrating mesenchymal stem cells (MSCs). In recent years, single cell transcriptomic studies allowed the identification of distinct CAF populations in pancreatic tumors. Nonetheless, the exact sources and functions of those different CAF phenotypes remain to be fully understood. Considering the importance of stromal cells in pancreatic cancer, many novel approaches have aimed at targeting the stroma but current stroma-targeting therapies have yielded subpar results, which may be attributed to heterogeneity in the fibroblast population. Thus, fully understanding the roles of different subsets of CAFs within the stroma, and the cellular dynamics at play that contribute to heterogeneity in CAF subsets may be essential for the design of novel therapies and improving clinical outcomes. Fortunately, recent advances in technologies such as microfluidics and bio-printing have made it possible to establish more advanced ex vivo models that will likely prove useful. In this review, we will present the different roles of stromal cells in pancreatic cancer, focusing on CAF origin as a source of heterogeneity, and the role this may play in therapy failure. We will discuss preclinical models that could be of benefit to the field and that may contribute to further clinical development.
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Affiliation(s)
- Paul Manoukian
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Maarten Bijlsma
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Hanneke van Laarhoven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.,Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
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25
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Cheng D, Chai J, Wang H, Fu L, Peng S, Ni X. Hepatic macrophages: Key players in the development and progression of liver fibrosis. Liver Int 2021; 41:2279-2294. [PMID: 33966318 DOI: 10.1111/liv.14940] [Citation(s) in RCA: 118] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/15/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022]
Abstract
Hepatic fibrosis is a common pathological process involving persistent liver injury with various etiologies and subsequent inflammatory responses that occur in chronic liver diseases. If left untreated, liver fibrosis can progress to liver cirrhosis, hepatocellular carcinoma and eventually, liver failure. Unfortunately, to date, there is no effective treatment for liver fibrosis, with the exception of liver transplantation. Although the pathophysiology of liver fibrosis is multifactorial and includes the activation of hepatic stellate cells, which are known to drive liver fibrogenesis, hepatic macrophages have emerged as central players in the development of liver fibrosis and regression. Hepatic macrophages, which consist of resident macrophages (Kupffer cells) and monocyte-derived macrophages, have been shown to play an intricate role in the initiation of inflammatory responses to liver injury, progression of fibrosis, and promotion of fibrosis resolution. These features have made hepatic macrophages uniquely attractive therapeutic targets in the fight against hepatic fibrosis. In this review, we synthesised the literature to highlight the functions and regulation of heterogeneity in hepatic macrophages. Furthermore, using the existing findings, we attempt to offer insights into the molecular mechanisms underlying the phenotypic switch from fibrogenic macrophages to restorative macrophages, the regulation of heterogeneity, and modes of action for hepatic macrophages. A better understanding of these mechanisms may guide the development of novel anti-fibrotic therapies (eg macrophage subset-targeted treatments) to combat liver fibrosis in the future.
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Affiliation(s)
- Da Cheng
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Jin Chai
- Cholestatic Liver Diseases Center, Department of Gastroenterology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Huiwen Wang
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
| | - Lei Fu
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Shifang Peng
- Department of Infectious Diseases, Xiangya Hospital Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
| | - Xin Ni
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China
- International Collaborative Research Center for Medical Metabolomics, Xiangya Hospital Central South University, Changsha, China
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26
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Roohani S, Tacke F. Liver Injury and the Macrophage Issue: Molecular and Mechanistic Facts and Their Clinical Relevance. Int J Mol Sci 2021; 22:ijms22147249. [PMID: 34298870 PMCID: PMC8306699 DOI: 10.3390/ijms22147249] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 06/28/2021] [Accepted: 07/01/2021] [Indexed: 12/11/2022] Open
Abstract
The liver is an essential immunological organ due to its gatekeeper position to bypassing antigens from the intestinal blood flow and microbial products from the intestinal commensals. The tissue-resident liver macrophages, termed Kupffer cells, represent key phagocytes that closely interact with local parenchymal, interstitial and other immunological cells in the liver to maintain homeostasis and tolerance against harmless antigens. Upon liver injury, the pool of hepatic macrophages expands dramatically by infiltrating bone marrow-/monocyte-derived macrophages. The interplay of the injured microenvironment and altered macrophage pool skews the subsequent course of liver injuries. It may range from complete recovery to chronic inflammation, fibrosis, cirrhosis and eventually hepatocellular cancer. This review summarizes current knowledge on the classification and role of hepatic macrophages in the healthy and injured liver.
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27
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Abstract
Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of a plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it fit a pro- versus anti-inflammatory paradigm. This review presents and discusses current knowledge on the developmental biology of macrophages from an evolutionary perspective focused on the function of macrophages, which may aid in study of developmental, inflammatory, tumoral, and degenerative diseases. We also propose a framework to investigate the functions of macrophages in vivo and discuss how inherited germline and somatic mutations may contribute to the roles of macrophages in diseases.
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Affiliation(s)
- Nehemiah Cox
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Maria Pokrovskii
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
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28
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Blériot C, Chakarov S, Ginhoux F. Determinants of Resident Tissue Macrophage Identity and Function. Immunity 2021; 52:957-970. [PMID: 32553181 DOI: 10.1016/j.immuni.2020.05.014] [Citation(s) in RCA: 324] [Impact Index Per Article: 81.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/27/2020] [Accepted: 05/27/2020] [Indexed: 12/23/2022]
Abstract
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. We review recent findings within this context and discuss the technological advances that are revolutionizing the study of macrophage biology.
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Affiliation(s)
- Camille Blériot
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore
| | - Svetoslav Chakarov
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore 169856, Singapore.
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29
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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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30
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Meijer EM, van Dijk CGM, Kramann R, Verhaar MC, Cheng C. Implementation of Pericytes in Vascular Regeneration Strategies. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:1-21. [PMID: 33231500 DOI: 10.1089/ten.teb.2020.0229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
For the survival and integration of complex large-sized tissue-engineered (TE) organ constructs that exceed the maximal nutrients and oxygen diffusion distance required for cell survival, graft (pre)vascularization to ensure medium or blood supply is crucial. To achieve this, the morphology and functionality of the microcapillary bed should be mimicked by incorporating vascular cell populations, including endothelium and mural cells. Pericytes play a crucial role in microvascular function, blood vessel stability, angiogenesis, and blood pressure regulation. In addition, tissue-specific pericytes are important in maintaining specific functions in different organs, including vitamin A storage in the liver, renin production in the kidneys and maintenance of the blood-brain-barrier. Together with their multipotential differentiation capacity, this makes pericytes the preferred cell type for application in TE grafts. The use of a tissue-specific pericyte cell population that matches the TE organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)-vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts. Impact statement The use of a tissue-specific pericyte cell population that matches the tissue-engineered (TE) organ may benefit organ function. In this review, we provide an overview of the literature for graft (pre)vascularization strategies and highlight the possible advantages of using tissue-specific pericytes for specific TE organ grafts.
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Affiliation(s)
- Elana M Meijer
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Christian G M van Dijk
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Rafael Kramann
- Division of Nephrology and Institute of Experimental Medicine and Systems Biology, University Hospital RWTH Aachen, Aachen, Germany.,Department of Internal Medicine, Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Caroline Cheng
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands.,Experimental Cardiology, Department of Cardiology, Thorax Center Erasmus University Medical Center, Rotterdam, The Netherlands
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31
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Blériot C, Ginhoux F. Understanding the Heterogeneity of Resident Liver Macrophages. Front Immunol 2019; 10:2694. [PMID: 31803196 PMCID: PMC6877662 DOI: 10.3389/fimmu.2019.02694] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/01/2019] [Indexed: 12/28/2022] Open
Abstract
Resident tissue macrophages (RTMs) are cells with a high functional plasticity assuming pleiotropic roles in their tissue of residence, from clearance of dead cells and metabolic sensing in steady state to cytokine production and tissue repair during inflammation. The liver has long been considered as only populated by Kupffer cells (KCs), a macrophage population assumed to be in charge of all of these functions. However, we know now that KCs are not the only macrophage population in the liver, that recently was shown to contain also capsular macrophages, monocyte-derived macrophages as well as recruited peritoneal macrophages inherited from previous inflammatory events. These macrophages exhibit different origins, time of establishing residence and locations in the liver, with both ontogenical and environmental factors shaping their identity and functions. Furthermore, liver macrophages reside in a complex environment with a pronounced metabolic zonation. Here, we briefly discuss how these intrinsic and extrinsic factors influence macrophage biology and liver physiology in general. We notably focus on how the recent advances of single cell transcriptomic approaches are changing our understanding of liver macrophages and diseases.
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Affiliation(s)
- Camille Blériot
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Singapore, Singapore.,Shanghai Institute of Immunology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.,Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
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32
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Bonnardel J, T'Jonck W, Gaublomme D, Browaeys R, Scott CL, Martens L, Vanneste B, De Prijck S, Nedospasov SA, Kremer A, Van Hamme E, Borghgraef P, Toussaint W, De Bleser P, Mannaerts I, Beschin A, van Grunsven LA, Lambrecht BN, Taghon T, Lippens S, Elewaut D, Saeys Y, Guilliams M. Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche. Immunity 2019; 51:638-654.e9. [PMID: 31561945 PMCID: PMC6876284 DOI: 10.1016/j.immuni.2019.08.017] [Citation(s) in RCA: 408] [Impact Index Per Article: 68.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Revised: 06/28/2019] [Accepted: 08/20/2019] [Indexed: 02/07/2023]
Abstract
Macrophages are strongly adapted to their tissue of residence. Yet, little is known about the cell-cell interactions that imprint the tissue-specific identities of macrophages in their respective niches. Using conditional depletion of liver Kupffer cells, we traced the developmental stages of monocytes differentiating into Kupffer cells and mapped the cellular interactions imprinting the Kupffer cell identity. Kupffer cell loss induced tumor necrosis factor (TNF)- and interleukin-1 (IL-1) receptor-dependent activation of stellate cells and endothelial cells, resulting in the transient production of chemokines and adhesion molecules orchestrating monocyte engraftment. Engrafted circulating monocytes transmigrated into the perisinusoidal space and acquired the liver-associated transcription factors inhibitor of DNA 3 (ID3) and liver X receptor-α (LXR-α). Coordinated interactions with hepatocytes induced ID3 expression, whereas endothelial cells and stellate cells induced LXR-α via a synergistic NOTCH-BMP pathway. This study shows that the Kupffer cell niche is composed of stellate cells, hepatocytes, and endothelial cells that together imprint the liver-specific macrophage identity.
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Affiliation(s)
- Johnny Bonnardel
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
| | - Wouter T'Jonck
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Djoere Gaublomme
- Unit for Molecular Immunology and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Robin Browaeys
- Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | - Charlotte L Scott
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
| | - Liesbet Martens
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium
| | - Bavo Vanneste
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sofie De Prijck
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sergei A Nedospasov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia
| | - Anna Kremer
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB BioImaging Core, VIB, Ghent, Belgium
| | - Evelien Van Hamme
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB BioImaging Core, VIB, Ghent, Belgium
| | - Peter Borghgraef
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB BioImaging Core, VIB, Ghent, Belgium
| | - Wendy Toussaint
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium
| | - Pieter De Bleser
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium
| | - Inge Mannaerts
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Alain Beschin
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Leo A van Grunsven
- Liver Cell Biology Research Group, Vrije Universiteit Brussel, Brussels, Belgium
| | - Bart N Lambrecht
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory of Mucosal Immunology and Immunoregulation, VIB Center for Inflammation Research, Ghent, Belgium
| | - Tom Taghon
- Department of Diagnostic Sciences, Ghent University, Ghent, Belgium
| | - Saskia Lippens
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium; VIB BioImaging Core, VIB, Ghent, Belgium
| | - Dirk Elewaut
- Unit for Molecular Immunology and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Yvan Saeys
- Data Mining and Modeling for Biomedicine, VIB Center for Inflammation Research, Ghent, Belgium; Department of Applied Mathematics, Computer Science and Statistics, Ghent University, Ghent, Belgium
| | - Martin Guilliams
- Laboratory of Myeloid Cell Ontogeny and Functional Specialization, VIB Center for Inflammation Research, Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
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33
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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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34
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Theret M, Mounier R, Rossi F. The origins and non-canonical functions of macrophages in development and regeneration. Development 2019; 146:146/9/dev156000. [PMID: 31048317 DOI: 10.1242/dev.156000] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The discovery of new non-canonical (i.e. non-innate immune) functions of macrophages has been a recurring theme over the past 20 years. Indeed, it has emerged that macrophages can influence the development, homeostasis, maintenance and regeneration of many tissues and organs, including skeletal muscle, cardiac muscle, the brain and the liver, in part by acting directly on tissue-resident stem cells. In addition, macrophages play crucial roles in diseases such as obesity-associated diabetes or cancers. Increased knowledge of their regulatory roles within each tissue will therefore help us to better understand the full extent of their functions and could highlight new mechanisms modulating disease pathogenesis. In this Review, we discuss recent studies that have elucidated the developmental origins of various macrophage populations and summarize our knowledge of the non-canonical functions of macrophages in development, regeneration and tissue repair.
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Affiliation(s)
- Marine Theret
- Department of Medical Genetics, The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.,Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
| | - Remi Mounier
- Institut Neuromyogène, CNRS UMR 5310, INSERM U1217, Université de Lyon, 69008 Lyon, France
| | - Fabio Rossi
- Department of Medical Genetics, The Biomedical Research Centre, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada .,Faculty of Medicine, The University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada
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35
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Shang L, Hosseini M, Liu X, Kisseleva T, Brenner DA. Human hepatic stellate cell isolation and characterization. J Gastroenterol 2018; 53:6-17. [PMID: 29094206 DOI: 10.1007/s00535-017-1404-4] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 09/22/2017] [Indexed: 02/04/2023]
Abstract
The hepatic stellate cells (HSCs) localize at the space of Disse in the liver and have multiple functions. They are identified as the major contributor to hepatic fibrosis. Significant understanding of HSCs has been achieved using rodent models and isolated murine HSCs; as well as investigating human liver tissues and human HSCs. There is growing interest and need of translating rodent study findings to human HSCs and human liver diseases. However, species-related differences impose challenges on the translational research. In this review, we focus on the current information on human HSCs isolation methods, human HSCs markers, and established human HSC cell lines.
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Affiliation(s)
- Linshan Shang
- Department of Medicine, University of California, San Diego, La Jolla, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California, San Diego, La Jolla, USA
| | - Xiao Liu
- Department of Surgery, University of California, San Diego, La Jolla, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, USA
| | - David Allen Brenner
- Department of Medicine, University of California, San Diego, La Jolla, USA.
- School of Medicine, UC San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0602, USA.
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36
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Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol 2017; 66:1300-1312. [PMID: 28267621 DOI: 10.1016/j.jhep.2017.02.026] [Citation(s) in RCA: 717] [Impact Index Per Article: 89.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 02/19/2017] [Accepted: 02/23/2017] [Indexed: 12/24/2022]
Abstract
UNLABELLED Our view on liver macrophages in the context of health and disease has been reformed by the recognition of a remarkable heterogeneity of phagocytes in the liver. Liver macrophages consist of ontogenically distinct populations termed Kupffer cells and monocyte-derived macrophages. Kupffer cells are self-renewing, resident and principally non-migratory phagocytes, serving as sentinels for liver homeostasis. Liver injury triggers Kupffer cell activation, leading to inflammatory cytokine and chemokine release. This fosters the infiltration of monocytes into the liver, which give rise to large numbers of inflammatory monocyte-derived macrophages. Liver macrophages are very plastic and adapt their phenotype according to signals derived from the hepatic microenvironment (e.g. danger signals, fatty acids, phagocytosis of cellular debris), which explains their manifold and even opposing functions during disease. These central functions include the perpetuation of inflammation and hepatocyte injury, activation of hepatic stellate cells with subsequent fibrogenesis, and support of tumor development by angiogenesis and T cell suppression. If liver injury ceases, specific molecular signals trigger hepatic macrophages to switch their phenotype towards reparative phagocytes that promote tissue repair and regression of fibrosis. Novel strategies to treat liver disease aim at targeting macrophages. These interventions modulate Kupffer cell activation (e.g. via gut-liver axis or inflammasome formation), monocyte recruitment (e.g. via inhibiting chemokine pathways like CCR2 or CCL2) or macrophage polarization and differentiation (e.g. by nanoparticles). Evidence from mouse models and early clinical studies in patients with non-alcoholic steatohepatitis and fibrosis support the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with liver disease. LAY SUMMARY Macrophages (Greek for "big eaters") are a frequent non-parenchymal cell type of the liver that ensures homeostasis, antimicrobial defense and proper metabolism. However, liver macrophages consist of different subtypes regarding their ontogeny (developmental origin), differentiation and function. Understanding this heterogeneity and the critical regulation of inflammation, fibrosis and cancer by macrophage subsets opens promising new options for treating liver diseases.
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Affiliation(s)
- Frank Tacke
- Department of Medicine III, University Hospital Aachen, Aachen, Germany.
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37
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Abstract
Macrophages represent a key cellular component of the liver, and are essential for maintaining tissue homeostasis and ensuring rapid responses to hepatic injury. Our understanding of liver macrophages has been revolutionized by the delineation of heterogeneous subsets of these cells. Kupffer cells are a self-sustaining, liver-resident population of macrophages and can be distinguished from the monocyte-derived macrophages that rapidly accumulate in the injured liver. Specific environmental signals further determine the polarization and function of hepatic macrophages. These cells promote the restoration of tissue integrity following liver injury or infection, but they can also contribute to the progression of liver diseases, including hepatitis, fibrosis and cancer. In this Review, we highlight novel findings regarding the origin, classification and function of hepatic macrophages, and we discuss their divergent roles in the healthy and diseased liver.
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Affiliation(s)
- Oliver Krenkel
- Department of Medicine III, University Hospital Aachen, D-52074 Aachen, Germany
| | - Frank Tacke
- Department of Medicine III, University Hospital Aachen, D-52074 Aachen, Germany
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38
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The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
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39
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40
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Kierdorf K, Prinz M, Geissmann F, Gomez Perdiguero E. Development and function of tissue resident macrophages in mice. Semin Immunol 2015; 27:369-78. [PMID: 27036090 PMCID: PMC4948121 DOI: 10.1016/j.smim.2016.03.017] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 03/22/2016] [Indexed: 12/24/2022]
Abstract
Macrophages are important for tissue development, homeostasis as well as immune response upon injury or infection. For a long time they were only seen as one uniform group of phagocytes with a common origin and similar functions. However, this view has been challenged in the last decade and revealed a complex diversity of tissue resident macrophages. Here, we want to present the current view on macrophage development and tissue specification and we will discuss differences as well as common patterns between heterogeneous macrophage subpopulations.
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Affiliation(s)
- Katrin Kierdorf
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London, UK
| | - Marco Prinz
- Institute of Neuropathology, University Freiburg, Freiburg, Germany; BIOSS Centre for Biological Signaling Studies, University of Freiburg, Freiburg, Germany
| | - Frederic Geissmann
- Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London, UK; Immunology Program, Memorial Sloan Kettering Cancer Center, NY, NY, USA
| | - Elisa Gomez Perdiguero
- Macrophages and Endothelial Cells group, Department of Developmental and Stem Cell Biology, CNRS UMR 3738, Institut Pasteur, Paris, France.
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Suraweera DB, Weeratunga AN, Hu RW, Pandol SJ, Hu R. Alcoholic hepatitis: The pivotal role of Kupffer cells. World J Gastrointest Pathophysiol 2015; 6:90-98. [PMID: 26600966 PMCID: PMC4644891 DOI: 10.4291/wjgp.v6.i4.90] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/27/2015] [Accepted: 09/08/2015] [Indexed: 02/06/2023] Open
Abstract
Kupffer cells play a central role in the pathogenesis of alcoholic hepatitis (AH). It is believed that alcohol increases the gut permeability that results in raised levels of serum endotoxins containing lipopolysaccharides (LPS). LPS binds to LPS-binding proteins and presents it to a membrane glycoprotein called CD14, which then activates Kupffer cells via a receptor called toll-like receptor 4. This endotoxin mediated activation of Kupffer cells plays an important role in the inflammatory process resulting in alcoholic hepatitis. There is no effective treatment for AH, although notable progress has been made over the last decade in understanding the underlying mechanism of alcoholic hepatitis. We specifically review the current research on the role of Kupffer cells in the pathogenesis of AH and the treatment strategies. We suggest that the imbalance between the pro-inflammatory and the anti-inflammatory process as well as the increased production of reactive oxygen species eventually lead to hepatocyte injury, the final event of alcoholic hepatitis.
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Wake K, Sato T. "The sinusoid" in the liver: lessons learned from the original definition by Charles Sedgwick Minot (1900). Anat Rec (Hoboken) 2015; 298:2071-80. [PMID: 26332299 DOI: 10.1002/ar.23263] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 02/05/2015] [Accepted: 02/17/2015] [Indexed: 11/06/2022]
Abstract
The hepatic sinusoid with its associated sinusoidal cells is a multifunctional cell-complex in the liver. Despite recent advances in research on the hepatic sinusoid, no investigator has played a more basic role in its characterization than Charles Sedgwick Minot (1852-1914), a pioneer who distinguished the sinusoid from the blood-capillary as early as 1900. According to Minot, sinusoids are typically larger in diameter than capillaries, particularly at the early embryonic stage. They closely approach the parenchymal tissue, are formed passively by the adjacent parenchymal tissue, and are on rare occasion surrounded with connective tissue. Sinusoids (sinus-like) are small blood-channels formed by subdivision of the lumen of large blood vessels (sinuses) by the invasion of developing parenchymal cell-cords. Although some of Minot's definitions may no longer be accepted, he described some fundamental and interesting characteristics of sinusoids, to which we have not paid much attention. Here, we have attempted to illustrate lessons we have learned from Minot's view point of sinusoids at this occasion of centenary of his death.
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Affiliation(s)
- Kenjiro Wake
- Department of Anatomy, Tissue and Cell Biology, School of Dental Medicine, Tsurumi University, Tsurumi, Yokohama, Japan.,Liver Research Unit, Minophagen Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Tetsuji Sato
- Department of Anatomy, Tissue and Cell Biology, School of Dental Medicine, Tsurumi University, Tsurumi, Yokohama, Japan
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All-In-One: Advanced preparation of Human Parenchymal and Non-Parenchymal Liver Cells. PLoS One 2015; 10:e0138655. [PMID: 26407160 PMCID: PMC4583235 DOI: 10.1371/journal.pone.0138655] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
Background & Aims Liver cells are key players in innate immunity. Thus, studying primary isolated liver cells is necessary for determining their role in liver physiology and pathophysiology. In particular, the quantity and quality of isolated cells are crucial to their function. Our aim was to isolate a large quantity of high-quality human parenchymal and non-parenchymal cells from a single liver specimen. Methods Hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and stellate cells were isolated from liver tissues by collagenase perfusion in combination with low-speed centrifugation, density gradient centrifugation, and magnetic-activated cell sorting. The purity and functionality of cultured cell populations were controlled by determining their morphology, discriminative cell marker expression, and functional activity. Results Cell preparation yielded the following cell counts per gram of liver tissue: 2.0±0.4×107 hepatocytes, 1.8±0.5×106 Kupffer cells, 4.3±1.9×105 liver sinusoidal endothelial cells, and 3.2±0.5×105 stellate cells. Hepatocytes were identified by albumin (95.5±1.7%) and exhibited time-dependent activity of cytochrome P450 enzymes. Kupffer cells expressed CD68 (94.5±1.2%) and exhibited phagocytic activity, as determined with 1μm latex beads. Endothelial cells were CD146+ (97.8±1.1%) and exhibited efficient uptake of acetylated low-density lipoprotein. Hepatic stellate cells were identified by the expression of α-smooth muscle actin (97.1±1.5%). These cells further exhibited retinol (vitamin A)-mediated autofluorescence. Conclusions Our isolation procedure for primary parenchymal and non-parenchymal liver cells resulted in cell populations of high purity and quality, with retained physiological functionality in vitro. Thus, this system may provide a valuable tool for determining liver function and disease.
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Usta OB, McCarty WJ, Bale S, Hegde M, Jindal R, Bhushan A, Golberg I, Yarmush ML. Microengineered cell and tissue systems for drug screening and toxicology applications: Evolution of in-vitro liver technologies. TECHNOLOGY 2015; 3:1-26. [PMID: 26167518 PMCID: PMC4494128 DOI: 10.1142/s2339547815300012] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
The liver performs many key functions, the most prominent of which is serving as the metabolic hub of the body. For this reason, the liver is the focal point of many investigations aimed at understanding an organism's toxicological response to endogenous and exogenous challenges. Because so many drug failures have involved direct liver toxicity or other organ toxicity from liver generated metabolites, the pharmaceutical industry has constantly sought superior, predictive in-vitro models that can more quickly and efficiently identify problematic drug candidates before they incur major development costs, and certainly before they are released to the public. In this broad review, we present a survey and critical comparison of in-vitro liver technologies along a broad spectrum, but focus on the current renewed push to develop "organs-on-a-chip". One prominent set of conclusions from this review is that while a large body of recent work has steered the field towards an ever more comprehensive understanding of what is needed, the field remains in great need of several key advances, including establishment of standard characterization methods, enhanced technologies that mimic the in-vivo cellular environment, and better computational approaches to bridge the gap between the in-vitro and in-vivo results.
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Affiliation(s)
- O B Usta
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - W J McCarty
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - S Bale
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - M Hegde
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - R Jindal
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - A Bhushan
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - I Golberg
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA
| | - M L Yarmush
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, MA 02114, USA ; Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd., Piscataway, NJ 08854, USA
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Damm G, Pfeiffer E, Burkhardt B, Vermehren J, Nüssler AK, Weiss TS. Human parenchymal and non-parenchymal liver cell isolation, culture and characterization. Hepatol Int 2013; 7:951-958. [PMID: 26202025 DOI: 10.1007/s12072-013-9475-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 09/11/2013] [Indexed: 02/06/2023]
Abstract
Many reports describing parenchymal liver cell isolation have been published so far. However, recent evidence has clearly demonstrated that non-parenchymal liver cells play an important role in many pathophysiologies of the liver, such as drug-induced liver diseases, inflammation, and the development of liver fibrosis and cirrhosis. In this study, we present an overview of the current methods for isolating and characterizing parenchymal and non-parenchymal liver cells.
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Affiliation(s)
- Georg Damm
- Charité University Medicine Berlin, Department of General, Visceral, and Transplant Surgery, Augustenburger Platz 1, 13353, Berlin, Germany.
| | - Elisa Pfeiffer
- Charité University Medicine Berlin, Department of General, Visceral, and Transplant Surgery, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Britta Burkhardt
- Eberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, BG-Tübingen, Siegfried Weller Institut, Schnarrenbergstr. 95, 72076, Tübingen, Germany
| | - Jan Vermehren
- Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Germany
| | - Andreas K Nüssler
- Eberhard Karls University Tübingen, BG Trauma Center, Siegfried Weller Institut, BG-Tübingen, Siegfried Weller Institut, Schnarrenbergstr. 95, 72076, Tübingen, Germany.
| | - Thomas S Weiss
- Department of Pediatrics and Juvenile Medicine, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, 93053, Regensburg, Germany.
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Froh M, Konno A, Thurman RG. Isolation of liver Kupffer cells. ACTA ACUST UNITED AC 2013; Chapter 14:Unit14.4. [PMID: 23045093 DOI: 10.1002/0471140856.tx1404s14] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of several diseases. This unit contains an easy-to-follow procedure for effective isolation of liver Kupffer cells from rats and mice. The protocol provides viable Kupffer cells in large amounts that can be used for further investigations.
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Fan WM, Liu DZ, Xiao L, Ma XH, Shi BY. Isolation of hepatic stellate cells by in vitro digestion. Shijie Huaren Xiaohua Zazhi 2012; 20:3244-3247. [DOI: 10.11569/wcjd.v20.i33.3244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To improve the Weiskirchen's method for isolation of hepatic stellate cells (HSCs) and increase cell purity and rate of survival.
METHODS: HSCs were isolated based on the Weiskirchen's method with some modifications. The rat liver was perfused with 0.25% pronase E after seperating in vitro. After digestion with 0.025% collagen IV and 0.01% DNAse I, cell homogenates were filtered using a cell mesh and centrifuged. Cell pellet was then subjected to density gradient centrifugation in the presence of 18% Nycodenz stock solution. The white cell layer was HSCs. Cell viability was assessed by trypan blue exclusion staining. The purity of HSCs was evaluated by immunocytochemistry to detect the expression of desmin.
RESULTS: The yield rate of HSCs was 2.7 × 107 per rat. The purity of HSCs was 90% and cell viability was 99%. This method could effectively reduce cell contamination and increase cell viability.
CONCLUSION: Our improved method for isolation of HSCs by in vitro digestion is simple and efficient, because it can avoid contamination and increase cell purity and survival.
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Senoo H, Imai K, Mezaki Y, Miura M, Morii M, Fujiwara M, Blomhoff R. Accumulation of Vitamin A in the Hepatic Stellate Cell of Arctic Top Predators. Anat Rec (Hoboken) 2012; 295:1660-8. [DOI: 10.1002/ar.22555] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2012] [Revised: 04/11/2012] [Accepted: 06/14/2012] [Indexed: 11/12/2022]
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Tacke F, Weiskirchen R. Update on hepatic stellate cells: pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev Gastroenterol Hepatol 2012; 6:67-80. [PMID: 22149583 DOI: 10.1586/egh.11.92] [Citation(s) in RCA: 147] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cells (HSCs), also called Ito cells or lipocytes, are vitamin A-storing cells located in the Dissé space between hepatocytes and sinusoidal endothelial cells. Upon liver injury, these cells transdifferentiate into extracellular matrix-producing, highly proliferative myofibroblasts that promote hepatic fibrogenesis. Other possible collagen-producing cells in liver fibrosis include portal fibroblasts, bone marrow-derived cells (mesenchymal stem cells, fibrocytes and hematopoietic cells) and parenchymal cells undergoing epithelial-to-mesenchymal transition. Important factors and signaling pathways for HSC activation, as well as different functions of HSC during homeostasis and fibrosis, such as collagen production, secretion of cytokines and chemokines, immune modulation and changes in contractile features, as well as vitamin A storage capacity, have been identified in vitro and in vivo. Novel isolation techniques, specifically HSC sorting by FACS via autofluorescence and antibodies, will provide us with further opportunities to advance our understanding of HSC biology in health and disease.
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Affiliation(s)
- Frank Tacke
- Department of Medicine III RWTH, University Hospital Aachen, Aachen, Germany.
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Tailleux A, Wouters K, Staels B. Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta Mol Cell Biol Lipids 2011; 1821:809-18. [PMID: 22056763 DOI: 10.1016/j.bbalip.2011.10.016] [Citation(s) in RCA: 205] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Revised: 10/14/2011] [Accepted: 10/18/2011] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a liver pathology with increasing prevalence due to the obesity epidemic. Hence, NAFLD represents a rising threat to public health. Currently, no effective treatments are available to treat NAFLD and its complications such as cirrhosis and liver cancer. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors which regulate lipid and glucose metabolism as well as inflammation. Here we review recent findings on the pathophysiological role of PPARs in the different stages of NAFLD, from steatosis development to steatohepatitis and fibrosis, as well as the preclinical and clinical evidence for potential therapeutical use of PPAR agonists in the treatment of NAFLD. PPARs play a role in modulating hepatic triglyceride accumulation, a hallmark of the development of NAFLD. Moreover, PPARs may also influence the evolution of reversible steatosis toward irreversible, more advanced lesions. Presently, large controlled trials of long duration are needed to assess the long-term clinical benefits of PPAR agonists in humans. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.
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Affiliation(s)
- Anne Tailleux
- Université Lille Nord de France, F-59000 Lille, France
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