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1
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Johnston EK, Fang Z, Soto-Gutierrez A, Taner CB, Cook KE, Yang L, Abbott RD. Engineering a three-dimensional liver steatosis model. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167888. [PMID: 40328412 DOI: 10.1016/j.bbadis.2025.167888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Revised: 04/28/2025] [Accepted: 05/02/2025] [Indexed: 05/08/2025]
Abstract
Liver transplantation is the key treatment for liver failure, yet organ scarcity, exacerbated by high discard rates of steatotic livers, leads to high waitlist mortality. Preclinical models of steatosis are necessary to understand the pathophysiology of the disease and to develop pharmacological interventions to decrease disease burden and liver discard rate. In this paper, we develop an expedited 3D steatotic organoid model containing primary human hepatocytes and non-parenchymal cells. We present our iterative approach as we transition from 2D to 3D models and from immortalized to primary cells to optimize conditions for the development of a 3D human steatosis model. Both primary cell aggregation and steatosis induction time were reduced from the standard, 5-7 days, to 2 days. Our 3D model incorporates human primary hepatocytes from discarded liver tissues, which have not been used in organoids previously due to their rapid loss of phenotype in culture. After optimizing our steatosis induction media there was a mix of macro- and micro-steatosis in these primary hepatocytes which is consistent with the human pathology. Our approach achieves a model reflective of the liver pathology, preserving cellular phenotypes and viability while exhibiting markers of oxidative stress, a key factor contributing to complications in the transplantation of steatotic livers.
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Affiliation(s)
- Elizabeth K Johnston
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Zhou Fang
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | | | - C Burcin Taner
- Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Keith E Cook
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA
| | - Liu Yang
- Department of Transplantation, Mayo Clinic, Jacksonville, FL 32224, USA
| | - Rosalyn D Abbott
- Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
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2
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Ning M, Lu D, Liang D, Ren PG. Single-cell RNA sequencing advances in revealing the development and progression of MASH: the identifications and interactions of non-parenchymal cells. Front Mol Biosci 2025; 12:1513993. [PMID: 40201243 PMCID: PMC11976672 DOI: 10.3389/fmolb.2025.1513993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Developing drugs for the treatment of Metabolic Associated Steatohepatitis (MASH) has always been a significant challenge. Researchers have been dedicated to exploring drugs and therapeutic strategies to alleviate disease progression, but treatments remain limited. This is partly due to the complexity of the pathophysiological processes, and inadequate knowledge of the cellular and molecular mechanisms in MASH. Especially, the liver non-parenchymal cells (NPCs) like Kupffer cells, hepatic stellate cells and sinusoidal endothelial cells which play critical roles in live function, immune responses, fibrosis and disease progression. Deciphering how these cells function in MASH, would help understand the pathophysiological processes and find potential drug targets. In recent years, new technologies have been developed for single-cell transcriptomic sequencing, making cell-specific transcriptome profiling a reality in healthy and diseased livers. In this review, we discussed how the use of single-cell transcriptomic sequencing provided us with an in-depth understanding of the heterogeneous, cellular interactions among non-parenchymal cells and tried to highlight recent discoveries in MASH by this technology. It is hoped that the summarized features and markers of various subclusters in this review could provide a technical reference for further experiments and a theoretical basis for clinical applications.
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Affiliation(s)
- Meng Ning
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Department of Endocrinology, First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Donghui Lu
- Department of Endocrinology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Dong Liang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Pei-Gen Ren
- Center for Cancer Immunology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- University of Chinese Academy of Sciences, Beijing, China
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3
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Yu Y, Tao Y, Ma J, Li J, Song Z. Targeting the tumor microenvironment with mesenchymal stem cells based delivery approach for efficient delivery of anticancer agents: An updated review. Biochem Pharmacol 2025; 232:116725. [PMID: 39746456 DOI: 10.1016/j.bcp.2024.116725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/14/2024] [Accepted: 12/18/2024] [Indexed: 01/04/2025]
Abstract
Drug delivery to cancer cells continues to present a major therapeutic challenge. Mesenchymal stem cells (MSCs) possess an intrinsic ability to migrate specifically to tumor tissues, making them promising candidates for targeted drug delivery. Evidence from preclinical studies indicates that MSCs loaded with therapeutic anti-cancer agents exhibit considerable anti-tumor activity. Moreover, several clinical trials are currently evaluating their effectiveness in cancer patients. The integration of MSCs with synthetic nanoparticles (NPs) enhances their therapeutic potential, particularly through the use of cell membrane-coated NPs, which represent a significant advancement in the field. This review systematically investigates the tumor microenvironment, the sources of MSCs, the tumor homing mechanisms, and the methods of loading and releasing anticancer drugs from MSCs. Furthermore, cutting-edge strategies to improve the efficacy of MSCs based drug delivery systems (DDS) including the innovative use of MSC membrane coated nanoparticles have been discussed. The study concludes with an overview of the therapeutic use of MSCs as drug carriers, including a detailed analysis of the mechanisms by which MSCs deliver therapeutics to cancer cells, enabling targeted drug delivery. It aims to elucidate the current state of this approach, identify key areas for development, and outline potential future directions for advancing MSCs based cancer therapies.
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Affiliation(s)
- Yang Yu
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun 130000, China
| | - Ying Tao
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun 130000, China
| | - Jingru Ma
- Department of Clinical Laboratory, the Second Hospital of Jilin University, Changchun 130000, China
| | - Jian Li
- Department of Emergency and Critical Care, the Second Hospital of Jilin University, Changchun 130000, China
| | - Zhidu Song
- Department of Ophthalmology, the Second Hospital of Jilin University, Changchun 130000, China.
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Porada M, Bułdak Ł. From Pathophysiology to Practice: Evolving Pharmacological Therapies, Clinical Complications, and Pharmacogenetic Considerations in Portal Hypertension. Metabolites 2025; 15:72. [PMID: 39997697 PMCID: PMC11857179 DOI: 10.3390/metabo15020072] [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] [Received: 12/11/2024] [Revised: 01/07/2025] [Accepted: 01/18/2025] [Indexed: 02/26/2025] Open
Abstract
Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.
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Affiliation(s)
- Michał Porada
- Students’ Scientific Society, Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland;
| | - Łukasz Bułdak
- Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Medyków 18, 40-752 Katowice, Poland
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Yamagata K, Takasuga S, Tatematsu M, Fuchimukai A, Yamada T, Mizuno M, Morii M, Ebihara T. FoxD1 expression identifies a distinct subset of hepatic stellate cells involved in liver fibrosis. Biochem Biophys Res Commun 2024; 734:150632. [PMID: 39226736 DOI: 10.1016/j.bbrc.2024.150632] [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: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/05/2024]
Abstract
Hepatic stellate cells (HSCs) are pericytes of the liver responsible for liver fibrosis and cirrhosis, which are the end stages of chronic liver diseases. TGF-β activates HSCs, leading to the differentiation of myofibroblasts in the process of liver fibrosis. While the heterogeneity of HSCs is appreciated in the fibrotic liver, it remains elusive which HSC subsets mainly contribute to fibrosis. Here, we show that the expression of the pericyte marker FoxD1 specifically marks a subset of HSCs in FoxD1-fate tracer mice. HSCs fate-mapped by FoxD1 were preferentially localized in the portal and peripheral areas of both the homeostatic and fibrotic liver induced by carbon tetrachloride. Furthermore, the deletion of Cbfβ, which is necessary for TGF-β signaling, in FoxD1-expressing cells ameliorated liver fibrosis. Thus, we identified an HSC subset that preferentially responds to liver injuries.
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Affiliation(s)
- Kenki Yamagata
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan; Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Shunsuke Takasuga
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Megumi Tatematsu
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Akane Fuchimukai
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Toshiki Yamada
- Department of Otorhinolaryngology, Head and Neck Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Masaru Mizuno
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan
| | - Mayako Morii
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita, 0108543, Japan.
| | - Takashi Ebihara
- Department of Medical Biology, Akita University Graduate School of Medicine, Akita, 0108543, Japan; Center for Integrated Control, Epidemiology and Molecular Pathophysiology of Infectious Diseases, Akita University, Akita, 0108543, Japan.
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Li Z, Ma Y, Fan C, Jiang H. The circAno6/miR-296-3p/TLR4 signaling axis mediates the inflammatory response to induce the activation of hepatic stellate cells. Gene 2024; 920:148497. [PMID: 38677350 DOI: 10.1016/j.gene.2024.148497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2024] [Revised: 03/29/2024] [Accepted: 04/22/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Circular RNA (circRNA) is a novel functional non-coding RNA(ncRNA) that plays a role in the occurrence and development of multiple human liver diseases, including liver fibrosis (LF). LF is a reversible repair response after liver injury, and the activation of hepatic stellate cells (HSCs) is the core event. However, the regulatory mechanisms by which circRNAs induce the activation of HSCs in LF are still poorly understood. The circAno6/miR-296-3p/toll-like receptor 4 (TLR4) signaling axis that mediates the inflammatory response and causes the activation of HSCs was investigated in this study. METHODS First, a circAno6 overexpression plasmid and small interfering RNA were transfected into cells to determine whether circAno6 can affect the function of HSCs. Second, real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), western blotting (WB) and immunofluorescence (IF) were used to detect the effects of circAno6 plasmid/siRNA transfection on HSC activation indices, inflammatory markers and the circAno6/miR-296-3p/TLR4 signaling axis. The subcellular position of circAno6 was then examined by nucleo-cytoplasmic separation and fluorescence in situ hybridization (FISH). Finally, a luciferase reporter gene assay was used to identify the relationship between circAno6 and miR-296-3p as well as the relationship between miR-296-3p and TLR4. RESULTS CircAno6 was considerably upregulated in HSCs and positively correlated with cell proliferation and alpha-smooth muscle actin (α-SMA), collagen I, NOD-likereceptorthermalproteindomainassociatedprotein 3 (NLRP3), interleukin-1β (IL-1β) and interleukin-18 (IL-18) expression. Overexpression of circAno6 increased the inflammatory response and induced HSC activation, whereas interference resulted in the opposite effects. FISH experiments revealed the localization of circAno6 in the cytoplasm. Then, a double luciferase reporter assay confirmed that miR-296-3p significantly inhibited luciferase activity in the circAno6-WT and TLR4-WT groups. CONCLUSION This study suggests that circAno6 and miR-296-3p/TLR4 may form a regulatory axis and regulate the inflammatory response, which in turn induces HSC activation. Targeting circAno6 may be a potential therapeutic strategy to treat LF.
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Affiliation(s)
- Zhen Li
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province 230031, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China
| | - Yanzhen Ma
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province 230031, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China
| | - Chang Fan
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province 230031, China
| | - Hui Jiang
- Experimental Center of Clinical Research, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui Province 230031, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui Province 230012, China.
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7
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Banerjee A, Farci P. Fibrosis and Hepatocarcinogenesis: Role of Gene-Environment Interactions in Liver Disease Progression. Int J Mol Sci 2024; 25:8641. [PMID: 39201329 PMCID: PMC11354981 DOI: 10.3390/ijms25168641] [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: 06/26/2024] [Revised: 07/23/2024] [Accepted: 07/29/2024] [Indexed: 09/02/2024] Open
Abstract
The liver is a complex organ that performs vital functions in the body. Despite its extraordinary regenerative capacity compared to other organs, exposure to chemical, infectious, metabolic and immunologic insults and toxins renders the liver vulnerable to inflammation, degeneration and fibrosis. Abnormal wound healing response mediated by aberrant signaling pathways causes chronic activation of hepatic stellate cells (HSCs) and excessive accumulation of extracellular matrix (ECM), leading to hepatic fibrosis and cirrhosis. Fibrosis plays a key role in liver carcinogenesis. Once thought to be irreversible, recent clinical studies show that hepatic fibrosis can be reversed, even in the advanced stage. Experimental evidence shows that removal of the insult or injury can inactivate HSCs and reduce the inflammatory response, eventually leading to activation of fibrolysis and degradation of ECM. Thus, it is critical to understand the role of gene-environment interactions in the context of liver fibrosis progression and regression in order to identify specific therapeutic targets for optimized treatment to induce fibrosis regression, prevent HCC development and, ultimately, improve the clinical outcome.
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Affiliation(s)
- Anindita Banerjee
- Department of Transfusion Transmitted Diseases, ICMR-National Institute of Immunohaematology, Mumbai 400012, Maharashtra, India;
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Wu W, Zhou S, Fei G, Wang R. The role of long noncoding RNA MEG3 in fibrosis diseases. Postgrad Med J 2024; 100:529-538. [PMID: 38430191 DOI: 10.1093/postmj/qgad124] [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: 11/02/2023] [Accepted: 11/17/2023] [Indexed: 03/03/2024]
Abstract
Fibrosis is a prevalent pathological condition observed in various organs and tissues. It primarily arises from the excessive and abnormal accumulation of the extracellular matrix, resulting in the structural and functional impairment of tissues and organs, which can culminate in death. Many forms of fibrosis, including liver, cardiac, pulmonary, and renal fibrosis, are considered irreversible. Maternally expressed gene 3 (MEG3) is an imprinted RNA gene. Historically, the downregulation of MEG3 has been linked to tumor pathogenesis. However, recent studies indicate an emerging association of MEG3 with fibrotic diseases. In this review, we delve into the current understanding of MEG3's role in fibrosis, aiming to shed light on the molecular mechanisms of fibrosis and the potential of MEG3 as a novel therapeutic target.
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Affiliation(s)
- Wenlong Wu
- Department of Respiratory and Critical Care Medicine, The First Afiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Sijing Zhou
- Department of Occupational Disease, Hefei Third Clinical College of Anhui Medical University, Hefei 230022, China
| | - Guanghe Fei
- Department of Respiratory and Critical Care Medicine, The First Afiliated Hospital of Anhui Medical University, Hefei 230022, China
| | - Ran Wang
- Department of Respiratory and Critical Care Medicine, The First Afiliated Hospital of Anhui Medical University, Hefei 230022, China
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Ariyachet C, Nokkeaw A, Boonkaew B, Tangkijvanich P. ZNF469 is a profibrotic regulator of extracellular matrix in hepatic stellate cells. J Cell Biochem 2024; 125:e30578. [PMID: 38704698 DOI: 10.1002/jcb.30578] [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: 01/17/2024] [Revised: 04/02/2024] [Accepted: 04/25/2024] [Indexed: 05/07/2024]
Abstract
Activation of quiescent hepatic stellate cells (HSCs) into proliferative myofibroblasts drives extracellular cellular matrix (ECM) accumulation and liver fibrosis; nevertheless, the transcriptional network that promotes such a process is not completely understood. ZNF469 is a putative C2H2 zinc finger protein that may bind to specific genome sequences. It is found to be upregulated upon HSC activation; however, the molecular function of ZNF469 is completely unknown. Here, we show that knockdown of ZNF469 in primary human HSCs impaired proliferation, migration, and collagen production. Conversely, overexpression of ZNF469 in HSCs yielded the opposite results. Transforming growth factor-β 1 promoted expression of ZNF469 in a Smad3-dependent manner, where the binding of Smad3 was confirmed at the ZNF469 promoter. RNA sequencing data of ZNF469-knockdown HSCs revealed the ECM-receptor interaction, which provides structural and signaling support to cells, was the most affected pathway, and significant downregulation of various collagen and proteoglycan genes was observed. To investigate the function of ZNF469, we cloned a full-length open reading frame of ZNF469 with an epitope tag and identified a nuclear localization of the protein. Luciferase reporter and chromatin immunoprecipitation assays revealed the presence of ZNF469 at the promoter of ECM genes, supporting its function as a transcription factor. Analysis of human fibrotic and cirrhotic tissues showed increased expression of ZNF469 and a positive correlation between expression levels of ZNF469 and ECM genes. Moreover, this observation was similar in other fibrotic organs, including the heart, lung, and skin, suggesting that myofibroblasts from various origins generally require ZNF469 to promote ECM production. Together, this study is the first to reveal the role of ZNF469 as a profibrotic factor in HSCs and suggests ZNF469 as a novel target for antifibrotic therapy.
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Affiliation(s)
- Chaiyaboot Ariyachet
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Archittapon Nokkeaw
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Medical Biochemistry Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Bootsakorn Boonkaew
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Department of Biochemistry, Medical Biochemistry Program, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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10
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El‐Ayoubi A, Arakelyan A, Klawitter M, Merk L, Hakobyan S, Gonzalez‐Menendez I, Quintanilla Fend L, Holm PS, Mikulits W, Schwab M, Danielyan L, Naumann U. Development of an optimized, non-stem cell line for intranasal delivery of therapeutic cargo to the central nervous system. Mol Oncol 2024; 18:528-546. [PMID: 38115217 PMCID: PMC10920084 DOI: 10.1002/1878-0261.13569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/23/2023] [Accepted: 12/13/2023] [Indexed: 12/21/2023] Open
Abstract
Neural stem cells (NSCs) are considered to be valuable candidates for delivering a variety of anti-cancer agents, including oncolytic viruses, to brain tumors. However, owing to the previously reported tumorigenic potential of NSC cell lines after intranasal administration (INA), here we identified the human hepatic stellate cell line LX-2 as a cell type capable of longer resistance to replication of oncolytic adenoviruses (OAVs) as a therapeutic cargo, and that is non-tumorigenic after INA. Our data show that LX-2 cells can longer withstand the OAV XVir-N-31 replication and oncolysis than NSCs. By selecting the highly migratory cell population out of LX-2, an offspring cell line with a higher and more stable capability to migrate was generated. Additionally, as a safety backup, we applied genomic herpes simplex virus thymidine kinase (HSV-TK) integration into LX-2, leading to high vulnerability to ganciclovir (GCV). Histopathological analyses confirmed the absence of neoplasia in the respiratory tracts and brains of immuno-compromised mice 3 months after INA of LX-2 cells. Our data suggest that LX-2 is a novel, robust, and safe cell line for delivering anti-cancer and other therapeutic agents to the brain.
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Affiliation(s)
- Ali El‐Ayoubi
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Arsen Arakelyan
- Research Group of BioinformaticsInstitute of Molecular Biology NAS RAYerevanArmenia
| | - Moritz Klawitter
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Luisa Merk
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
| | - Siras Hakobyan
- Research Group of BioinformaticsInstitute of Molecular Biology NAS RAYerevanArmenia
- Armenian Institute of BioinformaticsYerevanArmenia
| | - Irene Gonzalez‐Menendez
- Institute for Pathology, Department of General and Molecular PathologyUniversity Hospital TübingenGermany
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
| | - Leticia Quintanilla Fend
- Institute for Pathology, Department of General and Molecular PathologyUniversity Hospital TübingenGermany
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
| | - Per Sonne Holm
- Department of Urology, Klinikum rechts der IsarTechnical University of MunichGermany
- Department of Oral and Maxillofacial SurgeryMedical University InnsbruckAustria
- XVir Therapeutics GmbHMunichGermany
| | - Wolfgang Mikulits
- Center for Cancer Research, Comprehensive Cancer CenterMedical University of ViennaAustria
| | - Matthias Schwab
- Cluster of Excellence iFIT (EXC 2180) "Image‐Guided and Functionally Instructed Tumor Therapies"Eberhard Karls University of TübingenGermany
- Dr. Margarete Fischer‐Bosch Institute of Clinical PharmacologyStuttgartGermany
- Department of Pharmacy and BiochemistryUniversity of TübingenGermany
- Department of Clinical PharmacologyUniversity Hospital TübingenGermany
- Neuroscience Laboratory and Departments of Biochemistry and Clinical PharmacologyYerevan State Medical UniversityArmenia
| | - Lusine Danielyan
- Department of Pharmacy and BiochemistryUniversity of TübingenGermany
- Department of Clinical PharmacologyUniversity Hospital TübingenGermany
- Neuroscience Laboratory and Departments of Biochemistry and Clinical PharmacologyYerevan State Medical UniversityArmenia
| | - Ulrike Naumann
- Molecular Neurooncology, Department of Vascular Neurology, Hertie Institute for Clinical Brain Research and Center NeurologyUniversity Hospital of TübingenGermany
- Gene and RNA Therapy Center (GRTC)Faculty of Medicine University TübingenGermany
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11
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Sun YD, Zhang H, Li YM, Han JJ. Abnormal metabolism in hepatic stellate cells: Pandora's box of MAFLD related hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2024; 1879:189086. [PMID: 38342420 DOI: 10.1016/j.bbcan.2024.189086] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 12/25/2023] [Accepted: 02/06/2024] [Indexed: 02/13/2024]
Abstract
Metabolic associated fatty liver disease (MAFLD) is a significant risk factor for the development of hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs), as key mediators in liver injury response, are believed to play a crucial role in the repair process of liver injury. However, in MAFLD patients, the normal metabolic and immunoregulatory mechanisms of HSCs become disrupted, leading to disturbances in the local microenvironment. Abnormally activated HSCs are heavily involved in the initiation and progression of HCC. The metabolic disorders and abnormal activation of HSCs not only initiate liver fibrosis but also contribute to carcinogenesis. In this review, we provide an overview of recent research progress on the relationship between the abnormal metabolism of HSCs and the local immune system in the liver, elucidating the mechanisms of immune imbalance caused by abnormally activated HSCs in MAFLD patients. Based on this understanding, we discuss the potential and challenges of metabolic-based and immunology-based mechanisms in the treatment of MAFLD-related HCC, with a specific focus on the role of HSCs in HCC progression and their potential as targets for anti-cancer therapy. This review aims to enhance researchers' understanding of the importance of HSCs in maintaining normal liver function and highlights the significance of HSCs in the progression of MAFLD-related HCC.
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Affiliation(s)
- Yuan-Dong Sun
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China
| | - Hao Zhang
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China
| | - Yuan-Min Li
- NHC Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, China
| | - Jian-Jun Han
- Department of Interventional Radiology, Shandong Cancer Hospital and Institute Affiliated Shandong First Medical University, Shandong Academy of Medical Sciences, China.
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12
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Picoli CDC, Birbrair A, Li Z. Pericytes as the Orchestrators of Vasculature and Adipogenesis. Genes (Basel) 2024; 15:126. [PMID: 38275607 PMCID: PMC10815550 DOI: 10.3390/genes15010126] [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: 12/19/2023] [Revised: 01/17/2024] [Accepted: 01/18/2024] [Indexed: 01/27/2024] Open
Abstract
Pericytes (PCs) are located surrounding the walls of small blood vessels, particularly capillaries and microvessels. In addition to their functions in maintaining vascular integrity, participating in angiogenesis, and regulating blood flow, PCs also serve as a reservoir for multi-potent stem/progenitor cells in white, brown, beige, and bone marrow adipose tissues. Due to the complex nature of this cell population, the identification and characterization of PCs has been challenging. A comprehensive understanding of the heterogeneity of PCs may enhance their potential as therapeutic targets for metabolic syndromes or bone-related diseases. This mini-review summarizes multiple PC markers commonly employed in lineage-tracing studies, with an emphasis on their contribution to adipogenesis and functions in different adipose depots under diverse metabolic conditions.
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Affiliation(s)
| | - Alexander Birbrair
- Department of Dermatology, University of Wisconsin-Madison, Medical Sciences Center, Madison, WI 53706, USA;
| | - Ziru Li
- Center for Molecular Medicine, MaineHealth Institute for Research, Scarborough, ME 04074, USA;
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13
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Carvalho AM, Bansal R, Barrias CC, Sarmento B. The Material World of 3D-Bioprinted and Microfluidic-Chip Models of Human Liver Fibrosis. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2307673. [PMID: 37961933 DOI: 10.1002/adma.202307673] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 11/06/2023] [Indexed: 11/15/2023]
Abstract
Biomaterials are extensively used to mimic cell-matrix interactions, which are essential for cell growth, function, and differentiation. This is particularly relevant when developing in vitro disease models of organs rich in extracellular matrix, like the liver. Liver disease involves a chronic wound-healing response with formation of scar tissue known as fibrosis. At early stages, liver disease can be reverted, but as disease progresses, reversion is no longer possible, and there is no cure. Research for new therapies is hampered by the lack of adequate models that replicate the mechanical properties and biochemical stimuli present in the fibrotic liver. Fibrosis is associated with changes in the composition of the extracellular matrix that directly influence cell behavior. Biomaterials could play an essential role in better emulating the disease microenvironment. In this paper, the recent and cutting-edge biomaterials used for creating in vitro models of human liver fibrosis are revised, in combination with cells, bioprinting, and/or microfluidics. These technologies have been instrumental to replicate the intricate structure of the unhealthy tissue and promote medium perfusion that improves cell growth and function, respectively. A comprehensive analysis of the impact of material hints and cell-material interactions in a tridimensional context is provided.
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Affiliation(s)
- Ana Margarida Carvalho
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell Biophysics, Technical Medical Center, Faculty of Science and Technology, University of Twente, Enschede, 7522 NB, The Netherlands
| | - Cristina C Barrias
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, Porto, 4050-313, Portugal
| | - Bruno Sarmento
- i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- INEB - Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, Porto, 4200-135, Portugal
- IUCS - Instituto Universitário de Ciências da Saúde, CESPU, Rua Central de Gandra 1317, Gandra, 4585-116, Portugal
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14
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Zhu JH, Guan XC, Yi LL, Xu H, Li QY, Cheng WJ, Xie YX, Li WZ, Zhao HY, Wei HJ, Zhao SM. Single-nucleus transcriptome sequencing reveals hepatic cell atlas in pigs. BMC Genomics 2023; 24:770. [PMID: 38087243 PMCID: PMC10717992 DOI: 10.1186/s12864-023-09765-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND As the largest substantive organ of animals, the liver plays an essential role in the physiological processes of digestive metabolism and immune defense. However, the cellular composition of the pig liver remains poorly understood. This investigation used single-nucleus RNA sequencing technology to identify cell types from liver tissues of pigs, providing a theoretical basis for further investigating liver cell types in pigs. RESULTS The analysis revealed 13 cells clusters which were further identified 7 cell types including endothelial cells, T cells, hepatocytes, Kupffer cells, stellate cells, B cells, and cholangiocytes. The dominant cell types were endothelial cells, T cells and hepatocytes in the liver tissue of Dahe pigs and Dahe black pigs, which accounts for about 85.76% and 82.74%, respectively. The number of endothelial cells was higher in the liver tissue of Dahe pigs compared to Dahe black pigs, while the opposite tendency was observed for T cells. Moreover, functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic endothelial cells were significantly enriched in the protein processing in endoplasmic reticulum, MAPK signaling pathway, and FoxO signaling pathway. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic T cells were significantly enriched in the thyroid hormone signaling pathway, B cell receptor signaling pathway, and focal adhesion. Functional enrichment analysis demonstrated that the differentially expressed genes in pig hepatic hepatocytes were significantly enriched in the metabolic pathways. CONCLUSIONS In summary, this study provides a comprehensive cell atlas of porcine hepatic tissue. The number, gene expression level and functional characteristics of each cell type in pig liver tissue varied between breeds.
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Affiliation(s)
- Jun-Hong Zhu
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
| | - Xuan-Cheng Guan
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
| | - Lan-Lan Yi
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
| | - Hong Xu
- School of Public Finance and Economics, Yunnan University of Finance and Economics, Kunming, 650221, China
| | - Qiu-Yan Li
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
| | - Wen-Jie Cheng
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
| | - Yu-Xiao Xie
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China
- College of Biology and Agriculture, Zunyi Normal University, Zunyi, 563006, China
| | - Wei-Zhen Li
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Hong-Ye Zhao
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China
| | - Hong-Jiang Wei
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China.
- College of Veterinary Medicine, Yunnan Agricultural University, Kunming, 650201, China.
| | - Su-Mei Zhao
- Yunnan Key Laboratory of Animal Nutrition and Feed Science, Yunnan Agricultural University, Kunming, 650201, China.
- Yunnan Province Key Laboratory for Porcine Gene Editing and Xenotransplantation, Yunnan Agricultural University, Kunming, 650201, China.
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15
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Zhao J, Zhang X, Li Y, Yu J, Chen Z, Niu Y, Ran S, Wang S, Ye W, Luo Z, Li X, Hao Y, Zong J, Xia C, Xia J, Wu J. Interorgan communication with the liver: novel mechanisms and therapeutic targets. Front Immunol 2023; 14:1314123. [PMID: 38155961 PMCID: PMC10754533 DOI: 10.3389/fimmu.2023.1314123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 11/28/2023] [Indexed: 12/30/2023] Open
Abstract
The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as "hepatokines"). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body's innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.
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Affiliation(s)
- Jiulu Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xi Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuqing Niu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shuan Ran
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Song Wang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weicong Ye
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zilong Luo
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaohan Li
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanglin Hao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Junjie Zong
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengkun Xia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Organ Transplantation, Ministry of Education, National Health Commission Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, China
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16
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Abdel-Latif GA, Al-Kashef AS, Nooman MU, Khattab AENA, Gebril SM, Elmongy NF, Abbas SS. The mechanistic interplay between Nrf-2, NF-κB/MAPK, caspase-dependent apoptosis, and autophagy in the hepatoprotective effects of Sophorolipids produced by microbial conversion of banana peels using Saccharomyces cerevisiae against doxorubicin-induced hepatotoxicity in rats. Food Chem Toxicol 2023; 182:114119. [PMID: 37944788 DOI: 10.1016/j.fct.2023.114119] [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: 03/21/2023] [Revised: 05/07/2023] [Accepted: 10/21/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Doxorubicin (DOX) is a well-known chemotherapeutic agent which causes serious adverse effects due to multiple organ damage, including cardiotoxicity, nephrotoxicity, neurotoxicity, and hepatotoxicity. The mechanism of DOX-induced organ toxicity might be attributed to oxidative stress (OS) and, consequently, activation of inflammatory signaling pathways, apoptosis, and blockage of autophagy. Sophorolipids (SLs) as a glycolipid type of biosurfactants, are natural products that have unique properties and a wide range of applications attributed to their antioxidant and anti-inflammatory properties. AIMS Production of low-cost SLs from Saccharomyces cerevisiae grown on banana peels and investigating their possible protective effects against DOX-induced hepatotoxicity. MAIN METHODS The yeast was locally isolated and molecularly identified, then the yielded SLs were characterized by FTIR, 1H NMR and LC-MS/MS spectra. Posteriorly, thirty-two male Wistar rats were randomly divided into four groups; control (oral saline), SLs (200 mg/kg, p.o), DOX (10 mg/kg; i.p.), and SL + DOX (200 mg/kg p.o.,10 mg/kg; i.p., respectively). Liver function tests (LFTs), oxidative stress, inflammatory, apoptosis as well as autophagy markers were investigated. KEY FINDINGS SLs were produced with a yield of 49.04% and treatment with SLs improved LFTs, enhanced Nrf2 and suppressed NF-κB, IL-6, IL-1β, p38, caspase 3 and Bax/Bcl2 ratio in addition to promotion of autophagy when compared to DOX group. SIGNIFICANCE Our results revealed a novel promising protective effect of SLs against DOX-induced hepatotoxicity in rats.
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Affiliation(s)
- Ghada A Abdel-Latif
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt; Translational and Clinical Research Unit, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt.
| | - Amr S Al-Kashef
- Biochemistry Department, Biotechnology Research Institute, National Research Centre (NRC), Cairo, Egypt.
| | - Mohamed U Nooman
- Biochemistry Department, Biotechnology Research Institute, National Research Centre (NRC), Cairo, Egypt.
| | - Abd El-Nasser A Khattab
- Genetics & Cytology Department, Biotechnology Research Institute, National Research Centre (NRC), Cairo, Egypt.
| | - Sahar M Gebril
- Histology and Cell Biology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.
| | - Noura F Elmongy
- Physiology Department, Faculty of Medicine, Al-Azhar University, Damietta, Egypt.
| | - Samah S Abbas
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt; Translational and Clinical Research Unit, Faculty of Pharmacy, Misr International University (MIU), Cairo, Egypt.
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17
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Liang W, Huang X, Shi J. Macrophages Serve as Bidirectional Regulators and Potential Therapeutic Targets for Liver Fibrosis. Cell Biochem Biophys 2023; 81:659-671. [PMID: 37695501 DOI: 10.1007/s12013-023-01173-w] [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: 12/23/2022] [Accepted: 09/02/2023] [Indexed: 09/12/2023]
Abstract
Liver fibrosis is a dynamic pathological process in which the structure and function of the liver abnormally change due to long-term complex inflammatory reactions and chronic liver injury caused by multiple internal and external factors. Previous studies believed that the activation of hepatic stellate cells is a critical part of the occurrence and development of liver fibrosis. However, an increasing number of studies have indicated that the macrophage plays an important role as a central regulator in liver fibrosis, and it directly affects the development and recovery of liver fibrosis. Studies of macrophages and liver fibrosis in the recent 10 years will be reviewed in this paper. This review will not only clarify the molecular mechanism of liver fibrosis regulated by macrophages but also provide new strategies and methods for ameliorating and treating liver fibrosis.
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Affiliation(s)
- Wei Liang
- Clinical Medical Research Center, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.
| | - Xianing Huang
- Guangxi International Travel Healthcare Centre (Port Clinic of Nanning Customs District), Nanning, 530021, Guangxi, China
| | - Jingjing Shi
- Department of Gastrointestinal Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi Clinical Research Center for Colorectal Cancer, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
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18
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Abdalla N, Abo-ElMatty DM, Saleh S, Ghattas MH, Omar NN. Empagliflozin suppresses hedgehog pathway, alleviates ER stress, and ameliorates hepatic fibrosis in rats. Sci Rep 2023; 13:19046. [PMID: 37923828 PMCID: PMC10624673 DOI: 10.1038/s41598-023-46288-5] [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: 07/27/2023] [Accepted: 10/30/2023] [Indexed: 11/06/2023] Open
Abstract
Worldwide mortality from hepatic fibrosis remains high, due to hepatocellular carcinoma and end stage liver failure. The progressive nature of hepatic fibrosis from inflammation to cicatrized tissues warrants subtle intervention with pharmacological agents that hold potential. Empagliflozin (Empa), a novel hypoglycemic drug with antioxidant and anti-inflammatory properties, has lately been proposed to have additional antifibrotic activities. In the current study, we examined the antifibrotic effect of the Empa through modulating the activity of hepatic stellate cells by hedgehog (Hh) pathway. We also assessed the markers of inflammatory response and endoplasmic reticulum (ER) stress. Male Albino rats were treated with either CCl4 (0.4 mg/kg twice/week) and/or Empa (10 mg/kg/day) for eight weeks. In this study, CCl4 rats had active Hh signaling as indicated by overexpression of Patched 1, Smoothened and Glioblastoma-2. CCl4 induced ER stress as CHOP expression was upregulated and ERAD was downregulated. CCl4-induced inflammatory response was demonstrated through increased levels of TNF-α, IL-6 and mRNA levels of IL-17 while undetectable expression of IL-10. Conversely, Empa elicited immunosuppression, suppressed the expression of Hh markers, and reversed markers of ER stress. In conclusion, Empa suppressed CCl4-induced Hh signaling and proinflammatory response, meanwhile embraced ER stress in the hepatic tissues, altogether provided hepatoprotection.
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Affiliation(s)
- Nourihan Abdalla
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Mokattam, Cairo, 11585, Egypt
| | - Dina M Abo-ElMatty
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Sami Saleh
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia, 41522, Egypt
| | - Maivel H Ghattas
- Department of Medical Biochemistry, Faculty of Medicine, Port Said University, Port Said, Egypt.
| | - Nesreen Nabil Omar
- Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Mokattam, Cairo, 11585, Egypt
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19
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Mahli A, Thasler WE, Biendl M, Hellerbrand C. Hop-derived Humulinones Reveal Protective Effects in in vitro Models of Hepatic Steatosis, Inflammation and Fibrosis. PLANTA MEDICA 2023; 89:1138-1146. [PMID: 37343573 DOI: 10.1055/a-2103-3230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/23/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is emerging as leading cause of liver disease worldwide. Specific pharmacologic therapy for NAFLD is a major unmet medical need. Recently, iso-alpha acids, hop-derived bitter compounds in beer, have been shown to beneficially affect NAFLD pathology. Humulinones are further hop derived bitter acids particularly found in modern styles of beer. So far, biological effects of humulinones have been unknown. Here, we investigated the effect of humulinones in in vitro models for hepatic steatosis, inflammation and fibrosis. Humulinones dose-dependently inhibited fatty acid induced lipid accumulation in primary human hepatocytes. Humulinones reduced the expression of fatty acid uptake transporter CD36 and key enzymes of (de novo) lipid synthesis. Conversely, humulinones increased the expression of FABP1, CPT1 and ACOX1, indicative for increased lipid combustion. Furthermore, humulinones ameliorated steatosis induced pro-inflammatory gene expression. Furthermore, humulinones significantly reduced the expression of pro-inflammatory and pro-fibrogenic factors in control as well as lipopolysaccharide treated activated hepatic stellate cells, which play a key role in hepatic fibrosis. In conclusion, humulinones beneficially affect different pathophysiological steps of NAFLD. Our data suggest humulinones as promising therapeutic agents for the prevention and treatment of NAFLD.
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Affiliation(s)
- Abdo Mahli
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
- Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman, Jordan
| | - Wolfgang E Thasler
- Human Tissue and Cell Research-Services GmbH, Planegg/Martinsried, Germany
| | - Martin Biendl
- Hopsteiner, Hallertauer Hopfenveredelung GmbH, Mainburg, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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20
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Ge MX, Niu WX, Bao YY, Lu ZN, He HW. Sclareol attenuates liver fibrosis through SENP1-mediated VEGFR2 SUMOylation and inhibition of downstream STAT3 signaling. Phytother Res 2023; 37:3898-3912. [PMID: 37132081 DOI: 10.1002/ptr.7845] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/23/2023] [Accepted: 04/09/2023] [Indexed: 05/04/2023]
Abstract
Liver fibrosis is a key global health care burden. Sclareol, isolated from Salvia sclarea, possesses various biological activities. Its effect on liver fibrosis remains unknown. This study was proposed to evaluate the antifibrotic activity of sclareol (SCL) and explore its underlying mechanisms. Stimulated hepatic stellate cells served as an in vitro liver fibrosis model. The expression of fibrotic markers was assessed by western blot and real-time PCR. Two classical animal models, bile duct-ligated rats and carbon tetrachloride-treated mice, were utilized for the in vivo experiments. The liver function and fibrosis degree were determined by serum biochemical and histopathological analyses. VEGFR2 SUMOylation was analyzed using coimmunoprecipitation assay. Our results indicated that SCL treatment restricted the profibrotic propensity of activated HSCs. In fibrotic rodents, SCL administration alleviated hepatic injury and reduced collagen accumulation. Mechanistic studies indicated that SCL downregulated the protein level of SENP1 and enhanced VEGFR2 SUMOylation in LX-2 cells, which affected its intracellular trafficking. Blockade of the interaction between VEGFR2 and STAT3 was observed, resulting in the suppression of downstream STAT3 phosphorylation. Our findings demonstrated that SCL has therapeutic efficacy against liver fibrosis through mediating VEGFR2 SUMOylation, suggesting that SCL may be a potential candidate compound for its treatment.
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Affiliation(s)
- Mao-Xu Ge
- Department of Pharmacy, Qilu Hospital of Shandong University, Jinan, China
| | - Wei-Xiao Niu
- Medical Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yun-Yang Bao
- Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhen-Ning Lu
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hong-Wei He
- Key Laboratory of Biotechnology of Antibiotics, the National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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21
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Abstract
The vasculature consists of vessels of different sizes that are arranged in a hierarchical pattern. Two cell populations work in concert to establish this pattern during embryonic development and adopt it to changes in blood flow demand later in life: endothelial cells that line the inner surface of blood vessels, and adjacent vascular mural cells, including smooth muscle cells and pericytes. Despite recent progress in elucidating the signalling pathways controlling their crosstalk, much debate remains with regard to how mural cells influence endothelial cell biology and thereby contribute to the regulation of blood vessel formation and diameters. In this Review, I discuss mural cell functions and their interactions with endothelial cells, focusing on how these interactions ensure optimal blood flow patterns. Subsequently, I introduce the signalling pathways controlling mural cell development followed by an overview of mural cell ontogeny with an emphasis on the distinguishing features of mural cells located on different types of blood vessels. Ultimately, I explore therapeutic strategies involving mural cells to alleviate tissue ischemia and improve vascular efficiency in a variety of diseases.
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Affiliation(s)
- Arndt F. Siekmann
- Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, 1114 Biomedical Research Building, 421 Curie Boulevard, Philadelphia, PA 19104, USA
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22
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Abstract
Pericytes are specialized cells located in close proximity to endothelial cells within the microvasculature. They play a crucial role in regulating blood flow, stabilizing vessel walls, and maintaining the integrity of the blood-brain barrier. The loss of pericytes has been associated with the development and progression of various diseases, such as diabetes, Alzheimer's disease, sepsis, stroke, and traumatic brain injury. This review examines the detection of pericyte loss in different diseases, explores the methods employed to assess pericyte coverage, and elucidates the potential mechanisms contributing to pericyte loss in these pathological conditions. Additionally, current therapeutic strategies targeting pericytes are discussed, along with potential future interventions aimed at preserving pericyte function and promoting disease mitigation.
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Affiliation(s)
| | - Hongkuan Fan
- Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA;
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23
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Yao M, Liang S, Cheng B. Role of exosomes in hepatocellular carcinoma and the regulation of traditional Chinese medicine. Front Pharmacol 2023; 14:1110922. [PMID: 36733504 PMCID: PMC9886889 DOI: 10.3389/fphar.2023.1110922] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) usually occurs on the basis of chronic liver inflammatory diseases and cirrhosis. The liver microenvironment plays a vital role in the tumor initiation and progression. Exosomes, which are nanometer-sized membrane vesicles are secreted by a number of cell types. Exosomes carry multiple proteins, DNAs and various forms of RNA, and are mediators of cell-cell communication and regulate the tumor microenvironment. In the recent decade, many studies have demonstrated that exosomes are involved in the communication between HCC cells and the stromal cells, including endothelial cells, macrophages, hepatic stellate cells and the immune cells, and serve as a regulator in the tumor proliferation and metastasis, immune evasion and immunotherapy. In addition, exosomes can also be used for the diagnosis and treatment HCC. They can potentially serve as specific biomarkers for early diagnosis and drug delivery vehicles of HCC. Chinese herbal medicine, which is widely used in the prevention and treatment of HCC in China, may regulate the release of exosomes and exosomes-mediated intercellular communication. In this review, we summarized the latest progresses on the role of the exosomes in the initiation, progression and treatment of HCC and the potential value of Traditional Chinese medicine in exosomes-mediated biological behaviors of HCC.
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Affiliation(s)
- Man Yao
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Shufang Liang
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China
| | - Binbin Cheng
- Oncology Department of Traditional Chinese Medicine, Changhai Hospital, Naval Medical University (The Second Military Medical University), Shanghai, China,Faculty of Traditional Chinese Medicine, Naval Medical University (The Second Military Medical University), Shanghai, China,*Correspondence: Binbin Cheng,
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24
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Xia GQ, Fang Q, Cai JN, Li ZX, Zhang FZ, Lv XW. P2X7 Receptor in Alcoholic Steatohepatitis and Alcoholic Liver Fibrosis. J Clin Transl Hepatol 2022; 10:1205-1212. [PMID: 36381094 PMCID: PMC9634783 DOI: 10.14218/jcth.2022.00022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 04/12/2022] [Accepted: 04/21/2022] [Indexed: 12/04/2022] Open
Abstract
Alcoholic liver disease is one of the most common chronic liver diseases in the world. It is a liver disease caused by prolonged heavy drinking and its main clinical features are nausea, vomiting, enlargement of the liver, and jaundice. Recent studies suggest that Kupffer cell-mediated inflammatory response is a core driver in the development of alcoholic steatohepatitis and alcoholic liver fibrosis. As a danger signal, extracellular ATP activates the assembly of NLPR3 inflammasome by acting on purine P2X7 receptor, the activated NLRP3 inflammasome prompts ASC to cleave pro-cCaspase-1 into active caspase-1in KCs. Active caspase-1 promotes the conversion of pro-IL-1β to IL-1β, which further enhances the inflammatory response. Here, we briefly review the role of the P2X7R-NLRP3 inflammasome axis in the pathogenesis of alcoholic liver disease and the evolution of alcoholic steatohepatitis and alcoholic liver fibrosis. Regulation of the inflammasome axis of P2X7R-NLRP3 may be a new approach for the treatment of alcoholic liver disease.
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Affiliation(s)
- Guo-Qing Xia
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Qian Fang
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Jun-Nan Cai
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Zi-Xuan Li
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
| | - Feng-Zhi Zhang
- Wannan Medical College, Yijishan Hospital, Affiliated Hospital 1, Wuhu, Anhui, China
| | - Xiong-Wen Lv
- Institute for Liver Diseases of Anhui Medical University, Hefei, Anhui, China
- The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, Anhui, China
- Correspondence to: Xiong-Wen Lv, School of Pharmacy, Anhui Medical University, 81 Mei Shan Road, Hefei, Anhui 230032, China. ORCID: https://orcid.org/0000-0003-2354-0168. Tel: +86-13515519961, Fax: +86-551-63633742, E-mail:
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25
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Lv W, Zhou H, Aazmi A, Yu M, Xu X, Yang H, Huang YYS, Ma L. Constructing biomimetic liver models through biomaterials and vasculature engineering. Regen Biomater 2022; 9:rbac079. [PMID: 36338176 PMCID: PMC9629974 DOI: 10.1093/rb/rbac079] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/19/2022] [Accepted: 10/08/2022] [Indexed: 04/04/2024] Open
Abstract
The occurrence of various liver diseases can lead to organ failure of the liver, which is one of the leading causes of mortality worldwide. Liver tissue engineering see the potential for replacing liver transplantation and drug toxicity studies facing donor shortages. The basic elements in liver tissue engineering are cells and biomaterials. Both mature hepatocytes and differentiated stem cells can be used as the main source of cells to construct spheroids and organoids, achieving improved cell function. To mimic the extracellular matrix (ECM) environment, biomaterials need to be biocompatible and bioactive, which also help support cell proliferation and differentiation and allow ECM deposition and vascularized structures formation. In addition, advanced manufacturing approaches are required to construct the extracellular microenvironment, and it has been proved that the structured three-dimensional culture system can help to improve the activity of hepatocytes and the characterization of specific proteins. In summary, we review biomaterials for liver tissue engineering, including natural hydrogels and synthetic polymers, and advanced processing techniques for building vascularized microenvironments, including bioassembly, bioprinting and microfluidic methods. We then summarize the application fields including transplant and regeneration, disease models and drug cytotoxicity analysis. In the end, we put the challenges and prospects of vascularized liver tissue engineering.
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Affiliation(s)
- Weikang Lv
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | | | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
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26
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Elchaninov A, Vishnyakova P, Menyailo E, Sukhikh G, Fatkhudinov T. An Eye on Kupffer Cells: Development, Phenotype and the Macrophage Niche. Int J Mol Sci 2022; 23:9868. [PMID: 36077265 PMCID: PMC9456487 DOI: 10.3390/ijms23179868] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/14/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022] Open
Abstract
Macrophages are key participants in the maintenance of tissue homeostasis under normal and pathological conditions, and implement a rich diversity of functions. The largest population of resident tissue macrophages is found in the liver. Hepatic macrophages, termed Kupffer cells, are involved in the regulation of multiple liver functionalities. Specific differentiation profiles and functional activities of tissue macrophages have been attributed to the shaping role of the so-called tissue niche microenvironments. The fundamental macrophage niche concept was lately shaken by a flood of new data, leading to a revision and substantial update of the concept, which constitutes the main focus of this review. The macrophage community discusses contemporary evidence on the developmental origins of resident macrophages, notably Kupffer cells and the issues of heterogeneity of the hepatic macrophage populations, as well as the roles of proliferation, cell death and migration processes in the maintenance of macrophage populations of the liver. Special consideration is given to interactions of Kupffer cells with other local cell lineages, including Ito cells, sinusoidal endothelium and hepatocytes, which participate in the maintenance of their phenotypical and functional identity.
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Affiliation(s)
- Andrey Elchaninov
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Pirogov Russian National Research Medical University, 117997 Moscow, Russia
| | - Polina Vishnyakova
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
| | - Egor Menyailo
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
| | - Gennady Sukhikh
- Laboratory of Regenerative Medicine, National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 117997 Moscow, Russia
| | - Timur Fatkhudinov
- Histology Department, Medical Institute, Peoples’ Friendship University of Russia, 117198 Moscow, Russia
- Laboratory of Growth and Development, Avtsyn Research Institute of Human Morphology of FSBI “Petrovsky National Research Centre of Surgery”, 117418 Moscow, Russia
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27
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Niu L, Geyer PE, Gupta R, Santos A, Meier F, Doll S, Wewer Albrechtsen NJ, Klein S, Ortiz C, Uschner FE, Schierwagen R, Trebicka J, Mann M. Dynamic human liver proteome atlas reveals functional insights into disease pathways. Mol Syst Biol 2022; 18:e10947. [PMID: 35579278 PMCID: PMC9112488 DOI: 10.15252/msb.202210947] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/12/2022] Open
Abstract
Deeper understanding of liver pathophysiology would benefit from a comprehensive quantitative proteome resource at cell type resolution to predict outcome and design therapy. Here, we quantify more than 150,000 sequence-unique peptides aggregated into 10,000 proteins across total liver, the major liver cell types, time course of primary cell cultures, and liver disease states. Bioinformatic analysis reveals that half of hepatocyte protein mass is comprised of enzymes and 23% of mitochondrial proteins, twice the proportion of other liver cell types. Using primary cell cultures, we capture dynamic proteome remodeling from tissue states to cell line states, providing useful information for biological or pharmaceutical research. Our extensive data serve as spectral library to characterize a human cohort of non-alcoholic steatohepatitis and cirrhosis. Dramatic proteome changes in liver tissue include signatures of hepatic stellate cell activation resembling liver cirrhosis and providing functional insights. We built a web-based dashboard application for the interactive exploration of our resource (www.liverproteome.org).
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Affiliation(s)
- Lili Niu
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
| | - Philipp E Geyer
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
OmicEra Diagnostics GmbHPlaneggGermany
| | - Rajat Gupta
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Present address:
Pfizer Worldwide Research and DevelopmentSan DiegoCAUSA
| | - Alberto Santos
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Center for Health Data ScienceFaculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
- Big Data InstituteNuffield Department of MedicineUniversity of OxfordOxfordUK
| | - Florian Meier
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
Functional ProteomicsJena University HospitalJenaGermany
| | - Sophia Doll
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
- Present address:
OmicEra Diagnostics GmbHPlaneggGermany
| | - Nicolai J Wewer Albrechtsen
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Clinical BiochemistryRigshospitaletUniversity of CopenhagenCopenhagenDenmark
| | - Sabine Klein
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Cristina Ortiz
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
| | - Frank E Uschner
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Robert Schierwagen
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
| | - Jonel Trebicka
- Department of Internal Medicine IGoethe University Clinic FrankfurtFrankfurtGermany
- Department of Internal Medicine BWW University MünsterMünsterGermany
- European Foundation for the Study of Chronic Failure, EFCLIFBarcelonaSpain
| | - Matthias Mann
- Novo Nordisk Foundation Center for Protein ResearchFaculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
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28
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Bae M, Kim MB, Lee JY. Fucoxanthin Attenuates the Reprogramming of Energy Metabolism during the Activation of Hepatic Stellate Cells. Nutrients 2022; 14:nu14091902. [PMID: 35565869 PMCID: PMC9103095 DOI: 10.3390/nu14091902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/26/2022] [Accepted: 04/29/2022] [Indexed: 02/01/2023] Open
Abstract
Hepatic stellate cells (HSC) play a major role in developing liver fibrosis. Upon activation during liver injury, activated HSC (aHSC) increase cell proliferation, fibrogenesis, contractility, chemotaxis, and cytokine release. We previously showed that aHSC have increased mitochondrial respiration but decreased glycolysis compared to quiescent HSC (qHSC). We also demonstrated that fucoxanthin (FCX), a xanthophyll carotenoid, has an anti-fibrogenic effect in HSC. The objective of this study was to investigate whether FCX attenuates metabolic reprogramming occurring during HSC activation. Mouse primary HSC were activated in the presence or absence of FCX for seven days. aHSC displayed significantly decreased glycolysis and increased mitochondrial respiration compared to qHSC, which was ameliorated by FCX present during activation. In addition, FCX partially attenuated the changes in the expression of genes involved in glycolysis and mitochondrial respiration, including hexokinase 1 (Hk1), Hk2, peroxisome proliferator-activated receptor γ coactivator 1β, and pyruvate dehydrogenase kinase 3. Our data suggest that FCX may prevent HSC activation by modulating the expression of genes crucial for metabolic reprogramming in HSC.
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Affiliation(s)
- Minkyung Bae
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017, USA; (M.B.); (M.-B.K.)
- Department of Food and Nutrition, Interdisciplinary Program in Senior Human Ecology, BK21 FOUR, College of Natural Sciences, Changwon National University, Changwon 51140, Korea
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017, USA; (M.B.); (M.-B.K.)
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017, USA; (M.B.); (M.-B.K.)
- Correspondence: ; Tel.: +1-(860)-486-1827
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29
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Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022; 10:3662-3676. [PMID: 35647163 PMCID: PMC9100727 DOI: 10.12998/wjcc.v10.i12.3662] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/17/2021] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a complex pathological process controlled by a variety of cells, mediators and signaling pathways. Hepatic stellate cells play a central role in the development of liver fibrosis. In chronic liver disease, hepatic stellate cells undergo dramatic phenotypic activation and acquire fibrogenic properties. This review focuses on the pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. They enter the cell cycle under the influence of various triggers. The "Initiation" phase of hepatic stellate cells activation overlaps and continues with the "Perpetuation" phase, which is characterized by a pronounced inflammatory and fibrogenic reaction. This is followed by a resolution phase if the injury subsides. Knowledge of these pathophysiological mechanisms paved the way for drugs aimed at preventing the development and progression of liver fibrosis. In this respect, impairments in intracellular signaling, epigenetic changes and cellular stress response can be the targets of therapy where the goal is to deactivate hepatic stellate cells. Potential antifibrotic therapy may focus on inducing hepatic stellate cells to return to an inactive state through cellular aging, apoptosis, and/or clearance by immune cells, and serve as potential antifibrotic therapy. It is especially important to prevent the formation of liver cirrhosis since the only radical approach to its treatment is liver transplantation which can be performed in only a limited number of countries.
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30
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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31
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Ghanim AMH, Younis NS, Metwaly HA. Vanillin augments liver regeneration effectively in Thioacetamide induced liver fibrosis rat model. Life Sci 2021; 286:120036. [PMID: 34637793 DOI: 10.1016/j.lfs.2021.120036] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 07/05/2021] [Accepted: 10/04/2021] [Indexed: 12/12/2022]
Abstract
AIMS This study has been designed to investigate the role of vanillin either as prophylaxis or treatment in liver regeneration augmentation and liver fibrosis regression in thioacetamide (TAA) induced liver damage. MATERIALS AND METHODS Animals were injected with TAA to induce liver injury (200mg/kg twice weekly) for 8 weeks. In vanillin prophylaxis group; rats were administered vanillin (100 mg/Kg; IP, daily) from day 1 of TAA injection for 8 weeks. In vanillin treatment group; rats were confronted with the same dose of TAA injection for 8 weeks then treated with vanillin (100 mg/Kg, IP, daily) for 4 weeks. ALT, AST activities, serum albumin, hepatic GSH, MDA, HGF, VEGF, IL-6 and TNF-α levels were measured and also, MMP-2, TIMP-1 and cyclin D gene expression were determined. Liver sections were stained with H&E and Sirius red and immunostained for Ki-67 and α-SMA for histological and immunohistological changes analysis. KEY FINDINGS Vanillin improved liver function and histology. Also, showed a remarkable increase in hepatic HGF and VEGF level, and up-regulation of cyclin D1 expression accompanied by a significant up-regulation of MMP-2 and down- regulation of TIMP-1. All these effects were accompanied by TNF-α, IL-6 and oxidative stress significant attenuation. SIGNIFICANCE In conclusion, vanillin enhanced liver regeneration in TAA induced liver damage model; targeting growth factors (HGF, VEGF) and cellular proliferation marker cyclin D1. As well as stimulating fibrosis regression by inhibition of ECM accumulation and enhancing its degradation.
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Affiliation(s)
- Amal M H Ghanim
- Department of Biochemistry, Faculty of Pharmacy, Fayoum University, Fayoum 63514, Egypt.
| | - Nancy S Younis
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology, Zagazig University, Zagazig, Egypt.
| | - Heba A Metwaly
- Department of Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt; Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21500, Egypt.
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32
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Su Q, Kim SY, Adewale F, Zhou Y, Aldler C, Ni M, Wei Y, Burczynski ME, Atwal GS, Sleeman MW, Murphy AJ, Xin Y, Cheng X. Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver. iScience 2021; 24:103233. [PMID: 34755088 PMCID: PMC8560975 DOI: 10.1016/j.isci.2021.103233] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 09/22/2021] [Accepted: 10/04/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global health-care problem with limited therapeutic options. To obtain a cellular resolution of pathogenesis, 82,168 single-cell transcriptomes (scRNA-seq) across different NAFLD stages were profiled, identifying hepatocytes and 12 other non-parenchymal cell (NPC) types. scRNA-seq revealed insights into the cellular and molecular mechanisms of the disease. We discovered a dual role for hepatic stellate cells in gene expression regulation and in the potential to trans-differentiate into myofibroblasts. We uncovered distinct expression profiles of Kupffer cells versus monocyte-derived macrophages during NAFLD progression. Kupffer cells showed stronger immune responses, while monocyte-derived macrophages demonstrated a capability for differentiation. Three chimeric NPCs were identified including endothelial-chimeric stellate cells, hepatocyte-chimeric endothelial cells, and endothelial-chimeric Kupffer cells. Our work identified unanticipated aspects of mouse with NAFLD at the single-cell level and advanced the understanding of cellular heterogeneity in NAFLD livers.
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Affiliation(s)
- Qi Su
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Sun Y. Kim
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Funmi Adewale
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Ye Zhou
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Christina Aldler
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Min Ni
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Yi Wei
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Michael E. Burczynski
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Gurinder S. Atwal
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Mark W. Sleeman
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Andrew J. Murphy
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Yurong Xin
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
| | - Xiping Cheng
- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, New York 10591, USA
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Luo N, Li J, Wei Y, Lu J, Dong R. Hepatic Stellate Cell: A Double-Edged Sword in the Liver. Physiol Res 2021; 70:821-829. [PMID: 34717063 DOI: 10.33549/physiolres.934755] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Hepatic stellate cells (HSCs) are located in the space of Disse, between liver sinusoidal endothelia cells (LSECs) and hepatocytes. They have surprised and excited hepatologists for their biological characteristics. Under physiological quiescent conditions, HSCs are the major vitamin A-storing cells of the liver, playing crucial roles in the liver development, regeneration, and tissue homeostasis. Upon injury-induced activation, HSCs convert to a pro-fibrotic state, producing the excessive extracellular matrix (ECM) and promoting angiogenesis in the liver fibrogenesis. Activated HSCs significantly contribute to liver fibrosis progression and inactivated HSCs are key to liver fibrosis regression. In this review, we summarize the comprehensive understanding of HSCs features, including their roles in normal liver and liver fibrosis in hopes of advancing the development of emerging diagnosis and treatment for hepatic fibrosis.
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Affiliation(s)
- Nianan Luo
- Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China. ,
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34
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Jo S, Kim JW, Noh H, Kim H, Kim JH, Park HJ. Generation of an ACTA2-EGFP reporter human induced pluripotent stem cell line, KITi001-C-41, using CRISPR/Cas9-mediated homologous recombination. Stem Cell Res 2021; 56:102524. [PMID: 34481189 DOI: 10.1016/j.scr.2021.102524] [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] [Received: 07/09/2021] [Revised: 08/13/2021] [Accepted: 08/25/2021] [Indexed: 11/16/2022] Open
Abstract
Alpha-smooth muscle actin (α-SMA) is encoded by ACTA2 and is a key protein in the cellular contractile system of various mesodermal cell types, including hepatic stellate cells (HSCs), smooth muscle cells, and cardiomyocytes. α-SMA, which is a key protein in the development of hepatic fibrosis, is widely used as a reliable marker of HSC activation. Here, we generated an ACTA2-EGFP reporter human induced pluripotent stem cell line, KITi001-C-41, using a CRISPR/Cas9-based knock-in system. These reporter hiPSC lines can be used for lineage tracing of mesodermal cells and for screening of HSC activation factors.
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Affiliation(s)
- Seongyea Jo
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea; Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, Republic of Korea
| | - Ji-Woo Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Haneul Noh
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Hyemin Kim
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
| | - Jong-Hoon Kim
- Laboratory of Stem Cells and Tissue Regeneration, Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul, Republic of Korea.
| | - Han-Jin Park
- Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea.
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35
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Polidoro MA, Ferrari E, Marzorati S, Lleo A, Rasponi M. Experimental liver models: From cell culture techniques to microfluidic organs-on-chip. Liver Int 2021; 41:1744-1761. [PMID: 33966344 DOI: 10.1111/liv.14942] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 05/02/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022]
Abstract
The liver is one of the most studied organs of the human body owing to its central role in xenobiotic and drug metabolism. In recent decades, extensive research has aimed at developing in vitro liver models able to mimic liver functions to study pathophysiological clues in high-throughput and reproducible environments. Two-dimensional (2D) models have been widely used in screening potential toxic compounds but have failed to accurately reproduce the three-dimensionality (3D) of the liver milieu. To overcome these limitations, improved 3D culture techniques have been developed to recapitulate the hepatic native microenvironment. These models focus on reproducing the liver architecture, representing both parenchymal and nonparenchymal cells, as well as cell interactions. More recently, Liver-on-Chip (LoC) models have been developed with the aim of providing physiological fluid flow and thus achieving essential hepatic functions. Given their unprecedented ability to recapitulate critical features of the liver cellular environments, LoC have been extensively adopted in pathophysiological modelling and currently represent a promising tool for tissue engineering and drug screening applications. In this review, we discuss the evolution of experimental liver models, from the ancient 2D hepatocyte models, widely used for liver toxicity screening, to 3D and LoC culture strategies adopted for mirroring a more physiological microenvironment for the study of liver diseases.
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Affiliation(s)
- Michela Anna Polidoro
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Erika Ferrari
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Simona Marzorati
- Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Ana Lleo
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Marco Rasponi
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
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36
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Kitto LJ, Henderson NC. Hepatic Stellate Cell Regulation of Liver Regeneration and Repair. Hepatol Commun 2021; 5:358-370. [PMID: 33681672 PMCID: PMC7917274 DOI: 10.1002/hep4.1628] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/22/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
The hepatic mesenchyme has been studied extensively in the context of liver fibrosis; however, much less is known regarding the role of mesenchymal cells during liver regeneration. As our knowledge of the cellular and molecular mechanisms driving hepatic regeneration deepens, the key role of the mesenchymal compartment during the regenerative response has been increasingly appreciated. Single-cell genomics approaches have recently uncovered both spatial and functional zonation of the hepatic mesenchyme in homeostasis and following liver injury. Here we discuss how the use of preclinical models, from in vivo mouse models to organoid-based systems, are helping to shape our understanding of the role of the mesenchyme during liver regeneration, and how these approaches should facilitate the precise identification of highly targeted, pro-regenerative therapies for patients with liver disease.
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Affiliation(s)
- Laura J. Kitto
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUnited Kingdom
| | - Neil C. Henderson
- Centre for Inflammation ResearchThe Queen’s Medical Research InstituteEdinburgh BioQuarterUniversity of EdinburghEdinburghUnited Kingdom
- MRC Human Genetics UnitInstitute of Genetics and Molecular MedicineUniversity of EdinburghEdinburghUnited Kingdom
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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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38
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Kreisel W, Schaffner D, Lazaro A, Trebicka J, Merfort I, Schmitt-Graeff A, Deibert P. Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension. Int J Mol Sci 2020; 21:6223. [PMID: 32872119 PMCID: PMC7503357 DOI: 10.3390/ijms21176223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 08/23/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
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Affiliation(s)
- Wolfgang Kreisel
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Denise Schaffner
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
- Department of Radiology–Medical Physics, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Adhara Lazaro
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
| | - Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, 60590 Frankfurt, Germany;
| | - Irmgard Merfort
- Department of Pharmaceutical Biology and Biotechnology, University of Freiburg, 79104 Freiburg, Germany;
| | | | - Peter Deibert
- Institute for Exercise and Occupational Medicine, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; (D.S.); (A.L.); (P.D.)
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39
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Chowdhury E, Roberts J, Walz H, Hauck R, Morey A, Morgan S, Joiner K, Cattley R, Sengupta S, Wilson F, Hoerr F. Hepatic Perisinusoidal Myofibroblast Proliferation and Systemic Inflammatory Response Precedes Sep/Tox Hepatitis in Broilers. Avian Dis 2020; 65:10-17. [PMID: 34339116 DOI: 10.1637/aviandiseases-d-19-00157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 08/20/2020] [Indexed: 11/05/2022]
Abstract
Septicemia-toxemia (sep/tox) falls under U.S. Department of Agriculture (USDA) food safety Category 1 and is the most common and economically significant cause of broiler carcass condemnations. Hepatic lesions are considered a possible consequence of septicemia and associated bacterial contamination of the carcass. Thus, these lesions are considered an indicator of sep/tox (sep/tox hepatitis). This study was undertaken to analyze the histologic lesions preceding grossly visible liver lesions leading to condemnation because of sep/tox at the processing plant. Livers from carcasses of broilers condemned by USDA inspectors for sep/tox were used to establish microscopic and gross criteria of end-stage sep/tox hepatitis. Following the characterization of sep/tox hepatitis, broilers from a farm with a history of sep/tox condemnations were submitted for postmortem examination and bacteriologic investigation at four intervals during the final 20 days of production. Five healthy and five clinically ill chickens were submitted from four houses at 18, 25, 32, and 38 days of production (160 total). Microscopic lesions representing hepatic perisinusoidal myofibroblast proliferation (HPMP), periportal extramedullary granulopoiesis (PEMG), splenic follicular histiocytosis, and bone marrow cellularity (BMC) were graded subjectively for each bird, and subjective grading was evaluated with digital quantitative techniques. Perisinusoidal hepatic stellate cell morphology and progressive transformation of these cells into myofibroblasts was confirmed by immunohistochemistry for smooth muscle actin and desmin. Aerobic cultures of livers and gall bladders from sep/tox birds yielded no growth of bacteria associated with septicemia. Mild to severe HPMP was observed in all age groups, representing 28% of examined birds. Increases in inflammatory cells observed by PEMG and BMC were positively correlated with progressive HPMP and end-stage sep/tox hepatitis in broiler chickens.
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Affiliation(s)
- Erfan Chowdhury
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849.,Alabama Department of Agriculture and Industries, Veterinary Diagnostic Laboratory System, Auburn, AL 36832
| | - John Roberts
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849, .,Alabama Department of Agriculture and Industries, Veterinary Diagnostic Laboratory System, Auburn, AL 36832.,Department of Comparative, Diagnostic, and Population Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610
| | - Heather Walz
- Alabama Department of Agriculture and Industries, Veterinary Diagnostic Laboratory System, Auburn, AL 36832
| | - Rüdiger Hauck
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849.,Department of Poultry Science, College of Agriculture, Auburn University, AL 36849
| | - Amit Morey
- Department of Poultry Science, College of Agriculture, Auburn University, AL 36849
| | | | - Kellye Joiner
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849
| | - Russell Cattley
- Department of Pathobiology, College of Veterinary Medicine, Auburn University, AL 36849
| | | | - Floyd Wilson
- MVRDL & PVRDL, College of Veterinary Medicine, Mississippi State University, Pearl, MS 39288
| | - Frederic Hoerr
- Veterinary Diagnostic Pathology LLC, Fort Valley, VA 22652
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40
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Roife D, Sarcar B, Fleming JB. Stellate Cells in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1263:67-84. [PMID: 32588324 DOI: 10.1007/978-3-030-44518-8_6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
As tumor microenvironments share many of the same qualities as chronic wounds, attention is turning to the wound-repair cells that support the growth of cancerous cells. Stellate cells are star-shaped cells that were first discovered in the perisinusoidal spaces in the liver and have been found to support wound healing by the secretion of growth factors and extracellular matrix. They have since been also found to serve a similar function in the pancreas. In both organs, the wound-healing process may become dysregulated and lead to pathological fibrosis (also known as cirrhosis in the liver). In recent years there has been increasing attention paid to the role of these cells in tumor formation and progression. They may be a factor in initiating the first steps of carcinogenesis such as with liver cirrhosis and hepatocellular carcinoma and also contribute to continued tumor growth, invasion, metastasis, evasion of the immune system, and resistance to chemotherapy, in cancers of both the liver and pancreas. In this chapter we aim to review the structure and function of hepatic and pancreatic stellate cells and their contributions to the tumor microenvironment in their respective cancers and also discuss potential new targets for cancer therapy based on our new understanding of these vital components of the tumor stroma.
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Affiliation(s)
- David Roife
- Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL, USA.,Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Bhaswati Sarcar
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
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41
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Cengiz O, Baran M, Balcioglu E, Suna PA, Bilgici P, Goktepe O, Onder GO, Goc R, Yay A. Use of selenium to ameliorate doxorubicin induced hepatotoxicity by targeting pro-inflammatory cytokines. Biotech Histochem 2020; 96:67-75. [PMID: 32400214 DOI: 10.1080/10520295.2020.1760353] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Doxorubicin (DOX) is a widely used drug for the treatment of cancer,but its clinical use is limited by its liver toxicity. Administering DOX with an antioxidant has become a strategy for preventing the side effects of DOX. Although selenium (Se) is an important trace mineral, data concerning the effect of Se on DOX induced liver tissue are lacking. We investigated the mechanism of DOX hepatotoxicity and the protective effect of different doses of Se on Dox induced liver damage. Female Wistar albino rats were divided into eight equal groups. Se was injected intraperitoneally (i.p.) to rats at doses of 0.5, 1, and 2 mg 0.5 h after injection i.p. of 5 mg/kg DOX on days 1, 7, 14, 21 and 28. Liver histopathology was assessed to determine the dose at which Se may best inhibit Dox induced liver toxicity. Also, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) expression levels and proliferating cell nuclear antigen (PCNA) activity were determined using immunohistochemistry. We found that DOX caused liver damage and increased TNF-α, IL-1β and PCNA levels. Se prevented structural damage to liver tissues. Our findings reinforce the protective effects of Se in rat liver.
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Affiliation(s)
- Ozge Cengiz
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Munevver Baran
- Department of Pharmaceutical Basic Science, Faculty of Pharmacy, Erciyes University , Kayseri, Turkey
| | - Esra Balcioglu
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey.,Genome and Stem Cell Center (GENKOK), Erciyes University , Kayseri, Turkey
| | - Pinar Alisan Suna
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Pınar Bilgici
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Ozge Goktepe
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Gozde Ozge Onder
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Rumeysa Goc
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey
| | - Arzu Yay
- Faculty of Medicine, Department of Histology and Embryology, Erciyes University , Kayseri, Turkey.,Genome and Stem Cell Center (GENKOK), Erciyes University , Kayseri, Turkey
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42
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Zhang ZS, Zhou HN, He SS, Xue MY, Li T, Liu LM. Research advances in pericyte function and their roles in diseases. Chin J Traumatol 2020; 23:89-95. [PMID: 32192909 PMCID: PMC7156959 DOI: 10.1016/j.cjtee.2020.02.006] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Revised: 12/19/2019] [Accepted: 01/25/2020] [Indexed: 02/04/2023] Open
Abstract
Pericyte, a kind of pluripotent cell, may regulate the irrigation flow and permeability of microcirculation. Pericytes are similar to the smooth muscle cells, which express several kinds of contractile proteins and have contractility. The dysfunction of pericytes is related to many microvascular diseases, including hypoxia, hypertension, diabetic retinopathy, fibrosis, inflammation, Alzheimer's disease, multiple sclerosis, and tumor formation. For a long time, their existence and function have been neglected. The distribution, structure, biomarker, related signaling pathways as well as the roles of pericytes on vascular diseases will be introduced in this review.
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43
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Recent Advances in Practical Methods for Liver Cell Biology: A Short Overview. Int J Mol Sci 2020; 21:ijms21062027. [PMID: 32188134 PMCID: PMC7139397 DOI: 10.3390/ijms21062027] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/06/2020] [Accepted: 03/09/2020] [Indexed: 12/14/2022] Open
Abstract
Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
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44
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Yang J, Tao Q, Zhou Y, Chen Q, Li L, Hu S, Liu Y, Zhang Y, Shu J, Zhang X, Zhang L, Zhang L. MicroRNA-708 represses hepatic stellate cells activation and proliferation by targeting ZEB1 through Wnt/β-catenin pathway. Eur J Pharmacol 2020; 871:172927. [PMID: 31962101 DOI: 10.1016/j.ejphar.2020.172927] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 01/12/2020] [Accepted: 01/13/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is caused by a sustained wound healing response to chronic liver injury, and the activation of insubstantial hepatic stellate cells (HSCs) is the key process involved. The progression of liver fibrosis may be attenuated by suppressing activation and proliferation of the HSCs. MicroRNA (miRNA) have emerged as major players in governing fundamental biological processes through multiple mechanisms MiR-708 is known to inhibit the development of hepatocellular carcinoma. However, whether miR-708 can function as a transcriptional regulator in liver fibrosis remains unclear. Our study demonstrated that miR-708 expression was inhibited in fibrotic liver tissues and in activated HSCs, accompanied by an increase of the Zinc finger E-box binding homeobox 1 (ZEB1) level. Besides, overexpression of miR-708 and silencing of ZEB1 inhibited the activation and proliferation of LX-2 cells. While knockdown of miR-708 or overexpression of ZEB1 showed reversed results. Further, dual luciferase reporter assays showed that miR-708 directly targeted ZEB1 in vitro. Interestingly, ZEB1 was found to be involved in HSCs by regulating Wnt/β-catenin signaling pathway. Together, our data showed that miR-708 may be a potential therapeutic target in liver fibrosis therapy.
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Affiliation(s)
- Junfa Yang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China; School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qing Tao
- Department of Pathogen Biology, Anhui Medical University, China
| | - Yiwen Zhou
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Qingfeng Chen
- Clinic Medical College of Anhui Medical University, Hefei, 230032, China
| | - Liangyun Li
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Shuang Hu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yumin Liu
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China
| | - Yu Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Jinling Shu
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Xianzheng Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China
| | - Lei Zhang
- School of Pharmacy, Anhui Medical University, Hefei, 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Anhui Medical University, Hefei, 230032, China; Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, Hefei, 230032, China.
| | - Lingling Zhang
- Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Institute of Clinical Pharmacology, Anhui Medical University, Hefei, China.
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da Silva Meirelles L, Marson RF, Solari MIG, Nardi NB. Are Liver Pericytes Just Precursors of Myofibroblasts in Hepatic Diseases? Insights from the Crosstalk between Perivascular and Inflammatory Cells in Liver Injury and Repair. Cells 2020; 9:cells9010188. [PMID: 31940814 PMCID: PMC7017158 DOI: 10.3390/cells9010188] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/31/2019] [Accepted: 01/08/2020] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis, a late form of liver disease, is characterized by extensive scarring due to exacerbated secretion of extracellular matrix proteins by myofibroblasts that develop during this process. These myofibroblasts arise mainly from hepatic stellate cells (HSCs), liver-specific pericytes that become activated at the onset of liver injury. Consequently, HSCs tend to be viewed mainly as myofibroblast precursors in a fibrotic process driven by inflammation. Here, the molecular interactions between liver pericytes and inflammatory cells such as macrophages and neutrophils at the first moments after injury and during the healing process are brought into focus. Data on HSCs and pericytes from other tissues indicate that these cells are able to sense pathogen- and damage-associated molecular patterns and have an important proinflammatory role in the initial stages of liver injury. On the other hand, further data suggest that as the healing process evolves, activated HSCs play a role in skewing the initial proinflammatory (M1) macrophage polarization by contributing to the emergence of alternatively activated, pro-regenerative (M2-like) macrophages. Finally, data suggesting that some HSCs activated during liver injury could behave as hepatic progenitor or stem cells will be discussed.
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Affiliation(s)
- Lindolfo da Silva Meirelles
- PPGBioSaúde and School of Medicine, Lutheran University of Brazil, Av. Farroupilha 8001, 92425-900 Canoas, RS, Brazil
| | - Renan Fava Marson
- PPGBioSaúde, Lutheran University of Brazil, Av. Farroupilha 8001, 92425-900 Canoas, RS, Brazil
| | - Maria Inês Gonzalez Solari
- Institute of Cardiology of Rio Grande do Sul, Av Princesa Isabel 370, 90620-001 Porto Alegre, RS, Brazil
| | - Nance Beyer Nardi
- Institute of Cardiology of Rio Grande do Sul, Av Princesa Isabel 370, 90620-001 Porto Alegre, RS, Brazil
- Correspondence: ; Tel.: +55-51-3230-3600
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Shiraha H, Iwamuro M, Okada H. Hepatic Stellate Cells in Liver Tumor. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1234:43-56. [PMID: 32040854 DOI: 10.1007/978-3-030-37184-5_4] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are the most common types of primary liver cancers. Moreover, the liver is the second most frequently involved organ in cancer metastasis after lymph nodes. The tumor microenvironment is crucial for the development of both primary and secondary liver cancers. The hepatic microenvironment consists of multiple cell types, including liver sinusoidal endothelial cells, Kupffer cells, natural killer cells, liver-associated lymphocytes, and hepatic stellate cells (HSCs). The microenvironment of a normal liver changes to a tumor microenvironment when tumor cells exist or tumor cells migrate to and multiply in the liver. Interactions between tumor cells and non-transformed cells generate a tumor microenvironment that contributes significantly to tumor progression. HSCs play a central role in the tumor microenvironment crosstalk. As this crosstalk is crucial for liver carcinogenesis and liver-tumor development, elucidating the mechanism underlying the interaction of HSCs with the tumor microenvironment could provide potential therapeutic targets for liver cancer.
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Affiliation(s)
- Hidenori Shiraha
- Department of Gastroenterology and Hepatology, Okayama University Faculty of Medicine, Okayama, Japan.
| | - Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Faculty of Medicine, Okayama, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Faculty of Medicine, Okayama, Japan
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Deng B, Tang D, Qiang Y, Zheng X. Down-regulation of microRNA-31 suppresses hepatic fibrosis induced by carbon tetrachloride. EUR J INFLAMM 2020. [DOI: 10.1177/2058739220942630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
MicroRNA-31 (miR-31) is among the most frequently altered microRNAs in human diseases, and altered expression of miR-31 has been detected in a large variety of diseases types. miR-31 could also regulate a variety of cell functions including hepatic fibrosis. Hepatic stellate cells (HSCs) are regarded as the major cell type involved in hepatic fibrosis. Male BALB/c mice (five mice per group aged 6 weeks) received 200 μL of body weight of carbon tetrachloride (10% CCl4) mixed with olive oil intraperitoneally, and the first dose was doubled. To induce hepatic fibrosis, carbon tetrachloride was injected twice a week for 4, 6, 8, and 10 weeks. Control animals were injected with an equal volume of olive oil at the same time intervals. We found that miR-31 expression and fibrosis-related factors in four hepatic fibrosis stages. However, we noted that inhibition of miR-31 was down-regulated fibrosis-related factor expression in F1–F3 stages, but no F4 stage. Thus, we hypothesize that miR-31 may mediate hepatic fibrosis. In this research, we found that inhibition of miR-31 expression significantly inhibited HSC activation. The biological function of miR-31 during HSC activation might be through targeting hypoxia-inducible factor 1-alpha inhibitor (HIF1AN). Inhibition of miR-31 can reduce the transcription factor activity of hypoxia inducible factor 1 (HIF-1) by targeting the biological effects of HIF1AN with the condition of hypoxia. In later hepatic fibrosis could be rescue combining with inhibition of miR-31 and adding heparin-binding EGF-like growth factor (HBEGF).
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Affiliation(s)
- Bing Deng
- Department of Hepatobiliary Surgery, Second People’s Hospital of Jingmen, Jingmen, P.R. China
| | - Detao Tang
- Department of Gastrointestinal Surgery, Second People’s Hospital of Jingmen, Jingmen, P.R. China
| | - Yong Qiang
- Department of Hepatobiliary Surgery, Second People’s Hospital of Jingmen, Jingmen, P.R. China
| | - Xiang Zheng
- Department of Gastrointestinal Surgery, Second People’s Hospital of Jingmen, Jingmen, P.R. China
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48
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van der Heide D, Weiskirchen R, Bansal R. Therapeutic Targeting of Hepatic Macrophages for the Treatment of Liver Diseases. Front Immunol 2019; 10:2852. [PMID: 31849997 PMCID: PMC6901832 DOI: 10.3389/fimmu.2019.02852] [Citation(s) in RCA: 158] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/20/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatic macrophages play a central role in maintaining homeostasis in the liver, as well as in the initiation and progression of liver diseases. Hepatic macrophages are mainly derived from resident hepatic macrophages called Kupffer cells or circulating bone marrow-derived monocytes. Kupffer cells are self-renewing and typically non-migrating macrophages in the liver and are stationed in the liver sinusoids in contrast to macrophages originating from circulating monocytes. Kupffer cells regulate liver homeostasis by mediating immunity against non-pathogenic blood-borne molecules, while participating in coordinated immune responses leading to pathogen clearance, leukocyte recruitment and antigen presentation to lymphocytes present in the vasculature. Monocyte-derived macrophages infiltrate into the liver tissue when metabolic or toxic damage instigates and are likely dispensable for replenishing the macrophage population in homeostasis. In recent years, different populations of hepatic macrophages have been identified with distinct phenotypes with discrete functions, far beyond the central dogma of M1 and M2 macrophages. Hepatic macrophages play a central role in the pathogenesis of acute and chronic liver failure, liver fibrosis, non-alcoholic fatty liver disease, alcoholic liver disease, viral hepatitis, and hepatocellular carcinoma, as well as in disease resolution. The understanding of the role of hepatic macrophages in liver diseases provides opportunities for the development of targeted therapeutics for respective malignancies. This review will summarize the current knowledge of the hepatic macrophages, their origin, functions, their critical role in maintaining homeostasis and in the progression or resolution of liver diseases. Furthermore, we will provide a comprehensive overview of the therapeutic targeting strategies against hepatic macrophages developed for the treatment of liver diseases.
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Affiliation(s)
- Daphne van der Heide
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Aachen, Germany
| | - Ruchi Bansal
- Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Center, University of Twente, Enschede, Netherlands
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Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, Lokhonina AV, Sukhikh GT. Phenotypical and Functional Polymorphism of Liver Resident Macrophages. Cells 2019; 8:1032. [PMID: 31491903 PMCID: PMC6769646 DOI: 10.3390/cells8091032] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages.
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Affiliation(s)
- Andrey V Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Ministry of Healthcare of The Russian Federation, Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997, Russia.
| | - Timur Kh Fatkhudinov
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
- Scientific Research Institute of Human Morphology, 3 Tsurupa Street, Moscow 117418, Russia.
| | - Polina A Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
| | - Anastasia V Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
| | - Gennady T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
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50
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Xiong X, Kuang H, Ansari S, Liu T, Gong J, Wang S, Zhao XY, Ji Y, Li C, Guo L, Zhou L, Chen Z, Leon-Mimila P, Chung MT, Kurabayashi K, Opp J, Campos-Pérez F, Villamil-Ramírez H, Canizales-Quinteros S, Lyons R, Lumeng CN, Zhou B, Qi L, Huertas-Vazquez A, Lusis AJ, Xu XZS, Li S, Yu Y, Li JZ, Lin JD. Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis. Mol Cell 2019; 75:644-660.e5. [PMID: 31398325 PMCID: PMC7262680 DOI: 10.1016/j.molcel.2019.07.028] [Citation(s) in RCA: 524] [Impact Index Per Article: 87.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 04/15/2019] [Accepted: 07/19/2019] [Indexed: 12/27/2022]
Abstract
Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease.
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Affiliation(s)
- Xuelian Xiong
- Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Henry Kuang
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Sahar Ansari
- Department of Human Genetics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Tongyu Liu
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Jianke Gong
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, and Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuai Wang
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xu-Yun Zhao
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Yewei Ji
- Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Chuan Li
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Liang Guo
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Linkang Zhou
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Zhimin Chen
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Paola Leon-Mimila
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Meng Ting Chung
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
| | - Katsuo Kurabayashi
- Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48105, USA
| | - Judy Opp
- University of Michigan DNA Sequencing Core, University of Michigan, Ann Arbor, MI 48109, USA
| | - Francisco Campos-Pérez
- Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Dr. Rubén Lénero, Mexico City, Mexico
| | - Hugo Villamil-Ramírez
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Unidad de Genómica de Poblaciones Aplicada a la Salud, Mexico City, Mexico
| | - Samuel Canizales-Quinteros
- Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Unidad de Genómica de Poblaciones Aplicada a la Salud, Mexico City, Mexico
| | - Robert Lyons
- University of Michigan DNA Sequencing Core, University of Michigan, Ann Arbor, MI 48109, USA
| | - Carey N Lumeng
- Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Beiyan Zhou
- Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA
| | - Ling Qi
- Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Adriana Huertas-Vazquez
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - Aldons J Lusis
- Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA
| | - X Z Shawn Xu
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Siming Li
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Yonghao Yu
- Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jun Z Li
- Department of Human Genetics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
| | - Jiandie D Lin
- Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
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