|
1
|
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.
Collapse
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.
| |
Collapse
|
|
2
|
Xiang L, Qin Y, Li L, Xiang X, Zhang W, Jiao Q, Shao Y, Huang X, Wu M, Zhou T, Lin Y, Chen Y. Targeting hyperactive mitochondria in activated HSCs and inhibition of liver fibrogenesis in mice using sorafenib complex micelles. Int J Pharm 2025; 669:125058. [PMID: 39653289 DOI: 10.1016/j.ijpharm.2024.125058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/28/2024] [Accepted: 12/06/2024] [Indexed: 12/14/2024]
Abstract
Liver fibrosis is a pathological condition marked by the excessive buildup of extracellular matrix primarily resulting from the transformation of quiescent hepatic stellate cells (HSCs) to myofibroblastic (MF) phenotype and their resultant over-expansion. Activated HSCs completely rely on their hyperactive mitochondria to supply the energy and biomass for their rapid proliferation and collagen secretion, so an intervention targeting their mitochondria can effectively restrict their pathological amplification and contribution to liver fibrosis. Here we tried sorafenib, a drug that plays anticancer roles by inducing the disruption and loss of mitochondrial functions, to reach an antifibrotic goal. And a complex micellar system, VA-PEG-PCL/TPGS (VPP/TPGS), was specifically designed and fabricated to encapsulate and deliver sorafenib selectively to activated HSCs to overcome its application limitations in bioavailability, toxicity and intracellular stay, and eventually maximize its induction of mitochondrial dysfunction and therapeutically antifibrotic efficacy. The prepared sorafenib complex micelles not only exhibited a suitable particle size, uniform morphology, and nice stability, but also performed excellently in the biosafety and HSCs-targetability in vitro and in vivo. In human active HSC cell lines, they markedly attenuated mitochondrial hyperactivity, induced apoptosis, and downregulated fibrosis markers as expected; while in a CCl4-induced murine model of hepatic fibrosis, they effectively restricted the expansion of MF-HSCs, reduced collagen deposition, and promoted the healing of liver damage, showing a good potential in fibrosis curation. Collectively, our VPP/TPGS complex micelles provide an ideal drug delivery platform that has the potential to revolutionize the treatment of liver fibrosis via addressing its cellular and metabolic underpinnings and thus improve patient outcomes.
Collapse
Affiliation(s)
- Li Xiang
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China; Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China
| | - Yuting Qin
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Lei Li
- Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China
| | - Xianjing Xiang
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Wenhui Zhang
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Qiangqiang Jiao
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Yaru Shao
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Xinqiong Huang
- Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China
| | - Meichun Wu
- Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China
| | - Tianle Zhou
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Yukang Lin
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China
| | - Yuping Chen
- School of Pharmaceutical Sciences, University of South China, Hengyang 410001, China; Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China; MOE Key Laboratory of Rare Pediatric Diseases, Hengyang Medical School, University of South China, Hengyang, Hunan 410001, China.
| |
Collapse
|
|
3
|
Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
4
|
Wang T, Lu Z, Sun GF, He KY, Chen ZP, Qu XH, Han XJ. Natural Products in Liver Fibrosis Management: A Five-year Review. Curr Med Chem 2024; 31:5061-5082. [PMID: 38362686 DOI: 10.2174/0109298673288458240203064112] [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: 10/26/2023] [Revised: 01/11/2024] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
Liver fibrosis, characterized by the overproduction of extracellular matrix proteins within liver tissue, poses a rising global health concern. However, no approved antifibrotic drugs are currently available, highlighting the critical need for understanding the molecular mechanisms of liver fibrosis. This knowledge could not only aid in developing therapies but also enable early intervention, enhance disease prediction, and improve our understanding of the interaction between various underlying conditions and the liver. Notably, natural products used in traditional medicine systems worldwide and demonstrating diverse biochemical and pharmacological activities are increasingly recognized for their potential in treating liver fibrosis. This review aims to comprehensively understand liver fibrosis, emphasizing the molecular mechanisms and advancements in exploring natural products' antifibrotic potential over the past five years. It also acknowledges the challenges in their development and seeks to underscore their potency in enhancing patient prognosis and reducing the global burden of liver disease.
Collapse
Affiliation(s)
- Tao Wang
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhuo Lu
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, P.R. China
| | - Gui-Feng Sun
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Kai-Yi He
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Zhi-Ping Chen
- Department of Critical Care Medicine, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xin-Hui Qu
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| | - Xiao-Jian Han
- Institute of Geriatrics, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
- The Second Department of Neurology, Jiangxi Provincial People's Hospital, the First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, 330006, P.R. China
| |
Collapse
|
|
5
|
Petri BJ, Cave MC, Klinge CM. Changes in m6A in Steatotic Liver Disease. Genes (Basel) 2023; 14:1653. [PMID: 37628704 PMCID: PMC10454815 DOI: 10.3390/genes14081653] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/10/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Fatty liver disease is one of the major causes of morbidity and mortality worldwide. Fatty liver includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), now replaced by a consensus group as metabolic dysfunction-associated steatotic liver disease (MASLD). While excess nutrition and obesity are major contributors to fatty liver, the underlying mechanisms remain largely unknown and therapeutic interventions are limited. Reversible chemical modifications in RNA are newly recognized critical regulators controlling post-transcriptional gene expression. Among these modifications, N6-methyladenosine (m6A) is the most abundant and regulates transcript abundance in fatty liver disease. Modulation of m6A by readers, writers, and erasers (RWE) impacts mRNA processing, translation, nuclear export, localization, and degradation. While many studies focus on m6A RWE expression in human liver pathologies, limitations of technology and bioinformatic methods to detect m6A present challenges in understanding the epitranscriptomic mechanisms driving fatty liver disease progression. In this review, we summarize the RWE of m6A and current methods of detecting m6A in specific genes associated with fatty liver disease.
Collapse
Affiliation(s)
- Belinda J. Petri
- Department of Biochemistry, University of Louisville School of Medicine, Louisville, KY 40292, USA;
| | - Matthew C. Cave
- Center for Integrative Environmental Health Sciences (CIEHS), University of Louisville, Louisville, KY 40292, USA;
- Hepatobiology and Toxicology Center, University of Louisville, Louisville, KY 40292, USA
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, KY 40292, USA
| | - Carolyn M. Klinge
- Department of Biochemistry, University of Louisville School of Medicine, Louisville, KY 40292, USA;
- Center for Integrative Environmental Health Sciences (CIEHS), University of Louisville, Louisville, KY 40292, USA;
| |
Collapse
|
|
6
|
Mak KM, Wu C, Cheng CP. Lipid droplets, the Holy Grail of hepatic stellate cells: In health and hepatic fibrosis. Anat Rec (Hoboken) 2022; 306:983-1010. [PMID: 36516055 DOI: 10.1002/ar.25138] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/07/2022] [Accepted: 11/29/2022] [Indexed: 12/15/2022]
Abstract
Lipid droplets (LDs) are distinct morphological markers of hepatic stellate cells (HSCs). They are composed of a core of predominantly retinyl esters and triacylglycerols surrounded by a phospholipid layer; the latter harbors perilipins 2, 3, and 5, which help control LD lipolysis. Electron microscopy distinguishes between Types I and II LDs. Type I LDs are surrounded by acid phosphatase-positive lysosomes, which likely digest LDs. LD count and retinoid concentration are modulated by vitamin A intake. Alcohol consumption depletes hepatic retinoids and HSC LDs, with concomitant transformation of HSCs to fibrogenic myofibroblast-like cells. LD loss and accompanying HSC activation occur in HSC cell culture models. Loss of LDs is a consequence of and not a prerequisite for HSC activation. LDs are endowed with enzymes for synthesizing retinyl esters and triacylglycerols as well as neutral lipases and lysosomal acid lipase for breaking down LDs. HSCs have two distinct metabolic LD pools: an "original" pool in quiescent HSCs and a "new" pool emerging in HSC activation; this two-pool model provides a platform for analyzing LD dynamics in HSC activation. Besides lipolysis, LDs are degraded by lipophagy; however, the coordination between and relative contributions of these two pathways to LD removal are unclear. While induction of autophagy accelerates LD loss in quiescent HSCs and promotes HSC activation, blocking autophagy impairs LD degradation and inhibits HSC activation and fibrosis. This article is a critique of five decades of investigations into the morphology, molecular structure, synthesis, and degradation of LDs associated with HSC activation and fibrosis.
Collapse
Affiliation(s)
- Ki M Mak
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Catherine Wu
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Christopher P Cheng
- Department of Medical Education and Center for Anatomy and Functional Morphology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Mooli RGR, Mukhi D, Ramakrishnan SK. Oxidative Stress and Redox Signaling in the Pathophysiology of Liver Diseases. Compr Physiol 2022; 12:3167-3192. [PMID: 35578969 PMCID: PMC10074426 DOI: 10.1002/cphy.c200021] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The increased production of derivatives of molecular oxygen and nitrogen in the form of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to molecular damage called oxidative stress. Under normal physiological conditions, the ROS generation is tightly regulated in different cells and cellular compartments. Any disturbance in the balance between the cellular generation of ROS and antioxidant balance leads to oxidative stress. In this article, we discuss the sources of ROS (endogenous and exogenous) and antioxidant mechanisms. We also focus on the pathophysiological significance of oxidative stress in various cell types of the liver. Oxidative stress is implicated in the development and progression of various liver diseases. We narrate the master regulators of ROS-mediated signaling and their contribution to liver diseases. Nonalcoholic fatty liver diseases (NAFLD) are influenced by a "multiple parallel-hit model" in which oxidative stress plays a central role. We highlight the recent findings on the role of oxidative stress in the spectrum of NAFLD, including fibrosis and liver cancer. Finally, we provide a brief overview of oxidative stress biomarkers and their therapeutic applications in various liver-related disorders. Overall, the article sheds light on the significance of oxidative stress in the pathophysiology of the liver. © 2022 American Physiological Society. Compr Physiol 12:3167-3192, 2022.
Collapse
Affiliation(s)
- Raja Gopal Reddy Mooli
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Dhanunjay Mukhi
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sadeesh K Ramakrishnan
- Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
9
|
Ding Z, Cheng R, Liu J, Zhao Y, Ge W, Yang Y, Xu X, Wang S, Zhang J. The suppression of pancreatic lipase-related protein 2 ameliorates experimental hepatic fibrosis in mice. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159102. [PMID: 34995790 DOI: 10.1016/j.bbalip.2021.159102] [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: 06/05/2021] [Revised: 11/20/2021] [Accepted: 12/15/2021] [Indexed: 11/24/2022]
Abstract
Quiescent hepatic stellate cells (HSCs) store vitamin A as lipid droplets in the cytoplasm. When activated, these cells lose vitamin A and exhibit an increased capacity for proliferation, mobility, contractility, and the synthesis of collagen and other components of the extracellular matrix. Our previous work demonstrated that the lipid hydrolytic gene pancreatic lipase-related protein 2 (mPlrp2) is involved in the hydrolysis of retinyl esters (REs) in the liver. Here, we showed that bile duct ligation (BDL)-induced liver injury triggered the conditional expression of mPlrp2 in livers and describe evidence of a strong relationship between the expression of mPlrp2 and Acta-2, a marker for activated HSCs. RNA interference targeting mPlrp2 inhibited HSC activation and ameliorated hepatic fibrosis induced by BDL in mice. Liver BDL markedly reduced the adenosine level and increased the ratio between S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH). Chromatin immunoprecipitation (ChIP) analysis demonstrated an increase in trimethylated histone H3K4 at the mPlrp2 promoter in BDL mice, which was associated with the conditional expression of mPlrp2 in the liver. SAM, a well-known hepatoprotective substance, inhibited mPlrp2 expression and reduced RE hydrolysis in mice with hepatic fibrosis induced by chronic CCl4 treatment. Liver fibrosis induced by CCl4 or BDL was improved in Plrp2-/- mice. Our results reveal that mPlrp2 suppression is a potential approach for treating hepatic fibrosis.
Collapse
Affiliation(s)
- Zhao Ding
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Rui Cheng
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Junhao Liu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yang Zhao
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Wenhao Ge
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Yunxia Yang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Xi Xu
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Shiming Wang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China
| | - Jianfa Zhang
- Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, China.
| |
Collapse
|
|
10
|
Song D, Xu Y, Liu S, Wen L, Wang X. Progress of 3D Bioprinting in Organ Manufacturing. Polymers (Basel) 2021; 13:3178. [PMID: 34578079 PMCID: PMC8468820 DOI: 10.3390/polym13183178] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 01/17/2023] Open
Abstract
Three-dimensional (3D) bioprinting is a family of rapid prototyping technologies, which assemble biomaterials, including cells and bioactive agents, under the control of a computer-aided design model in a layer-by-layer fashion. It has great potential in organ manufacturing areas with the combination of biology, polymers, chemistry, engineering, medicine, and mechanics. At present, 3D bioprinting technologies can be used to successfully print living tissues and organs, including blood vessels, skin, bones, cartilage, kidney, heart, and liver. The unique advantages of 3D bioprinting technologies for organ manufacturing have improved the traditional medical level significantly. In this article, we summarize the latest research progress of polymers in bioartificial organ 3D printing areas. The important characteristics of the printable polymers and the typical 3D bioprinting technologies for several complex bioartificial organs, such as the heart, liver, nerve, and skin, are introduced.
Collapse
Affiliation(s)
- Dabin Song
- Center of 3D Printing & Organ Manufacturing, School of Intelligent Medicine, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; (D.S.); (Y.X.); (S.L.); (L.W.)
| | - Yukun Xu
- Center of 3D Printing & Organ Manufacturing, School of Intelligent Medicine, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; (D.S.); (Y.X.); (S.L.); (L.W.)
| | - Siyu Liu
- Center of 3D Printing & Organ Manufacturing, School of Intelligent Medicine, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; (D.S.); (Y.X.); (S.L.); (L.W.)
| | - Liang Wen
- Center of 3D Printing & Organ Manufacturing, School of Intelligent Medicine, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; (D.S.); (Y.X.); (S.L.); (L.W.)
| | - Xiaohong Wang
- Center of 3D Printing & Organ Manufacturing, School of Intelligent Medicine, China Medical University (CMU), No. 77 Puhe Road, Shenyang North New Area, Shenyang 110122, China; (D.S.); (Y.X.); (S.L.); (L.W.)
- Key Laboratory for Advanced Materials Processing Technology, Department of Mechanical Engineering, Tsinghua University, Ministry of Education & Center of Organ Manufacturing, Beijing 100084, China
| |
Collapse
|
|
11
|
Carazo A, Macáková K, Matoušová K, Krčmová LK, Protti M, Mladěnka P. Vitamin A Update: Forms, Sources, Kinetics, Detection, Function, Deficiency, Therapeutic Use and Toxicity. Nutrients 2021; 13:1703. [PMID: 34069881 PMCID: PMC8157347 DOI: 10.3390/nu13051703] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/07/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Vitamin A is a group of vital micronutrients widely present in the human diet. Animal-based products are a rich source of the retinyl ester form of the vitamin, while vegetables and fruits contain carotenoids, most of which are provitamin A. Vitamin A plays a key role in the correct functioning of multiple physiological functions. The human organism can metabolize natural forms of vitamin A and provitamin A into biologically active forms (retinol, retinal, retinoic acid), which interact with multiple molecular targets, including nuclear receptors, opsin in the retina and, according to the latest research, also some enzymes. In this review, we aim to provide a complex view on the present knowledge about vitamin A ranging from its sources through its physiological functions to consequences of its deficiency and metabolic fate up to possible pharmacological administration and potential toxicity. Current analytical methods used for its detection in real samples are included as well.
Collapse
Affiliation(s)
- Alejandro Carazo
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
| | - Kateřina Macáková
- Department of Pharmacognosy, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
| | - Kateřina Matoušová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; (K.M.); (L.K.K.)
| | - Lenka Kujovská Krčmová
- Department of Clinical Biochemistry and Diagnostics, University Hospital Hradec Králové, Sokolská 581, 500 05 Hradec Králové, Czech Republic; (K.M.); (L.K.K.)
- Department of Analytical Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic
| | - Michele Protti
- The Department of Pharmacy and Biotechnology (FaBiT), Alma Mater Studiorum–University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy;
| | - Přemysl Mladěnka
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic;
| |
Collapse
|
|
12
|
Khanam A, Saleeb PG, Kottilil S. Pathophysiology and Treatment Options for Hepatic Fibrosis: Can It Be Completely Cured? Cells 2021; 10:cells10051097. [PMID: 34064375 PMCID: PMC8147843 DOI: 10.3390/cells10051097] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/26/2021] [Accepted: 05/01/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic fibrosis is a dynamic process that occurs as a wound healing response against liver injury. During fibrosis, crosstalk between parenchymal and non-parenchymal cells, activation of different immune cells and signaling pathways, as well as a release of several inflammatory mediators take place, resulting in inflammation. Excessive inflammation drives hepatic stellate cell (HSC) activation, which then encounters various morphological and functional changes before transforming into proliferative and extracellular matrix (ECM)-producing myofibroblasts. Finally, enormous ECM accumulation interferes with hepatic function and leads to liver failure. To overcome this condition, several therapeutic approaches have been developed to inhibit inflammatory responses, HSC proliferation and activation. Preclinical studies also suggest several targets for the development of anti-fibrotic therapies; however, very few advanced to clinical trials. The pathophysiology of hepatic fibrosis is extremely complex and requires comprehensive understanding to identify effective therapeutic targets; therefore, in this review, we focus on the various cellular and molecular mechanisms associated with the pathophysiology of hepatic fibrosis and discuss potential strategies to control or reverse the fibrosis.
Collapse
Affiliation(s)
- Arshi Khanam
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Paul G. Saleeb
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Shyam Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Correspondence: ; Tel.: +1-410-706-4872
| |
Collapse
|
|
13
|
Guillon C, Ferraro S, Clément S, Bouschbacher M, Sigaudo-Roussel D, Bonod C. Glycation by glyoxal leads to profound changes in the behavior of dermal fibroblasts. BMJ Open Diabetes Res Care 2021; 9:9/1/e002091. [PMID: 33903117 PMCID: PMC8076933 DOI: 10.1136/bmjdrc-2020-002091] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/17/2021] [Accepted: 03/21/2021] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Diabetes is a worldwide health problem that is associated with severe complications. Advanced Glycation End products (AGEs) such as Nε-(carboxymethyl)lysine, which result from chronic hyperglycemia, accumulate in the skin of patients with diabetes. The effect of AGEs on fibroblast functionality and their impact on wound healing are still poorly understood. RESEARCH DESIGN AND METHODS To investigate this, we treated cultured human fibroblasts with 0.6 mM glyoxal to induce acute glycation. The behavior of fibroblasts was analyzed by time-lapse monolayer wounding healing assay, seahorse technology and atomic force microscopy. Production of extracellular matrix was studied by transmission electronic microscopy and western blot. Lipid metabolism was investigated by staining of lipid droplets (LDs) with BODIPY 493/503. RESULTS We found that the proliferative and migratory capacities of the cells were greatly reduced by glycation, which could be explained by an increase in fibroblast tensile strength. Measurement of the cellular energy balance did not indicate that there was a change in the rate of oxygen consumption of the fibroblasts. Assessment of collagen I revealed that glyoxal did not influence type I collagen secretion although it did disrupt collagen I maturation and it prevented its deposition in the extracellular matrix. We noted a pronounced increase in the number of LDs after glyoxal treatment. AMPK phosphorylation was reduced by glyoxal treatment but it was not responsible for the accumulation of LDs. CONCLUSION Glyoxal promotes a change in fibroblast behavior in favor of lipogenic activity that could be involved in delaying wound healing.
Collapse
Affiliation(s)
- Cécile Guillon
- Urgo Research Innovation and Development, Chenôve, France
- Université de Lyon, Université Claude Bernard Lyon 1, CNRS, LBTI UMR 5305, Lyon, France
| | - Sandra Ferraro
- Université de Lyon, Université Claude Bernard Lyon 1, CNRS, LBTI UMR 5305, Lyon, France
| | - Sophie Clément
- Urgo Research Innovation and Development, Chenôve, France
| | | | | | - Christelle Bonod
- Université de Lyon, Université Claude Bernard Lyon 1, CNRS, LBTI UMR 5305, Lyon, France
| |
Collapse
|
|
14
|
Sufleţel RT, Melincovici CS, Gheban BA, Toader Z, Mihu CM. Hepatic stellate cells - from past till present: morphology, human markers, human cell lines, behavior in normal and liver pathology. ROMANIAN JOURNAL OF MORPHOLOGY AND EMBRYOLOGY 2021; 61:615-642. [PMID: 33817704 PMCID: PMC8112759 DOI: 10.47162/rjme.61.3.01] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Hepatic stellate cell (HSC), initially analyzed by von Kupffer, in 1876, revealed to be an extraordinary mesenchymal cell, essential for both hepatocellular function and lesions, being the hallmark of hepatic fibrogenesis and carcinogenesis. Apart from their implications in hepatic injury, HSCs play a vital role in liver development and regeneration, xenobiotic response, intermediate metabolism, and regulation of immune response. In this review, we discuss the current state of knowledge regarding HSCs morphology, human HSCs markers and human HSC cell lines. We also summarize the latest findings concerning their roles in normal and liver pathology, focusing on their impact in fibrogenesis, chronic viral hepatitis and liver tumors.
Collapse
Affiliation(s)
- Rada Teodora Sufleţel
- Discipline of Histology, Department of Morphological Sciences, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;
| | | | | | | | | |
Collapse
|
|
15
|
Ba HZ, Liang ZH, Kim HS, Cao W. TGF- β1 can be regulated by NDRG2 via the NF-κB pathway in hypoxia-induced liver fibrosis. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:505. [PMID: 33850902 PMCID: PMC8039646 DOI: 10.21037/atm-21-1298] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Background The identification of the important elements that control hepatic stellate cell (HSC) activation will expand our understanding of the mechanism of liver fibrosis induced by hypoxia and affect the outcome of clinical treatment. A previous research demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) is a potential regulator of fibrosis and a downstream target gene of hypoxia-inducible factor 1 (HIF-1). In this research, we studied the expression and function of NDRG2 in liver fibrosis induced by hypoxia. Methods LX-2 cells/NF-κB-silenced LX-2 cells were exposed to hypoxic conditions (1% O2) to activate HSCs in vitro. The protein and mRNA expression levels of NDRG2, α-SMA and transforming growth factor beta 1 (TGF-β1) were evaluated by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. Functional studies were performed using adenovirus-mediated gene upregulation. Results The NDRG2 mRNA and protein levels were reduced under hypoxic conditions in LX-2 cells and overexpression of NDRG2 resulted in a decrease in the expression of TGF-β1 and α-SMA. Interestingly, no relationship was observed between NDRG2 and TGF-β1 when the NF-κB pathway was blocked, which indicates that NDRG2 can regulate the expression of TGF-β1 in LX-2 cells via the NF-κB pathway under hypoxic conditions. Conclusions NDRG2 may regulate the expression of TGF-β1 via the NF-κB pathway and may be a novel therapeutic target for liver fibrosis induced by hypoxia.
Collapse
Affiliation(s)
- Hong-Zhen Ba
- Department of Medical Imaging, Yan'an University Medical College, Yan'an, China
| | - Zhi-Hui Liang
- Department of Radiology, The 980 Hospital of PLA Logistic Force, Shijiazhuang, China
| | - Hyung Sik Kim
- School of Pharmacy, Sungkyunkwan University, Suwon, Korea
| | - Wei Cao
- Department of Interventional Radiology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
16
|
Maharjan S, Bonilla D, Sindurakar P, Li H, Li W, Duarte S, Zarrinpar A, Zhang YS. 3D human nonalcoholic hepatic steatosis and fibrosis models. Biodes Manuf 2021. [DOI: 10.1007/s42242-020-00121-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
17
|
He X, Chen J, Mu Y, Zhang H, Chen G, Liu P, Liu W. The effects of inhibiting the activation of hepatic stellate cells by lignan components from the fruits of Schisandra chinensis and the mechanism of schisanhenol. J Nat Med 2020; 74:513-524. [PMID: 32193805 DOI: 10.1007/s11418-020-01394-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 03/06/2020] [Indexed: 12/15/2022]
Abstract
Liver fibrosis is a pathological manifestation induced by chronic liver injury and may cause cirrhosis and liver cancer with the chronic progression of fibrosis. During the onset and progression of liver fibrosis, the activation of hepatic stellate cells (HSCs) is the core mechanism for the secretion of many extracellular matrices to induce fibrosis. Lignans are reportedly the main effective components of Schisandra chinensis with good anti-fibrosis effects. In this study, we compared the inhibiting effects of the seven lignan components from S. chinensis on HSC activation. We found that the seven lignans inhibited the activation of human HSCs (LX-2) in various degrees. Among all lignans, schisanhenol showed the best effect in inhibiting the activation of LX-2 with a dose-effect relationship. Sal also inhibited the phosphorylations of Smad1, Smad2, Smad3, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), p38, and nuclear transcription factor-κB (NF-κB), as well as downregulated Smad4. All these findings suggested that schisanhenol may ameliorate liver fibrosis by inhibiting the transforming growth factor β (TGF-β)/Smad and mitogen-activated protein kinase (MAPK) signaling pathways. Remarkably, schisanhenol may be a potential anti-liver fibrosis drug and warrants further research.
Collapse
Affiliation(s)
- Xiaoli He
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- TCM Department, Ningbo Huamei Hospital Affiliated to Chinese Academy of Sciences, 41 Xibei Road, Ningbo, 315010, China
| | - Jiamei Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Yongping Mu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Hua Zhang
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Gaofeng Chen
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China
| | - Ping Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
| | - Wei Liu
- Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, 528 Zhangheng Road, Shanghai, 201203, China.
| |
Collapse
|
|
18
|
Kuznetsova D, Rodimova S, Gulin A, Reunov D, Bobrov N, Polozova A, Vasin A, Shcheslavskiy V, Vdovina N, Zagainov V, Zagaynova E. Metabolic imaging and secondary ion mass spectrometry to define the structure and function of liver with acute and chronic pathology. JOURNAL OF BIOMEDICAL OPTICS 2019; 25:1-14. [PMID: 31849207 PMCID: PMC7008498 DOI: 10.1117/1.jbo.25.1.014508] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/03/2019] [Indexed: 05/09/2023]
Abstract
Conventional techniques are insufficient precisely to describe the internal structure, the heterogeneous cell populations, and the dynamics of biological processes occurring in diseased liver during surgery. There is a need for a rapid and safe method for the successful diagnosis of liver disease in order to plan surgery and to help avoid postoperative liver failure. We analyze the progression of both acute (cholestasis) and chronic (fibrosis) liver pathology using multiphoton microscopy with fluorescence lifetime imaging and second-harmonic generation modes combined with time-of-flight secondary ion mass spectrometry chemical analysis to obtain new data about pathological changes to hepatocytes at the cellular and molecular levels. All of these techniques allow the study of cellular metabolism, lipid composition, and collagen structure without staining the biological materials or the incorporation of fluorescent or other markers, enabling the use of these methods in a clinical situation. The combination of multiphoton microscopy and mass spectrometry provides more complete information about the liver structure and function than could be assessed using either method individually. The data can be used both to obtain new criteria for the identification of hepatic pathology and to develop a rapid technique for liver quality analysis in order to plan surgery and to help avoid postoperative liver failure in clinic.
Collapse
Affiliation(s)
- Daria Kuznetsova
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
- Address all correspondence to Daria Kuznetsova, E-mail:
| | - Svetlana Rodimova
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
| | - Alexander Gulin
- Russian Academy of Sciences, N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
- Lomonosov Moscow State University, Department of Chemistry, Moscow, Russia
| | - Dmitry Reunov
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
| | - Nikolai Bobrov
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
- Federal Medical and Biological Agency, Volga District Medical Centre, Nizhny Novgorod, Russia
| | - Anastasia Polozova
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
| | - Alexander Vasin
- Russian Academy of Sciences, N.N. Semenov Federal Research Center for Chemical Physics, Moscow, Russia
- Lomonosov Moscow State University, Department of Chemistry, Moscow, Russia
| | - Vladislav Shcheslavskiy
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
- Becker & Hickl GmbH, Berlin, Germany
| | - Natalia Vdovina
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
| | - Vladimir Zagainov
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
- Federal Medical and Biological Agency, Volga District Medical Centre, Nizhny Novgorod, Russia
| | - Elena Zagaynova
- Privolzhsky Research Medical University, Institute of Experimental Oncology and Biomedical Technologies, Nizhny Novgorod, Russia
| |
Collapse
|
|
19
|
Attrill E, Ramsay C, Ross R, Richards S, Sutherland BA, Keske MA, Eringa E, Premilovac D. Metabolic-vascular coupling in skeletal muscle: A potential role for capillary pericytes? Clin Exp Pharmacol Physiol 2019; 47:520-528. [PMID: 31702069 DOI: 10.1111/1440-1681.13208] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 10/22/2019] [Accepted: 11/05/2019] [Indexed: 01/23/2023]
Abstract
The matching of capillary blood flow to metabolic rate of the cells within organs and tissues is a critical microvascular function which ensures appropriate delivery of hormones and nutrients, and the removal of waste products. This relationship is particularly important in tissues where local metabolism, and hence capillary blood flow, must be regulated to avoid a mismatch between nutrient demand and supply that would compromise normal function. The consequences of a mismatch in microvascular blood flow and metabolism are acutely apparent in the brain and heart, where a sudden cessation of blood flow, for example following an embolism, acutely manifests as stroke or myocardial infarction. Even in more resilient tissues such as skeletal muscle, a short-term mismatch reduces muscle performance and exercise tolerance, and can cause intermittent claudication. In the longer-term, a microvascular-metabolic mismatch in skeletal muscle reduces insulin-mediated muscle glucose uptake, leading to disturbances in whole-body metabolic homeostasis. While the notion that capillary blood flow is fine-tuned to meet cellular metabolism is well accepted, the mechanisms that control this function and where and how different parts of the vascular tree contribute to capillary blood flow regulation remain poorly understood. Here, we discuss the emerging evidence implicating pericytes, mural cells that surround capillaries, as key mediators that match tissue metabolic demand with adequate capillary blood flow in a number of organs, including skeletal muscle.
Collapse
Affiliation(s)
- Emily Attrill
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| | - Ciaran Ramsay
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| | - Renee Ross
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| | - Stephen Richards
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| | - Brad A Sutherland
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| | - Michelle A Keske
- The Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Melbourne, Vic., Australia
| | - Etto Eringa
- Laboratory for Physiology, VU University Medical Center, Amsterdam, The Netherlands
| | - Dino Premilovac
- School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tas, Australia
| |
Collapse
|
|
20
|
Kostallari E, Shah VH. Pericytes in the Liver. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1122:153-167. [PMID: 30937868 DOI: 10.1007/978-3-030-11093-2_9] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Liver pericytes, commonly named hepatic stellate cells (HSCs), reside in the space between liver sinusoidal endothelial cells (LSECs) and hepatocytes. They display important roles in health and disease. HSCs ensure the storage of the majority of vitamin A in a healthy body, and they represent the major source of fibrotic tissue in liver disease. Surrounding cells, such as LSECs, hepatocytes, and Kupffer cells, present a significant role in modulating HSC behavior. Therapeutic strategies against liver disease are being currently developed, where HSCs represent an ideal target. In this chapter, we will discuss HSC quiescence and activation in the context of healthy liver and diseases, such as fibrosis, steatohepatitis, and hepatocellular carcinoma.
Collapse
Affiliation(s)
- Enis Kostallari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
| |
Collapse
|
|
21
|
Shajari S, Saeed A, Smith-Cortinez NF, Heegsma J, Sydor S, Faber KN. Hormone-sensitive lipase is a retinyl ester hydrolase in human and rat quiescent hepatic stellate cells. Biochim Biophys Acta Mol Cell Biol Lipids 2019; 1864:1258-1267. [PMID: 31150775 DOI: 10.1016/j.bbalip.2019.05.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/13/2019] [Accepted: 05/24/2019] [Indexed: 01/04/2023]
Abstract
Hepatic stellate cells (HSC) store vitamin A as retinyl esters and control circulating retinol levels. Upon liver injury, quiescent (q)HSC lose their vitamin A and transdifferentiate to myofibroblasts, e.g. activated (a)HSC, which promote fibrosis by producing excessive extracellular matrix. Adipose triglyceride lipase/patatin-like phospholipase domain-containing protein 2 (ATGL/PNPLA2) and adiponutrin (ADPN/PNPLA3) have so far been shown to mobilize retinol from retinyl esters in HSC. Here, we studied the putative role of hormone-sensitive lipase (HSL/LIPE) in HSC, as it is the major retinyl ester hydrolase (REH) in adipose tissue. Lipe/HSL expression was analyzed in rat liver and primary human and rat qHSC and culture-activated aHSC. Retinyl hydrolysis was analyzed after Isoproterenol-mediated phosphorylation/activation of HSL. Primary human HSC contain 2.5-fold higher LIPE mRNA levels compared to hepatocytes. Healthy rat liver contains significant mRNA and protein levels of HSL/Lipe, which predominates in qHSC and cells of the portal tree. Q-PCR comparison indicates that Lipe mRNA levels in qHSC are dominant over Pnpla2 and Pnpla3. HSL is mostly phosphorylated/activated in qHSC and partly colocalizes with vitamin A-containing lipid droplets. Lipe/HSL and Pnpla3 expression is rapidly lost during HSC culture-activation, while Pnpla2 expression is maintained. HSL super-activation by isoproterenol accelerates loss of lipid droplets and retinyl palmitate from HSC, which coincided with a small, but significant reduction in HSC proliferation and suppression of Collagen1A1 mRNA and protein levels. In conclusion, HSL participates in vitamin A metabolism in qHSC. Equivalent activities of ATGL and ADPN provide the healthy liver with multiple routes to control circulating retinol levels.
Collapse
Affiliation(s)
- Shiva Shajari
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Ali Saeed
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Institute of Molecular Biology & Biotechnology, Bahauddin Zakariya University, Multan, Pakistan
| | - Natalia F Smith-Cortinez
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Janette Heegsma
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Svenja Sydor
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University Magdeburg, Magdeburg, Germany
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
| |
Collapse
|
|
22
|
Davidson MD, Song KH, Lee MH, Llewellyn J, Du Y, Baker BM, Wells RG, Burdick JA. Engineered Fibrous Networks To Investigate the Influence of Fiber Mechanics on Myofibroblast Differentiation. ACS Biomater Sci Eng 2019; 5:3899-3908. [PMID: 33438429 DOI: 10.1021/acsbiomaterials.8b01276] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Tissue fibrosis is a leading cause of mortality and is characterized by excessive protein deposition and altered tissue mechanical properties. In pathological fibrosis, as well as cancer related fibrosis, tissue pericytes and fibroblasts transition from a quiescent to a myofibroblastic phenotype. In vitro models are needed to better understand how these cells are influenced by their local microenvironment. Here, we developed a fibrous network platform to mimic the structure of the extracellular matrix, where fibers consist of cross-linked hyaluronic acid hydrogels with controlled cross-link density and mechanical properties. As a model myofibroblast precursor, primary hepatic stellate cells were seeded onto fibers with either low (soft) or high (stiff) cross-link density, either directly after isolation (quiescent) or following preculture on tissue culture plates (activated). In general, both quiescent and activated cells showed an increase in spreading, alpha smooth muscle actin expression, and the formation of multicellular clusters on soft fibers when compared to stiff fibers. Further, inhibition of alpha smooth muscle actin decreased activation of cells on soft fibers. This is likely due to fiber recruitment in soft fibers that increased local fiber density, whereas stiff fibers resisted recruitment. This work emphasizes the importance of substrate topography on cell-material interactions and shows that tunable fibrous hydrogels are a relevant culture platform for studying fibrosis and mechanotransduction in disease.
Collapse
Affiliation(s)
- Matthew D Davidson
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Kwang Hoon Song
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Mu-Huan Lee
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Jessica Llewellyn
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Yu Du
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Brendon M Baker
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Rebecca G Wells
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| | - Jason A Burdick
- Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.,NSF Science and Technology Center for Engineering Mechanobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States
| |
Collapse
|
|
23
|
Role of hepatic stellate cell (HSC)-derived cytokines in hepatic inflammation and immunity. Cytokine 2018; 124:154542. [PMID: 30241896 DOI: 10.1016/j.cyto.2018.09.004] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2018] [Revised: 09/01/2018] [Accepted: 09/07/2018] [Indexed: 12/15/2022]
Abstract
In their quiescent state, Hepatic stellate cells (HSCs), are present in the sub-endothelial space of Disse and have minimal interaction with immune cells. However, upon activation following injury, HSCs directly or indirectly interact with various immune cells that enter the space of Disse and thereby regulate diverse hepatic function and immune physiology. Other than the normal physiological functions of HSCs such as hepatic homeostasis, maturation and differentiation, they also participate in hepatic inflammation by releasing a battery of inflammatory cytokines and chemokines and interacting with other liver cells. Here, we have reviewed the role of HSC in the pathogenesis of liver inflammation and some infectious diseases in order to understand how the interplay between immune cells and HSCs regulates the overall outcome and disease pathology.
Collapse
|
|
24
|
Jiroutová A, Majdiaková L, Čermáková M, Köhlerová R, Kanta J. Expression of Cytoskeletal Proteins in Hepatic Stellatecells Isolated from Normal and Cirrhotic Rat Liver. ACTA MEDICA (HRADEC KRÁLOVÉ) 2018. [DOI: 10.14712/18059694.2018.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
Hepatic stellate cells (HSC) are located in Disse spaces of normal rat liver. In their quiescent state they serve as a storage site for vitamin A. In fibrotic liver they become activated, proliferate and they undergo transdifferentiation into myofibroblast-like cells. Changes in the cell phenotype are accompanied by changes in the cellular cytoskeleton. We have studied the expression of α-smooth muscle actin and intermediate filament proteins vimentin, desmin and glial fibrillary acidic protein (GFAP) by immunocytochemistry in HSC cultured for 2 or 7 days after isolation. Normal or cirrhotic rat liver was perfused with solutions of pronase and collagenase and HSC were isolated by density gradient centrifugation of the resulting cell suspension. Liver cirrhosis was produced in rats by repeated carbon tetrachloride administration. Vimentin was detected in all cells from normal and cirrhotic liver. The concentration of desmin in the cells from cirrhotic liver was slightly higher than that in normal cells and it increased with time in culture. GFAP could be detected only in normal cells 2 days after their isolation. In contrast, alpha smooth muscle actin (α-SMA) was absent from normal cells at this time but its expression was pronouced later. In most cells from cirrhotic liver this antigen was already present on the second day of culture and its expression further increased.
Collapse
|
|
25
|
Lian M, Selmi C, Gershwin ME, Ma X. Myeloid Cells and Chronic Liver Disease: a Comprehensive Review. Clin Rev Allergy Immunol 2018; 54:307-317. [PMID: 29313221 DOI: 10.1007/s12016-017-8664-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Myeloid cells play a major role in the sensitization to liver injury, particularly in chronic inflammatory liver diseases with a biliary or hepatocellular origin, and the interplay between myeloid cells and the liver may explain the increased incidence of hepatic osteodystrophy. The myeloid cell-liver axis involves several mature myeloid cells as well as immature or progenitor cells with the complexity of the liver immune microenvironment aggravating the mist of cell differentiation. The unique positioning of the liver at the junction of the peripheral and portal circulation systems underlines the interaction of myeloid cells and hepatic cells and leads to immune tolerance breakdown. We herein discuss the scenarios of different chronic liver diseases closely modulated by myeloid cells and illustrate the numerous potential targets, the understanding of which will ultimately steer the development of solid immunotherapeutic regimens. Ultimately, we are convinced that an adequate modulation of the liver microenvironment to modify the functional and quantitative characteristics of myeloid cells will be a successful approach to treating chronic liver diseases of different etiologies.
Collapse
Affiliation(s)
- Min Lian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China
| | - Carlo Selmi
- Division of Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.,BIOMETRA Department, University of Milan, Milan, Italy
| | - M Eric Gershwin
- Division of Rheumatology, Department of Medicine, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Xiong Ma
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai, 200001, China.
| |
Collapse
|
|
26
|
Friedman A, Siewe N. Chronic hepatitis B virus and liver fibrosis: A mathematical model. PLoS One 2018; 13:e0195037. [PMID: 29634771 PMCID: PMC5892900 DOI: 10.1371/journal.pone.0195037] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 03/15/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a liver disorder that can result in cirrhosis, liver failure and hepatocellular carcinoma. HBV infection remains a major global health problem, as it affects more 350 million people chronically and kills roughly 600,000 people annually. Drugs currently used against HBV include IFN-α that decreases viremia, inflammation and the growth of liver fibrosis, and adefovir that decreases the viral load. Each of these drugs can have severe side-effects. In the present paper, we consider the treatment of chronic HBV by a combination of IFN-α and adefovir, and raise the following question: What should be the optimal ratio between IFN-α and adefovir in order to achieve the best 'efficacy' under constraints on the total amount of the drugs; here the efficacy is measured by the reduction of the levels of inflammation and of fibrosis? We develop a mathematical model of HBV pathogenesis by a system of partial differential equations (PDEs) and use the model to simulate a 'synergy map' which addresses the above question.
Collapse
Affiliation(s)
- Avner Friedman
- Mathematical Biosciences Institute & Department of Mathematics, The Ohio State University, Columbus, Ohio, United States of America
| | - Nourridine Siewe
- National Institute for Mathematical and Biological Synthesis, University of Tennessee, Knoxville, Tennessee, United States of America
| |
Collapse
|
|
27
|
Yamaguchi M, Saito SY, Nishiyama R, Nakamura M, Todoroki K, Toyo'oka T, Ishikawa T. Caffeine Suppresses the Activation of Hepatic Stellate Cells cAMP-Independently by Antagonizing Adenosine Receptors. Biol Pharm Bull 2018; 40:658-664. [PMID: 28458351 DOI: 10.1248/bpb.b16-00947] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
During liver injury, hepatic stellate cells (HSCs) are activated by various cytokines and transdifferentiated into myofibroblast-like activated HSCs, which produce collagen, a major source of liver fibrosis. Therefore, the suppression of HSC activation is regarded as a therapeutic target for liver fibrosis. Several epidemiological reports have revealed that caffeine intake decreases the risk of liver disease. In this study, therefore, we investigated the effect of caffeine on the activation of primary HSCs isolated from mice. Caffeine suppressed the activation of HSC in a concentration-dependent manner. BAPTA-AM, an intracellular Ca2+ chelator, had no effect on the caffeine-induced suppression of HSC activation. None of the isoform-selective inhibitors of phosphodiesterase1 to 5 affected changes in the morphology of HSC during activation, whereas CGS-15943, an adenosine receptor antagonist, inhibited them. Caffeine had no effect on intracellular cAMP level or on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2. In contrast, caffeine significantly decreased the phosphorylation of Akt1. These results suggest that caffeine inhibits HSC activation by antagonizing adenosine receptors, leading to Akt1 signaling activation.
Collapse
Affiliation(s)
- Momoka Yamaguchi
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
| | - Shin-Ya Saito
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
| | - Ryota Nishiyama
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
| | - Misuzu Nakamura
- Laboratory of Analytical and Bio-analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka
| | - Kenichiro Todoroki
- Laboratory of Analytical and Bio-analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka
| | - Toshimasa Toyo'oka
- Laboratory of Analytical and Bio-analytical Chemistry, School of Pharmaceutical Sciences, University of Shizuoka
| | - Tomohisa Ishikawa
- Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
| |
Collapse
|
|
28
|
Liaw CY, Ji S, Guvendiren M. Engineering 3D Hydrogels for Personalized In Vitro Human Tissue Models. Adv Healthc Mater 2018; 7. [PMID: 29345429 DOI: 10.1002/adhm.201701165] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 11/13/2017] [Indexed: 01/17/2023]
Abstract
There is a growing interest in engineering hydrogels for 3D tissue and disease models. The major motivation is to better mimic the physiological microenvironment of the disease and human condition. 3D tissue models derived from patients' own cells can potentially revolutionize the way treatment and diagnostic alternatives are developed. This requires development of tissue mimetic hydrogels with user defined and tunable properties. In this review article, a recent summary of 3D hydrogel platforms for in vitro tissue and disease modeling is given. Hydrogel design considerations and available hydrogel systems are summarized, followed by the types of currently available hydrogel models, such as bulk hydrogels, porous scaffolds, fibrous scaffolds, hydrogel microspheres, hydrogel sandwich systems, microwells, and 3D bioprinted constructs. Although hydrogels are utilized for a wide range of tissue models, this article focuses on liver and cancer models. This article also provides a detailed section on current challenges and future perspectives of hydrogel-based tissue models.
Collapse
Affiliation(s)
- Chya-Yan Liaw
- Instructive Biomaterials and Additive Manufacturing Laboratory; Otto H. York Chemical; Biological and Pharmaceutical Engineering; Newark College of Engineering; New Jersey Institute of Technology; University Heights; 138 York Center Newark NJ 07102 USA
| | - Shen Ji
- Instructive Biomaterials and Additive Manufacturing Laboratory; Otto H. York Chemical; Biological and Pharmaceutical Engineering; Newark College of Engineering; New Jersey Institute of Technology; University Heights; 138 York Center Newark NJ 07102 USA
| | - Murat Guvendiren
- Instructive Biomaterials and Additive Manufacturing Laboratory; Otto H. York Chemical; Biological and Pharmaceutical Engineering; Newark College of Engineering; New Jersey Institute of Technology; University Heights; 138 York Center Newark NJ 07102 USA
| |
Collapse
|
|
29
|
Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function, and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:1-87. [DOI: 10.1016/b978-0-7020-6697-9.00001-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
30
|
Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, Aghaei F, Esfandiari A, Azarpira N, Niknahad H. Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother 2018; 97:1086-1095. [DOI: 10.1016/j.biopha.2017.10.166] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 12/27/2022] Open
|
|
31
|
Saeed A, Dullaart RPF, Schreuder TCMA, Blokzijl H, Faber KN. Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD). Nutrients 2017; 10:nu10010029. [PMID: 29286303 PMCID: PMC5793257 DOI: 10.3390/nu10010029] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/13/2017] [Accepted: 12/19/2017] [Indexed: 12/22/2022] Open
Abstract
Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs) and retinoid X receptors (RXRs).The liver plays a central role in vitamin A metabolism: (1) it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2) it produces retinol binding protein 4 (RBP4) that distributes vitamin A, as retinol, to peripheral tissues; and (3) it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs). In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH); it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M) is the most prominent heritable factor associated with NAFLD. Interestingly, PNPLA3 harbors retinyl ester hydrolase activity and PNPLA3-I148M is associated with low serum retinol level, but enhanced retinyl esters in the liver of NAFLD patients. Low circulating retinol in NAFLD may therefore not reflect true “vitamin A deficiency”, but rather disturbed vitamin A metabolism. Here, we summarize current knowledge about vitamin A metabolism in NAFLD and its putative role in the progression of liver disease, as well as the therapeutic potential of vitamin A metabolites.
Collapse
Affiliation(s)
- Ali Saeed
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
- Institute of Molecular Biology & Bio-Technology, Bahauddin Zakariya University, Multan 60800, Pakistan.
| | - Robin P F Dullaart
- Department of Endocrinology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Tim C M A Schreuder
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Hans Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands.
| |
Collapse
|
|
32
|
Lee S, Kim Y, Shin HS, Lim JY. Comparative characteristics of laryngeal-resident mesenchymal stromal cell populations isolated from distinct sites in the rat larynx. Stem Cell Res Ther 2017; 8:200. [PMID: 28962587 PMCID: PMC5622476 DOI: 10.1186/s13287-017-0650-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2017] [Revised: 08/11/2017] [Accepted: 08/22/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Although tissue-resident mesenchymal stromal cells (MSCs) in the larynx have been described, their distinct characteristics and roles have not been thoroughly explored. Therefore, we investigated stem cell characteristics and regenerative potentials of single clonal populations isolated from rat epiglottic mucosa (EM), lamina propria (LP), and macula flava (MF) to determine whether they comprised laryngeal tissue-resident stem cells. METHODS Single clonal laryngeal cells were isolated following microdissection of the EM, LP, and MF from the rat larynx. Several clonal populations from the three laryngeal subsites were selected and expanded in vitro. We compared the stem cell characteristics of self-renewal and differentiation potential, as well as the cell surface phenotypes and gene expression profiles, of laryngeal MSC-like cells to that of bone marrow MSCs (BM-MSCs). We also investigated the regenerative potential of the laryngeal cells in a radiation-induced laryngeal injury animal model. RESULTS Self-renewing, clonal cell populations were obtained from rat EM, LP, and MF. EM-derived and LP-derived clonal cells had fibroblast-like features, while MF-resident clonal cells had stellate cell morphology and lipid droplets containing vitamin A. All laryngeal clonal cell populations had MSC-like cell surface marker expression (CD29, CD44, CD73, and CD90) and the potential to differentiate into bone and cartilage cell lineages; EM-derived and MF-derived cells, but not LP-derived cells, were also able to differentiate into adipocytes. Clonal cells isolated from the laryngeal subsites exhibited differential extracellular matrix-related gene expression. We found that the mesenchymal and stellate cell-related genes desmin and nestin were enriched in laryngeal MSC-like cells relative to BM-MSCs (P < 0.001). Growth differentiation factor 3 (GDF3) and glial fibrillary acidic protein (GFAP) transcript and protein levels were higher in MF-derived cells than in other laryngeal populations (P < 0.001). At 4 weeks after transplantation, laryngeal MF-derived and EM-derived cells contributed to laryngeal epithelial and/or glandular regeneration in response to radiation injury. CONCLUSIONS These results suggest that cell populations with MSC characteristics reside in the EM, LP, and MF of the larynx. Laryngeal MSC-like cells contribute to regeneration of the larynx following injury; further investigation is needed to clarify the differential roles of the populations in laryngeal tissue regeneration, as well as the clinical implications for the treatment of laryngeal disease.
Collapse
Affiliation(s)
- Songyi Lee
- Department of Otorhinolaryngology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Yeseulmi Kim
- Department of Otorhinolaryngology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Hyun-Soo Shin
- Department of Otorhinolaryngology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea
| | - Jae-Yol Lim
- Department of Otorhinolaryngology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul, 06273, Republic of Korea.
| |
Collapse
|
|
33
|
The stellate cell system (vitamin A-storing cell system). Anat Sci Int 2017; 92:387-455. [PMID: 28299597 DOI: 10.1007/s12565-017-0395-9] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 02/15/2017] [Indexed: 01/18/2023]
Abstract
Past, present, and future research into hepatic stellate cells (HSCs, also called vitamin A-storing cells, lipocytes, interstitial cells, fat-storing cells, or Ito cells) are summarized and discussed in this review. Kupffer discovered black-stained cells in the liver using the gold chloride method and named them stellate cells (Sternzellen in German) in 1876. Wake rediscovered the cells in 1971 using the same gold chloride method and various modern histological techniques including electron microscopy. Between their discovery and rediscovery, HSCs disappeared from the research history. Their identification, the establishment of cell isolation and culture methods, and the development of cellular and molecular biological techniques promoted HSC research after their rediscovery. In mammals, HSCs exist in the space between liver parenchymal cells (PCs) or hepatocytes and liver sinusoidal endothelial cells (LSECs) of the hepatic lobule, and store 50-80% of all vitamin A in the body as retinyl ester in lipid droplets in the cytoplasm. SCs also exist in extrahepatic organs such as pancreas, lung, and kidney. Hepatic (HSCs) and extrahepatic stellate cells (EHSCs) form the stellate cell (SC) system or SC family; the main storage site of vitamin A in the body is HSCs in the liver. In pathological conditions such as liver fibrosis, HSCs lose vitamin A, and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan, glycosaminoglycan, and adhesive glycoproteins. The morphology of these cells also changes from the star-shaped HSCs to that of fibroblasts or myofibroblasts.
Collapse
|
|
34
|
Zhang Y, Zhou X, Xu L, Wang L, Liu J, Ye J, Qiu P, Liu Q. Apoptosis of rat hepatic stellate cells induced by diallyl trisulfide and proteomics profiling in vitro. Can J Physiol Pharmacol 2017; 95:463-473. [PMID: 28177695 DOI: 10.1139/cjpp-2015-0527] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Diallyl trisulfide (DATS), a major garlic derivative, inhibits cell proliferation and triggers apoptosis in a variety of cancer cell lines. However, the effects of DATS on hepatic stellate cells (HSCs) remain unknown. The aim of this study was to analyze the effects of DATS on cell proliferation and apoptosis, as well as the protein expression profile in rat HSCs. Rat HSCs were treated with or without 12 and 24 μg/mL DATS for various time intervals. Cell proliferation and apoptosis were determined using tetrazolium dye (MTT) colorimetric assay, bromodeoxyuridine (5-bromo-2'-deoxyuridine; BrdU) assay, Hoechst 33342 staining, electroscopy, and flow cytometry. Protein expression patterns in HSCs were systematically studied using 2-dimensional electrophoresis and mass spectrometry. DATS inhibited cell proliferation and induced apoptosis of HSCs in a time-dependent manner. We observed clear morphological changes in apoptotic HSCs and dramatically increased annexin V-positive - propidium iodide negative apoptosis compared with the untreated control group. Twenty-one significant differentially expressed proteins, including 9 downregulated proteins and 12 upregulated proteins, were identified after DATS administration, and most of them were involved in apoptosis. Our results suggest that DATS is an inducer of apoptosis in HSCs, and several key proteins may be involved in the molecular mechanism of apoptosis induced by DATS.
Collapse
Affiliation(s)
- Yajie Zhang
- a Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Xiaoming Zhou
- a Department of Pathology, Guangzhou Medical University, Guangzhou, Guangdong Province, China
| | - Lipeng Xu
- b Institute of New Drug Research and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University College of Pharmacy, Guangzhou, Guangdong Province, China
| | - Lulu Wang
- c Center of Community Health Services, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China
| | - Jinling Liu
- d Department of Digestive System Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China
| | - Jing Ye
- d Department of Digestive System Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China
| | - Pengxin Qiu
- e Department of Pharmacology, Zhong-Shan Medical College, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Qinghua Liu
- f Department of Oncology, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China
| |
Collapse
|
|
35
|
Saeed A, Hoekstra M, Hoeke MO, Heegsma J, Faber KN. The interrelationship between bile acid and vitamin A homeostasis. Biochim Biophys Acta Mol Cell Biol Lipids 2017; 1862:496-512. [PMID: 28111285 DOI: 10.1016/j.bbalip.2017.01.007] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 01/04/2017] [Accepted: 01/18/2017] [Indexed: 12/12/2022]
Abstract
Vitamin A is a fat-soluble vitamin important for vision, reproduction, embryonic development, cell differentiation, epithelial barrier function and adequate immune responses. Efficient absorption of dietary vitamin A depends on the fat-solubilizing properties of bile acids. Bile acids are synthesized in the liver and maintained in an enterohepatic circulation. The liver is also the main storage site for vitamin A in the mammalian body, where an intimate collaboration between hepatocytes and hepatic stellate cells leads to the accumulation of retinyl esters in large cytoplasmic lipid droplet hepatic stellate cells. Chronic liver diseases are often characterized by disturbed bile acid and vitamin A homeostasis, where bile production is impaired and hepatic stellate cells lose their vitamin A in a transdifferentiation process to myofibroblasts, cells that produce excessive extracellular matrix proteins leading to fibrosis. Chronic liver diseases thus may lead to vitamin A deficiency. Recent data reveal an intricate crosstalk between vitamin A metabolites and bile acids, in part via the Retinoic Acid Receptor (RAR), Retinoid X Receptor (RXR) and the Farnesoid X Receptor (FXR), in maintaining vitamin A and bile acid homeostasis. Here, we provide an overview of the various levels of "communication" between vitamin A metabolites and bile acids and its relevance for the treatment of chronic liver diseases.
Collapse
Affiliation(s)
- Ali Saeed
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Institute of Molecular biology & Bio-technology, Bahauddin Zakariya University, Multan, Pakistan.
| | - Mark Hoekstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Martijn Oscar Hoeke
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Janette Heegsma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; Laboratory Medicine, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
| |
Collapse
|
|
36
|
Zhang YS, Yue K, Aleman J, Moghaddam KM, Bakht SM, Yang J, Jia W, Dell’Erba V, Assawes P, Shin SR, Dokmeci MR, Oklu R, Khademhosseini A. 3D Bioprinting for Tissue and Organ Fabrication. Ann Biomed Eng 2017; 45:148-163. [PMID: 27126775 PMCID: PMC5085899 DOI: 10.1007/s10439-016-1612-8] [Citation(s) in RCA: 357] [Impact Index Per Article: 44.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 04/05/2016] [Indexed: 12/15/2022]
Abstract
The field of regenerative medicine has progressed tremendously over the past few decades in its ability to fabricate functional tissue substitutes. Conventional approaches based on scaffolding and microengineering are limited in their capacity of producing tissue constructs with precise biomimetic properties. Three-dimensional (3D) bioprinting technology, on the other hand, promises to bridge the divergence between artificially engineered tissue constructs and native tissues. In a sense, 3D bioprinting offers unprecedented versatility to co-deliver cells and biomaterials with precise control over their compositions, spatial distributions, and architectural accuracy, therefore achieving detailed or even personalized recapitulation of the fine shape, structure, and architecture of target tissues and organs. Here we briefly describe recent progresses of 3D bioprinting technology and associated bioinks suitable for the printing process. We then focus on the applications of this technology in fabrication of biomimetic constructs of several representative tissues and organs, including blood vessel, heart, liver, and cartilage. We finally conclude with future challenges in 3D bioprinting as well as potential solutions for further development.
Collapse
Affiliation(s)
- Yu Shrike Zhang
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Kan Yue
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Julio Aleman
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Kamyar Mollazadeh Moghaddam
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Syeda Mahwish Bakht
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Comsats Institute of Information and Technology, Islamabad 45550, Pakistan
| | - Jingzhou Yang
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- School of Mechanical and Chemical Engineering, University of Western Australia, Perth, WA 6009, Australia
| | - Weitao Jia
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, P.R. China
| | - Valeria Dell’Erba
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Department of Biomedical Engineering, Politecnico di Torino, 10129 Torino, Italy
| | - Pribpandao Assawes
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Su Ryon Shin
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Mehmet Remzi Dokmeci
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
| | - Rahmi Oklu
- Division of Vascular & Interventional Radiology, Mayo Clinic, Scottsdale, AZ 85259, USA
| | - Ali Khademhosseini
- Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, MA 02139, USA
- Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115, USA
- Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea
- Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia
| |
Collapse
|
|
37
|
Vasconcellos R, Alvarenga ÉC, Parreira RC, Lima SS, Resende RR. Exploring the cell signalling in hepatocyte differentiation. Cell Signal 2016; 28:1773-88. [DOI: 10.1016/j.cellsig.2016.08.011] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 08/18/2016] [Accepted: 08/18/2016] [Indexed: 02/08/2023]
|
|
38
|
Alidori S, Bowman RL, Yarilin D, Romin Y, Barlas A, Mulvey JJ, Fujisawa S, Xu K, Ruggiero A, Riabov V, Thorek DLJ, Ulmert HDS, Brea EJ, Behling K, Kzhyshkowska J, Manova-Todorova K, Scheinberg DA, McDevitt MR. Deconvoluting hepatic processing of carbon nanotubes. Nat Commun 2016; 7:12343. [PMID: 27468684 PMCID: PMC4974572 DOI: 10.1038/ncomms12343] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 06/17/2016] [Indexed: 12/25/2022] Open
Abstract
Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs. Here we provide the unexpected details of hepatic processing of covalently functionalized nanotubes including receptor-mediated endocytosis, cellular trafficking and biliary elimination. Ammonium-functionalized fibrillar nanocarbon is found to preferentially localize in the fenestrated sinusoidal endothelium of the liver but not resident macrophages. Stabilin receptors mediate the endocytic clearance of nanotubes. Biocompatibility is evidenced by the absence of cell death and no immune cell infiltration. Towards clinical application of this platform, nanotubes were evaluated for the first time in non-human primates. The pharmacologic profile in cynomolgus monkeys is equivalent to what was reported in mice and suggests that nanotubes should behave similarly in humans. Application of carbon nanotubes as drug delivery carriers is stalled by uncertainties over their distribution and toxicity in vivo. Here, the authors use animal models to show that, while the bulk of nanotubes is renally cleared, a fraction can be eliminated through an alternative hepatobiliary pathway.
Collapse
Affiliation(s)
- Simone Alidori
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Robert L Bowman
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Dmitry Yarilin
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Yevgeniy Romin
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Afsar Barlas
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - J Justin Mulvey
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Sho Fujisawa
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Ke Xu
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Alessandro Ruggiero
- Department of Radiology, Papworth Hospital NHS Foundation Trust, Cambridge University Health Partners, Cambridge CB23 3RE, UK
| | - Vladimir Riabov
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim 68167, Germany.,Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia
| | - Daniel L J Thorek
- Department of Radiology and Radiological Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
| | - Hans David S Ulmert
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Elliott J Brea
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Katja Behling
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - Julia Kzhyshkowska
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim 68167, Germany.,Laboratory for Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk 634050, Russia.,Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim 68167, Germany
| | - Katia Manova-Todorova
- Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York 10065, USA
| | - David A Scheinberg
- Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.,Department of Pharmacology, Weill Cornell Medical College, New York 10065, USA
| | - Michael R McDevitt
- Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA.,Department of Medicine, Weill Cornell Medical College, New York 10065, USA
| |
Collapse
|
|
39
|
Masserdotti C, Bertazzolo W. Cytologic features of hepatic fibrosis in dogs: a retrospective study on 22 cases. Vet Clin Pathol 2016; 45:361-7. [PMID: 27159883 DOI: 10.1111/vcp.12352] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Liver cytology has diagnostic value for the identification of neoplastic and nonneoplastic hepatic diseases. However, so far the diagnosis of fibrotic changes has traditionally been restricted to histopathology. OBJECTIVES The aim of this study was to describe the cytologic features that may help in the recognition of hepatic fibrosis. MATERIALS AND METHODS Cytologic smears from the liver of dogs histologically diagnosed with hepatic fibrosis (Group A) were selected and compared to liver smears from dogs without hepatic fibrosis (Group B). A differential count of hepatocytes, spindle cells, mast cells, granulocytes, lymphocytes/plasma cells, and macrophages was documented for each case, and means for the fibrosis and nonfibrosis group were compared. RESULTS The relative and total numbers of spindle cells and mast cells were significantly higher in the fibrosis group than in the nonfibrosis group. The optimal cutoff point for the spindle cells to hepatocytes ratio was 0.107 (ie, one spindle cell per 10 hepatocytes), with 95.5% sensitivity and 100% specificity for the cytologic diagnosis of hepatic fibrosis. The optimal cutoff point for the ratio mast cells to hepatocytes was 0.04 (ie, 4 mast cells per 100 hepatocytes) with 86.4% sensitivity and 90% specificity. DISCUSSION The presence of relatively and absolutely increased numbers of spindle and mast cells in hepatic cytology provides a rational basis to identify fibrosis of hepatic parenchyma. Based on a reasonable sensitivity and specificity, the cytologic diagnosis of hepatic fibrosis seems feasible.
Collapse
Affiliation(s)
| | - Walter Bertazzolo
- Laboratorio Analisi - Ospedale Veterinario Città di Pavia, Pavia, Italy.,Laboratorio Veterinario LaVallonea, Alessano, Italy
| |
Collapse
|
|
40
|
Hepatic Stellate Cells and microRNAs in Pathogenesis of Liver Fibrosis. J Clin Med 2016; 5:jcm5030038. [PMID: 26999230 PMCID: PMC4810109 DOI: 10.3390/jcm5030038] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 02/23/2016] [Accepted: 03/07/2016] [Indexed: 12/18/2022] Open
Abstract
microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression by either blocking translation or inducing degradation of target mRNA. miRNAs play essential roles in diverse biological and pathological processes, including development of hepatic fibrosis. Hepatic stellate cells (HSCs) play a central role in development of hepatic fibrosis and there are intricate regulatory effects of miRNAs on their activation, proliferation, collagen production, migration, and apoptosis. There are multiple differentially expressed miRNAs in activated HSCs, and in this review we aim to summarize current data on miRNAs that participate in the development of hepatic fibrosis. Based on this review, miRNAs may serve as biomarkers for diagnosis of liver disease, as well as markers of disease progression. Most importantly, dysregulated miRNAs may potentially be targeted by novel therapies to treat and reverse progression of hepatic fibrosis.
Collapse
|
|
41
|
Hünigen H, Mainzer K, Hirschberg RM, Custodis P, Gemeinhardt O, Al Masri S, Richardson KC, Hafez HM, Plendl J. Structure and age-dependent development of the turkey liver: a comparative study of a highly selected meat-type and a wild-type turkey line. Poult Sci 2016; 95:901-11. [PMID: 26908884 DOI: 10.3382/ps/pev358] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Accepted: 10/20/2015] [Indexed: 01/22/2023] Open
Abstract
In this study the macroscopic and microscopic structure of the liver of a fast growing, meat-type turkey line (British United turkeys BUT Big 6, n=25) and a wild-type turkey line (Wild Canadian turkey, n=48) were compared at the age of 4, 8, 12, 16, and 20 wk. Because the growth plates of long bones were still detectable in the 20-week-old wild-type turkeys, indicating immaturity, a group of 8 wild-type turkeys at the age of 24 wk was included in the original scope of the study. Over the term of the study, the body and liver weights of birds from the meat-type turkey line increased at a faster rate than those of the wild-type turkey line. However, the relative liver weight of the meat-type turkeys declined (from 2.7 to 0.9%) to a greater extent than that of the wild-type turkeys (from 2.8 to 1.9%), suggesting a mismatch in development between muscle weights and liver weights of the meat-type turkeys. Signs of high levels of fat storage in the liver were detected in both lines but were greater in the wild-type turkey line, suggesting a better feed conversion by the extreme-genotype birds i.e., meat-type birds. For the first time, this study presents morphologic data on the structure and arrangement of the lymphatic tissue within the healthy turkey liver, describing two different types of lymphatic aggregations within the liver parenchyma, i.e., aggregations with and without fibrous capsules. Despite differences during development, both adult meat-type and adult wild-type turkeys had similar numbers of lymphatic aggregations.
Collapse
Affiliation(s)
- Hana Hünigen
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Kathleen Mainzer
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Ruth M Hirschberg
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Pia Custodis
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Ole Gemeinhardt
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Salah Al Masri
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| | - Kenneth C Richardson
- College of Veterinary Medicine, School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia
| | - Hafez Mohamed Hafez
- Institute of Poultry Diseases, Faculty of Veterinary Medicine, Freie Universität Berlin, Königsweg 63, 14163 Berlin, Germany
| | - Johanna Plendl
- Institute of Veterinary Anatomy, Department of Veterinary Medicine, Freie Universität Berlin, Koserstraße 20, 14195 Berlin, Germany
| |
Collapse
|
|
42
|
Silva P, Fernandes E, Carvalho F. Dual effect of red wine on liver redox status: a concise and mechanistic review. Arch Toxicol 2015; 89:1681-1693. [PMID: 26026610 DOI: 10.1007/s00204-015-1538-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Accepted: 05/12/2015] [Indexed: 01/09/2023]
Abstract
Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies.
Collapse
Affiliation(s)
- Paula Silva
- UCIBIO-REQUIMTE, Laboratory of Histology and Embryology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313, Porto, Portugal.
| | - Eduarda Fernandes
- UCIBIO-REQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
| | - Félix Carvalho
- UCIBIO-REQUIMTE, Department of Biological Sciences, Laboratory of Toxicology, Faculty of Pharmacy, University of Porto, Rua de Jorge Viterbo Ferreira no. 228, 4050-313, Porto, Portugal.
| |
Collapse
|
|
43
|
Prodanov L, Jindal R, Bale SS, Hegde M, McCarty WJ, Golberg I, Bhushan A, Yarmush ML, Usta OB. Long-term maintenance of a microfluidic 3D human liver sinusoid. Biotechnol Bioeng 2015; 113:241-6. [PMID: 26152452 DOI: 10.1002/bit.25700] [Citation(s) in RCA: 147] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 06/24/2015] [Accepted: 07/02/2015] [Indexed: 12/21/2022]
Abstract
The development of long-term human organotypic liver-on-a-chip models for successful prediction of toxic response is one of the most important and urgent goals of the NIH/DARPA's initiative to replicate and replace chronic and acute drug testing in animals. For this purpose, we developed a microfluidic chip that consists of two microfluidic chambers separated by a porous membrane. The aim of this communication is to demonstrate the recapitulation of a liver sinusoid-on-a-chip, using human cells only for a period of 28 days. Using a step-by-step method for building a 3D microtissue on-a-chip, we demonstrate that an organotypic in vitro model that reassembles the liver sinusoid microarchitecture can be maintained successfully for a period of 28 days. In addition, higher albumin synthesis (synthetic) and urea excretion (detoxification) were observed under flow compared to static cultures. This human liver-on-a-chip should be further evaluated in drug-related studies.
Collapse
Affiliation(s)
- Ljupcho Prodanov
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Rohit Jindal
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Shyam Sundhar Bale
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Manjunath Hegde
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - William J McCarty
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Inna Golberg
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Abhinav Bhushan
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts
| | - Martin L Yarmush
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts. .,Department of Biomedical Engineering, Rutgers University, 599 Taylor Rd., Piscataway, 08854, New Jersey.
| | - Osman Berk Usta
- Center for Engineering in Medicine at Massachusetts General Hospital, Harvard Medical School and Shriners Hospital for Children, 51 Blossom St., Boston, 02144, Massachusetts.
| |
Collapse
|
|
44
|
Stone LC, Thorne LS, Weston CJ, Graham M, Hodges NJ. Cytoglobin expression in the hepatic stellate cell line HSC-T6 is regulated by extracellular matrix proteins dependent on FAK-signalling. FIBROGENESIS & TISSUE REPAIR 2015; 8:15. [PMID: 26300973 PMCID: PMC4546255 DOI: 10.1186/s13069-015-0032-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 08/06/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND Fibrosis is a physiological response to cellular injury in the liver and is mediated by the activation of hepatic stellate cells resulting in the replacement of hepatocytes with extracellular matrix comprised principally of collagen 1 to form a hepatic scar. Although the novel hexaco-ordinated globin cytoglobin was identified in activated hepatic stellate cells more than 10 years ago, its role in stellate cell biology and liver fibrosis remains enigmatic. RESULTS In the current study, we investigated the role of different extracellular matrix proteins in stellate cell proliferation, activation (alpha smooth muscle actin expression and retinoic acid uptake) and cytoglobin expression. Our results demonstrate that cytoglobin expression is correlated with a more quiescent phenotype of stellate cells in culture and that cytoglobin is regulated by the extracellular matrix through integrin signalling dependent on activation of focal adhesion kinase. CONCLUSIONS Although further studies are required, we provide evidence that cytoglobin is a negative regulator of stellate cell activation and therefore may represent a novel target for anti-fibrotic treatments in the future.
Collapse
Affiliation(s)
- Louise Catherine Stone
- />School of Biosciences and School of Medicine, The University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| | - Lorna Susan Thorne
- />School of Biosciences and School of Medicine, The University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| | - Christopher John Weston
- />School of Biosciences and School of Medicine, The University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| | - Mark Graham
- />School of Biosciences and MG Toxicology Consulting Ltd, Birmingham, UK
| | - Nikolas John Hodges
- />School of Biosciences and School of Medicine, The University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
| |
Collapse
|
|
45
|
Wang H, Liang X, Mohammed YH, Thomas JA, Bridle KR, Thorling CA, Grice JE, Xu ZP, Liu X, Crawford DHG, Roberts MS. Real-time histology in liver disease using multiphoton microscopy with fluorescence lifetime imaging. BIOMEDICAL OPTICS EXPRESS 2015; 6:780-92. [PMID: 25798303 PMCID: PMC4361433 DOI: 10.1364/boe.6.000780] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Revised: 01/30/2015] [Accepted: 01/31/2015] [Indexed: 05/07/2023]
Abstract
Conventional histology with light microscopy is essential in the diagnosis of most liver diseases. Recently, a concept of real-time histology with optical biopsy has been advocated. In this study, live mice livers (normal, with fibrosis, steatosis, hepatocellular carcinoma and ischemia-reperfusion injury) were imaged by MPM-FLIM for stain-free real-time histology. The acquired MPM-FLIM images were compared with conventional histological images. MPM-FLIM imaged subsurface cellular and subcellular histopathological hallmarks of live liver in mice models at high resolution. Additional information such as distribution of stellate cell associated autofluorescence and fluorescence lifetime changes was also gathered by MPM-FLIM simultaneously, which cannot be obtained from conventional histology. MPM-FLIM could simultaneously image and quantify the cellular morphology and microenvironment of live livers without conventional biopsy or fluorescent dyes. We anticipate that in the near future MPM-FLIM will be evaluated from bench to bedside, leading to real-time histology and dynamic monitoring of human liver diseases.
Collapse
Affiliation(s)
- Haolu Wang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
- Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 1630 S. Dongfang Road, Shanghai, 200127,
China
- These authors contributed equally to this work
| | - Xiaowen Liang
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
- These authors contributed equally to this work
| | - Yousuf H. Mohammed
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
| | - James A. Thomas
- Department of Gastroenterology, Princess Alexandra Hospital, School of Medicine, The University of Queensland, Woolloongabba, QLD 4102,
Australia
| | - Kim R. Bridle
- School of Medicine, The University of Queensland, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD 4120,
Australia
| | - Camilla A. Thorling
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
| | - Jeffrey E. Grice
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
| | - Zhi Ping Xu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072,
Australia
| | - Xin Liu
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
| | - Darrell H. G. Crawford
- School of Medicine, The University of Queensland, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Greenslopes, QLD 4120,
Australia
| | - Michael S. Roberts
- Therapeutics Research Centre, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, QLD 4102,
Australia
- School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001,
Australia
| |
Collapse
|
|
46
|
Zhu D, Song K, Chen J, Wang J, Sun X, Qian H, Gu X, Zhang L, Qin Y, Duan Y. Expression of Septin4 in Schistosoma japonicum-infected mouse livers after praziquantel treatment. Parasit Vectors 2015; 8:19. [PMID: 25582427 PMCID: PMC4298944 DOI: 10.1186/s13071-015-0640-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 01/03/2015] [Indexed: 12/18/2022] Open
Abstract
Background Septin4 (SEPT4) exists widely in human tissues and is related to mechanical stability, actin dynamics, membrane trafficking, viral replication and apoptosis. Data from many studies have suggested that SEPT4 plays a significant role in liver fibrosis. SEPT4 is down-regulated in the model of CCl4 and BDL treated liver fibrosis. However, it is up-regulated and peaked at 12 weeks post-infection (p.i.), and then decreased subsequently in Schistosoma japonicum (S. japonicum) egg-induced liver fibrosis. The aim of this study was to observe the dynamic alteration of SEPT4 after the treatment of praziquantel (PZQ) in ICR mice infected with S. japonicum. Methods Expression of SEPT4 was determined by western blot, immunofluorescence and qRT-PCR. And pro-inflammatory cytokines IL-6 and TNF-α were detected by qRT-PCR. The number of eggs, the diameter of egg granulomas and fibrosis-associated genes were also measured. Results Our results showed that the granulomatous inflammation was reduced, whereafter the expression of SEPT4 on hepatic stellate cells (HSCs) was decreased after PZQ anti-schistosome therapy. And the variation tendency of SEPT4 had positive correlation with the inflammatory response in the area of S. japonicum egg granulomas. Conclusions Based on these findings, the inhibition of the expression of the SEPT4 by PZQ might be due to alleviation of the inflammatory response at the chronic and advanced stage of S. japonicum infection.
Collapse
Affiliation(s)
- Dandan Zhu
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Ke Song
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Jinling Chen
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Jianxin Wang
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China. .,Laboratory Medicine Center, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Xiaolei Sun
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Hongyan Qian
- Cancer Research Center, Affiliated Tumor Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Xijuan Gu
- Nantong University Xinglin College, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Lingbo Zhang
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Yongwei Qin
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Yinong Duan
- Department of Pathogen Biology, School of Medicine, Nantong University, 19 Qixiu Road, Nantong, 226001, Jiangsu, People's Republic of China.
| |
Collapse
|
|
47
|
Hebiguchi T, Mezaki Y, Morii M, Watanabe R, Yoshikawa K, Miura M, Imai K, Senoo H, Yoshino H. Massive bowel resection upregulates the intestinal mRNA expression levels of cellular retinol-binding protein II and apolipoprotein A-IV and alters the intestinal vitamin A status in rats. Int J Mol Med 2015; 35:724-30. [PMID: 25585692 DOI: 10.3892/ijmm.2015.2066] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 12/24/2014] [Indexed: 11/06/2022] Open
Abstract
Short bowel (SB) syndrome causes the malabsorption of various nutrients. Among these, vitamin A is important for a number of physiological activities. Vitamin A is absorbed by epithelial cells of the small intestine and is discharged into the lymphatic vessels as a component of chylomicrons and is delivered to the liver. In the present study, we used a rat model of SB syndrome in order to assess its effects on the expression of genes associated with the absorption, transport and metabolism of vitamin A. In the rats with SB, the intestinal mRNA expression levels of cellular retinol-binding protein II (CRBP II, gene symbol Rbp2) and apolipoprotein A-IV (gene symbol Apoa4) were higher than those in the sham-operated rats, as shown by RT-qPCR. Immunohistochemical analysis revealed that absorptive epithelial cells stained positive for both CRBP II and lecithin retinol acyltransferase, which are both required for the effective esterification of vitamin A. In the rats with SB, the retinol content in the ileum and the retinyl ester content in the jejunum were lower than those in the sham-operated rats, as shown by quantitative analysis of retinol and retinyl esters by high performance liquid chromatography. These results suggest that the elevated mRNA expression levels of Rbp2 and Apoa4 in the rats with SB contribute to the effective esterification and transport of vitamin A.
Collapse
Affiliation(s)
- Taku Hebiguchi
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Yoshihiro Mezaki
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Mayako Morii
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Ryo Watanabe
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Kiwamu Yoshikawa
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Mitsutaka Miura
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Katsuyuki Imai
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Haruki Senoo
- Department of Cell Biology and Morphology, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| | - Hiroaki Yoshino
- Department of Pediatric Surgery, Akita University Graduate School of Medicine, Akita 010-8543, Japan
| |
Collapse
|
|
48
|
Gao X, Chau YY, Xie J, Wan J, Ren Y, Qin J, Wen W. Regulating cell behaviors on micropillar topographies affected by interfacial energy. RSC Adv 2015. [DOI: 10.1039/c5ra02084k] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Micropillar topographies can greatly influence the individual hepatic stellate cell behaviors, being triggered by a minimum interfacial energy.
Collapse
Affiliation(s)
- Xinghua Gao
- Biomedical Research Institute
- Shenzhen Peking University – The Hong Kong University of Science and Technology Medical Center
- Shenzhen
- China
| | - Yeung Yeung Chau
- Department of Physics
- The Hong Kong University of Science and Technology
- Kowloon
- Hong Kong
| | - Jiao Xie
- Soft Matter and Interdisciplinary Research Institute
- College of Physics
- Chongqing University
- Chongqing
- China
| | - Jun Wan
- Biomedical Research Institute
- Shenzhen Peking University – The Hong Kong University of Science and Technology Medical Center
- Shenzhen
- China
- Division of life science
| | - Yanxiao Ren
- The Hong Kong University of Science and Technology Shenzhen Research Institute
- Shenzhen
- China
| | - Jianhua Qin
- Key Laboratory of Separation Science for Analytical Chemistry
- Dalian Institute of Chemical Physics
- Chinese Academy of Sciences
- Dalian
- China
| | - Weijia Wen
- Biomedical Research Institute
- Shenzhen Peking University – The Hong Kong University of Science and Technology Medical Center
- Shenzhen
- China
- Department of Physics
| |
Collapse
|
|
49
|
Yi HS, Lee YS, Byun JS, Seo W, Jeong JM, Park O, Duester G, Haseba T, Kim SC, Park KG, Gao B, Jeong WI. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 2014; 60:1044-53. [PMID: 24668648 PMCID: PMC4867000 DOI: 10.1002/hep.27137] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Accepted: 03/15/2014] [Indexed: 01/03/2023]
Abstract
UNLABELLED The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-β1 (TGF-β1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-β1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. CONCLUSION ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis.
Collapse
Affiliation(s)
- Hyon-Seung Yi
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
| | - Young-Sun Lee
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
| | - Jin-Seok Byun
- Department of Oral Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
| | - Wonhyo Seo
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
| | - Jong-Min Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
| | - Ogyi Park
- Laboratory of Liver Study, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland, USA
| | - Gregg Duester
- Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA
| | - Takeshi Haseba
- Department of Legal Medicine, Nippon Medical School, Tokyo 113-8602, Japan
| | - Sun Chang Kim
- Intelligent Synthetic Biology Center, 373-1, Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea
,Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
| | - Keun-Gyu Park
- Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Bin Gao
- Laboratory of Liver Study, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, Maryland, USA
| | - Won-Il Jeong
- Laboratory of Liver Research, Graduate School of Medical Science and Engineering, KAIST, Daejeon 305-701, Republic of Korea
| |
Collapse
|
|
50
|
Su X, Wang Y, Zhou G, Yang X, Yu R, Lin Y, Zheng C. Probucol attenuates ethanol-induced liver fibrosis in rats by inhibiting oxidative stress, extracellular matrix protein accumulation and cytokine production. Clin Exp Pharmacol Physiol 2014; 41:73-80. [PMID: 24117782 DOI: 10.1111/1440-1681.12182] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Revised: 09/22/2013] [Accepted: 09/23/2013] [Indexed: 01/18/2023]
Abstract
1. Liver fibrosis is characterized by excessive accumulation of extracellular matrix (ECM) proteins in the liver. Probucol, a lipid-lowering drug, was found to prevent liver injury in rats treated with carbon tetrachloride (CCl4 ). In the present study, we investigated whether probucol has protective effect against liver fibrosis in rats treated with ethanol and CCl4 . 2. Thirty rats were randomly divided into five groups. Groups I and II served as the normal control and the model of liver fibrosis, respectively. Groups III-V were treated with probucol at a doses of 250, 500 and 1000 mg/kg, respectively. Rats in Group II were fed a complex diet that includes alcohol, corn oil and pyrazole, and were injected intraperitoneally with CCl4 to induce hepatic fibrosis. Blood was obtained to assess markers of liver function. Liver samples were collected to evaluate mRNA and protein expression, histological changes and oxidative stress. 3. Probucol significantly attenuated the histological changes induced by ethanol + CCl4 and improved liver function. Expression levels of α-smooth muscle actin and collagen I was decreased in the probucol-treated groups. Moreover, probucol markedly suppressed increases in oxidative stress, ECM protein accumulation and cytokine production induced by ethanol + CCl4 . Finally, probucol inhibited activation of the extracellular signal-regulated kinase signalling pathway induced by ethanol + CCl4 . 4. Our findings reveal that probucol attenuates ethanol + CCl4 -induced liver fibrosis by inhibiting oxidative stress, ECM protein accumulation and cytokine production. These data suggest that probucol may be useful for the prevention and treatment of hepatic fibrosis.
Collapse
Affiliation(s)
- Xuesong Su
- Department of Nephrology, Shengjing Hospital, China Medical University, Shenyang, China
| | | | | | | | | | | | | |
Collapse
|