|
1
|
Peng Y, Yin Q, Yuan M, Chen L, Shen X, Xie W, Liu J. Role of hepatic stellate cells in liver ischemia-reperfusion injury. Front Immunol 2022; 13:891868. [PMID: 35967364 PMCID: PMC9366147 DOI: 10.3389/fimmu.2022.891868] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/27/2022] [Indexed: 12/13/2022] Open
Abstract
Liver ischemia-reperfusion injury (IRI) is a major complication of liver trauma, resection, and transplantation. IRI may lead to liver dysfunction and failure, but effective approach to address it is still lacking. To better understand the cellular and molecular mechanisms of liver IRI, functional roles of numerous cell types, including hepatocytes, Kupffer cells, neutrophils, and sinusoidal endothelial cells, have been intensively studied. In contrast, hepatic stellate cells (HSCs), which are well recognized by their essential functions in facilitating liver protection and repair, have gained less attention in their role in IRI. This review provides a comprehensive summary of the effects of HSCs on the injury stage of liver IRI and their associated molecular mechanisms. In addition, we discuss the regulation of liver repair and regeneration after IRI by HSCs. Finally, we highlight unanswered questions and future avenues of research regarding contributions of HSCs to IRI in the liver.
Collapse
Affiliation(s)
- Yuming Peng
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Qiang Yin
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
- *Correspondence: Yuming Peng, ; Qiang Yin,
| | - Miaoxian Yuan
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Lijian Chen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Xinyi Shen
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Weixin Xie
- First Department of General Surgery, Hunan Children’s Hospital, Changsha, China
- Zhaolong Chen Academician Workstation, Changsha, China
| | - Jinqiao Liu
- Department of Ultrasound, Hunan Children’s Hospital, Changsha, China
| |
Collapse
|
|
2
|
Brougham-Cook A, Jain I, Kukla DA, Masood F, Kimmel H, Ryoo H, Khetani SR, Underhill GH. High throughput interrogation of human liver stellate cells reveals microenvironmental regulation of phenotype. Acta Biomater 2022; 138:240-253. [PMID: 34800715 PMCID: PMC8738161 DOI: 10.1016/j.actbio.2021.11.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 11/10/2021] [Accepted: 11/11/2021] [Indexed: 01/17/2023]
Abstract
Liver fibrosis is a common feature of progressive liver disease and is manifested as a dynamic series of alterations in both the biochemical and biophysical properties of the liver. Hepatic stellate cells (HSCs) reside within the perisinusoidal space of the liver sinusoid and are one of the main drivers of liver fibrosis, yet it remains unclear how changes to the sinusoidal microenvironment impact HSC phenotype in the context of liver fibrosis. Cellular microarrays were used to examine and deconstruct the impacts of bio-chemo-mechanical changes on activated HSCs in vitro. Extracellular matrix (ECM) composition and stiffness were found to act individually and in combination to regulate HSC fibrogenic phenotype and proliferation. Hyaluronic acid and collagen III promoted elevated collagen I expression while collagen IV mediated a decrease. Previously activated HSCs exhibited reduced lysyl oxidase (Lox) expression as array substrate stiffness increased, with less dependence on ECM composition. Collagens III and IV increased HSC proliferation, whereas hyaluronic acid had the opposite effect. Meta-analysis performed on these data revealed distinct phenotypic clusters (e.g. low fibrogenesis/high proliferation) as a direct function of their microenvironmental composition. Notably, soft microenvironments mimicking healthy tissue (1 kPa), promoted higher levels of intracellular collagen I and Lox expression in activated HSCs, compared to stiff microenvironments mimicking fibrotic tissue (25 kPa). Collectively, these data suggest potential HSC functional adaptations in response to specific bio-chemo-mechanical changes relevant towards the development of therapeutic interventions. These findings also underscore the importance of the microenvironment when interrogating HSC behavior in healthy, disease, and treatment settings. STATEMENT OF SIGNIFICANCE: In this work we utilized high-throughput cellular microarray technology to systematically interrogate the complex interactions between HSCs and their microenvironment in the context of liver fibrosis. We observed that HSC phenotype is regulated by ECM composition and stiffness, and that these phenotypes can be classified into distinct clusters based on their microenvironmental context. Moreover, the range of these phenotypic responses to microenvironmental stimuli is substantial and a direct consequence of the combinatorial pairing of ECM protein and stiffness signals. We also observed a novel role for microenvironmental context in affecting HSC responses to potential fibrosis therapeutics.
Collapse
Affiliation(s)
- Aidan Brougham-Cook
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Ishita Jain
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - David A Kukla
- University of Illinois Chicago, Department of Bioengineering, United States.
| | - Faisal Masood
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Hannah Kimmel
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Hyeon Ryoo
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| | - Salman R Khetani
- University of Illinois Chicago, Department of Bioengineering, United States.
| | - Gregory H Underhill
- University of Illinois at Urbana-Champaign, Department of Bioengineering, 1406W Green St, Urbana, IL 61801, United States.
| |
Collapse
|
|
3
|
Ezhilarasan D. Hepatic stellate cells in the injured liver: Perspectives beyond hepatic fibrosis. J Cell Physiol 2021; 237:436-449. [PMID: 34514599 DOI: 10.1002/jcp.30582] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/22/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022]
Abstract
Over the last two decades, our understanding of the pathological role of hepatic stellate cells (HSCs) in fibrotic liver disease has increased dramatically. As HSCs are identified as the principal collagen-producing cells in the injured liver, several experimental and clinical studies have targeted HSCs to treat liver fibrosis. However, HSCs also play a critical role in developing nonfibrotic liver diseases such as cholestasis, portal hypertension, and hepatocellular carcinoma (HCC). Therefore, this review exclusively focuses on the role of activated HSCs beyond hepatic fibrosis. In cholestasis conditions, elevated bile salts and bile acids activate HSCs to secrete collagen and other extracellular matrix products, which cause biliary fibrosis and cholangitis. In the chronically injured liver, autocrine and paracrine signaling from liver sinusoidal endothelial cells activates HSCs to induce portal hypertension via endothelin-1 release. In the tumor microenvironment (TME), activated HSCs are the major source of cancer-associated fibroblasts (CAF). The crosstalk between activated HSC/CAF and tumor cells is associated with tumor cell proliferation, migration, metastasis, and chemoresistance. In TME, activated HSCs convert macrophages to tumor-associated macrophages and induce the differentiation of dendritic cells (DCs) and monocytes to regulatory DCs and myeloid-derived suppressor cells, respectively. This differentiation, in turn, increases T cells proliferation and induces their apoptosis leading to reduced immune surveillance in TME. Thus, HSCs activation in chronically injured liver is a critical process involved in the progression of cholestasis, portal hypertension, and liver cancer.
Collapse
Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, The Blue Lab, Molecular Medicine and Toxicology Division, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
| |
Collapse
|
|
4
|
Ezhilarasan D. Endothelin-1 in portal hypertension: The intricate role of hepatic stellate cells. Exp Biol Med (Maywood) 2020; 245:1504-1512. [PMID: 32791849 DOI: 10.1177/1535370220949148] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
IMPACT STATEMENT Portal hypertension is pathologically defined as increase of portal venous pressure, mainly due to chronic liver diseases such as fibrosis and cirrhosis. In fibrotic liver, activated hepatic stellate cells increase their contraction in response to endothelin-1 (ET-1) via autocrine and paracrine stimulation from liver sinusoidal endothelial cells and injured hepatocytes. Clinical studies are limited with ET receptor antagonists in cirrhotic patients with portal hypertension. Hence, studies are needed to find molecules that block ET-1 synthesis. Accumulation of extracellular matrix proteins in the perisinusoidal space, tissue contraction, and alteration in blood flow are prominent during portal hypertension. Therefore, novel matrix modulators should be tested experimentally as well as in clinical studies. Specifically, tumor necrosis factor-α, transforming growth factor-β1, Wnt, Notch, rho-associated protein kinase 1 signaling antagonists, and peroxisome proliferator-activated receptor α and γ, interferon-γ and sirtuin 1 agonists should be tested elaborately against cirrhosis patients with portal hypertension.
Collapse
Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Biomedical Research Unit and Laboratory Animal Centre, Saveetha Dental College, 194347Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai 600 077, India
| |
Collapse
|
|
5
|
Cairo MS, Cooke KR, Lazarus HM, Chao N. Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation. Br J Haematol 2020; 190:822-836. [PMID: 32133623 DOI: 10.1111/bjh.16557] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease (VOD), remains a multi-organ system complication following haematopoietic cell transplantation (HCT). When SOS/VOD is accompanied by multi-organ dysfunction, overall mortality rates remain >80%. However, the definitions related to the diagnosis and grading of SOS/VOD after HCT are almost 25 years old and require new and contemporary modifications. Importantly, the pathophysiology of SOS/VOD, including the contribution of dysregulated inflammatory and coagulation cascades as well as the critical importance of liver and vascular derived endothelial dysfunction, have been elucidated. Here we summarise new information on pathogenesis of SOS/VOD; identify modifiable and unmodifiable risk factors for disease development; propose novel, contemporary and panel opinion-based diagnostic criteria and an innovative organ-based method of SOS/VOD grading classification; and review current approaches for prophylaxis and treatment of SOS/VOD. This review will hopefully illuminate pathways responsible for drug-induced liver injury and manifestations of disease, sharpen awareness of risk for disease development and enhance the timely and correct diagnosis of SOS/VOD post-HCT.
Collapse
Affiliation(s)
- Mitchell S Cairo
- Departments of, Department of, Pediatrics, New York Medical College, Valhalla, NY, USA.,Department of, Medicine, New York Medical College, Valhalla, NY, USA.,Department of, Pathology, New York Medical College, Valhalla, NY, USA.,Department of, Microbiology and Immunology, New York Medical College, Valhalla, NY, USA.,Department of, Cell Biology & Anatomy, New York Medical College, Valhalla, NY, USA
| | - Kenneth R Cooke
- Department of Oncology, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
| | - Hillard M Lazarus
- Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
| | - Nelson Chao
- Departments of, Department of, Medicine, Duke University, Durham, NC, USA.,Department of, Immunology, Duke University, Durham, NC, USA.,Department of, Pathology, Duke University, Durham, NC, USA
| |
Collapse
|
|
6
|
Zhangdi HJ, Su SB, Wang F, Liang ZY, Yan YD, Qin SY, Jiang HX. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol 2019; 25:4835-4849. [PMID: 31543677 PMCID: PMC6737310 DOI: 10.3748/wjg.v25.i33.4835] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 07/24/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.
Collapse
Affiliation(s)
- Han-Jing Zhangdi
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Si-Biao Su
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Fei Wang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Zi-Yu Liang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Yu-Dong Yan
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Shan-Yu Qin
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| | - Hai-Xing Jiang
- Department of Gastroenterology, the First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Zhuang Autonomous Region, China
| |
Collapse
|
|
7
|
Blum AE, Venkitachalam S, Ravillah D, Chelluboyina AK, Kieber-Emmons AM, Ravi L, Kresak A, Chandar AK, Markowitz SD, Canto MI, Wang JS, Shaheen NJ, Guo Y, Shyr Y, Willis JE, Chak A, Varadan V, Guda K. Systems Biology Analyses Show Hyperactivation of Transforming Growth Factor-β and JNK Signaling Pathways in Esophageal Cancer. Gastroenterology 2019; 156:1761-1774. [PMID: 30768984 PMCID: PMC6701681 DOI: 10.1053/j.gastro.2019.01.263] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 12/27/2018] [Accepted: 01/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Esophageal adenocarcinoma (EAC) is resistant to standard chemoradiation treatments, and few targeted therapies are available. We used large-scale tissue profiling and pharmacogenetic analyses to identify deregulated signaling pathways in EAC tissues that might be targeted to slow tumor growth or progression. METHODS We collected 397 biopsy specimens from patients with EAC and nonmalignant Barrett's esophagus (BE), with or without dysplasia. We performed RNA-sequencing analyses and used systems biology approaches to identify pathways that are differentially activated in EAC vs nonmalignant dysplastic tissues; pathway activities were confirmed with immunohistochemistry and quantitative real-time polymerase chain reaction analyses of signaling components in patient tissue samples. Human EAC (FLO-1 and EsoAd1), dysplastic BE (CP-B, CP-C, CP-D), and nondysplastic BE (CP-A) cells were incubated with pharmacologic inhibitors or transfected with small interfering RNAs. We measured effects on proliferation, colony formation, migration, and/or growth of xenograft tumors in nude mice. RESULTS Comparisons of EAC vs nondysplastic BE tissues showed hyperactivation of transforming growth factor-β (TGFB) and/or Jun N-terminal kinase (JNK) signaling pathways in more than 80% of EAC samples. Immunohistochemical analyses showed increased nuclear localization of phosphorylated JUN and SMAD proteins in EAC tumor tissues compared with nonmalignant tissues. Genes regulated by the TGFB and JNK pathway were overexpressed specifically in EAC and dysplastic BE. Pharmacologic inhibition or knockdown of TGFB or JNK signaling components in EAC cells (FLO-1 or EsoAd1) significantly reduced cell proliferation, colony formation, cell migration, and/or growth of xenograft tumors in mice in a SMAD4-independent manner. Inhibition of the TGFB pathway in BE cell lines reduced the proliferation of dysplastic, but not nondysplastic, cells. CONCLUSIONS In a transcriptome analysis of EAC and nondysplastic BE tissues, we found the TGFB and JNK signaling pathways to be hyperactivated in EACs and the genes regulated by these pathways to be overexpressed in EAC and dysplastic BE. Inhibiting these pathways in EAC cells reduces their proliferation, migration, and formation of xenograft tumors. Strategies to block the TGFB and JNK signaling pathways might be developed for treatment of EAC.
Collapse
Affiliation(s)
- Andrew E. Blum
- Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Srividya Venkitachalam
- Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Durgadevi Ravillah
- Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Aruna K. Chelluboyina
- Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Ann Marie Kieber-Emmons
- Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Lakshmeswari Ravi
- Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Adam Kresak
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Apoorva K. Chandar
- Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Sanford D. Markowitz
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,Division of Hematology and Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Marcia I. Canto
- Division of Gastroenterology and Hepatology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD-21205 U.S.A
| | - Jean S. Wang
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, M0-63110 U.S.A
| | - Nicholas J. Shaheen
- Center for Esophageal Diseases and Swallowing, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, NC-27599 U.S.A
| | - Yan Guo
- Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, TN-37232 U.S.A
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt Ingram Cancer Center, Nashville, TN-37232 U.S.A
| | - Joseph E. Willis
- University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Amitabh Chak
- Division of Gastroenterology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A,University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Vinay Varadan
- Division of General Medical Sciences-Oncology, Case Western Reserve University School of Medicine, Cleveland, OH-44106 U.S.A
| | - Kishore Guda
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
| |
Collapse
|
|
8
|
Upregulation of the actin cytoskeleton via myocardin leads to increased expression of type 1 collagen. J Transl Med 2017; 97:1412-1426. [PMID: 29035375 PMCID: PMC6437559 DOI: 10.1038/labinvest.2017.96] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 06/19/2017] [Accepted: 07/05/2017] [Indexed: 12/28/2022] Open
Abstract
Liver fibrosis, a model wound healing system, is characterized by excessive deposition of extracellular matrix (ECM) in the liver. Although many fibrogenic cell types may express ECM, the hepatic stellate cell (HSC) is currently considered to be the major effector. HSCs transform into myofibroblast-like cells, also known as hepatic myofibroblasts in a process known as activation; this process is characterized in particular by de novo expression of smooth muscle alpha actin (SM α-actin) and type 1 collagen. The family of actins, which form the cell's cytoskeleton, are essential in many cellular processes. β-actin and cytoplasmic γ-actin (γ-actin) are ubiquitously expressed, whereas SM α-actin defines smooth muscle cell and myofibroblast phenotypes. Thus, SM α-actin is tightly associated with multiple functional properties. However, the regulatory mechanisms by which actin isoforms might regulate type 1 collagen remain unclear. In primary HSCs from normal and fibrotic rat liver, we demonstrate that myocardin, a canonical SRF cofactor, is upregulated in hepatic myofibroblasts and differentially regulates SM α-actin, γ-actin, and β-actins through activation of an ATTA box in the SM α-actin and a CCAAT box in γ-actin and β-actin promoters, respectively; moreover, myocardin differentially activated serum response factor (SRF) in CArG boxes of actin promoters. In addition, myocardin-stimulated Smad2 phosphorylation and RhoA expression, leading to increased expression of type 1 collagen in an actin cytoskeleton-dependent manner. Myocardin also directly enhanced SRF expression and stimulated collagen 1α1 and 1α2 promoter activities. In addition, overexpression of myocardin in vivo during carbon tetrachloride-induced liver injury led to increased HSC activation and fibrogenesis. In summary, our data suggest that myocardin plays a critical role in actin cytoskeletal dynamics during HSC activation, in turn, specifically regulating type I collagen expression in hepatic myofibroblasts.
Collapse
|
|
9
|
Hepatic stellate cells as key target in liver fibrosis. Adv Drug Deliv Rev 2017; 121:27-42. [PMID: 28506744 DOI: 10.1016/j.addr.2017.05.007] [Citation(s) in RCA: 1032] [Impact Index Per Article: 129.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/21/2017] [Accepted: 05/09/2017] [Indexed: 02/06/2023]
Abstract
Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or "activation") of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.
Collapse
|
|
10
|
ROCKEY DONC. The Molecular Basis of Portal Hypertension. TRANSACTIONS OF THE AMERICAN CLINICAL AND CLIMATOLOGICAL ASSOCIATION 2017; 128:330-345. [PMID: 28790516 PMCID: PMC5525430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Cirrhosis leads to portal hypertension and vascular abnormalities in multiple vascular beds. There is intense vasoconstriction in the liver and the kidneys, but also vasodilation in the other vascular beds, including the periphery, lungs, brain, and mesentery. The derangement in each of these beds leads to specific clinical disease. The vasoconstrictive phenotype in the liver ultimately leads to clinical portal hypertension, and is caused by an imbalance of vasoconstrictive and vasorelaxing molecules, which will be the focus of this review.
Collapse
Affiliation(s)
- DON C. ROCKEY
- Correspondence and reprint requests: Don C. Rockey, MD, Department of Internal Medicine, Medical University of South Carolina,
96 Jonathan Lucas Street, Suite 803, MSC 623, Charleston, South Carolina 29425843-792-2914
| |
Collapse
|
|
11
|
|
|
12
|
Jia H, Aw W, Saito K, Hanate M, Hasebe Y, Kato H. Eggshell membrane ameliorates hepatic fibrogenesis in human C3A cells and rats through changes in PPARγ-Endothelin 1 signaling. Sci Rep 2014; 4:7473. [PMID: 25503635 PMCID: PMC5378949 DOI: 10.1038/srep07473] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 11/20/2014] [Indexed: 12/22/2022] Open
Abstract
Our previous nutrigenomic findings indicate that eggshell membrane (ESM) may prevent liver fibrosis. Here we investigated the effects and mechanisms underlying ESM intervention against liver injury by using DNA microarray analysis and comparative proteomics. In vitro hydrolyzed ESM attenuated the TGFβ1-induced procollagen production of human hepatocyte C3A cells and inhibited the expression of Endothelin 1 (EDN1) and its two receptors, and extracellular matrix components. In vivo male Wistar rats were allocated into a normal control group, a CCl4 group (hypodermic injection of 50% CCl4 2×/wk) and an ESM group (20 g ESM/kg diet with CCl4 injection) for 7 wks. Dietary ESM ameliorated the elevated activity of ALT/AST, oxidative stress and collagen accumulation in liver, accompanied by the down-regulated expression of Edn1 signaling and notable profibrogenic genes and growth factors as well as peroxisome proliferator-activated receptor gamma (PPARγ). Concomitantly, the decreased expressions of Galectin-1 and Desmin protein in the ESM group indicated the deactivation of hepatic stellate cells (HSCs). Through a multifaceted integrated omics approach, we have demonstrated that ESM can exert an antifibrotic effect by suppressing oxidative stress and promoting collagen degradation by inhibiting HSCs' transformation, potentially via a novel modulation of the PPARγ-Endothelin 1 interaction signaling pathway.
Collapse
Affiliation(s)
- Huijuan Jia
- Corporate Sponsored Research Program "Food for Life, " Organization for Interdisciplinary Research Projects, The University of Tokyo, Tokyo, Japan
| | - Wanping Aw
- Institute of Advanced Biosciences, Keio University, Yamagata, Japan
| | - Kenji Saito
- Corporate Sponsored Research Program "Food for Life, " Organization for Interdisciplinary Research Projects, The University of Tokyo, Tokyo, Japan
| | - Manaka Hanate
- Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| | | | - Hisanori Kato
- 1] Corporate Sponsored Research Program "Food for Life, " Organization for Interdisciplinary Research Projects, The University of Tokyo, Tokyo, Japan [2] Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
13
|
Abstract
Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin-expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen-mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer.
Collapse
Affiliation(s)
- Juan E Puche
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai Hospital, New York, New York, New York
| | | | | |
Collapse
|
|
14
|
Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury. PLoS One 2014; 9:e108505. [PMID: 25290689 PMCID: PMC4188519 DOI: 10.1371/journal.pone.0108505] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/22/2014] [Indexed: 12/11/2022] Open
Abstract
Liver fibrosis is mediated by hepatic stellate cells (HSCs), which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR)-mediated signaling, via endothelin-1 (ET-1) and angiotensin II (AngII), increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5), an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs). Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4)-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.
Collapse
|
|
15
|
Richards J, Welch AK, Barilovits SJ, All S, Cheng KY, Wingo CS, Cain BD, Gumz ML. Tissue-specific and time-dependent regulation of the endothelin axis by the circadian clock protein Per1. Life Sci 2014; 118:255-62. [PMID: 24721511 PMCID: PMC4387882 DOI: 10.1016/j.lfs.2014.03.028] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/01/2014] [Accepted: 03/26/2014] [Indexed: 01/08/2023]
Abstract
AIMS The present study is designed to consider a role for the circadian clock protein Per1 in the regulation of the endothelin axis in mouse kidney, lung, liver and heart. Renal endothelin-1 (ET-1) is a regulator of the epithelial sodium channel (ENaC) and blood pressure (BP), via activation of both endothelin receptors, ETA and ETB. However, ET-1 mediates many complex events in other tissues. MAIN METHODS Tissues were collected in the middle of murine rest and active phases, at noon and midnight, respectively. ET-1, ETA and ETB mRNA expressions were measured in the lung, heart, liver, renal inner medulla and renal cortex of wild type and Per1 heterozygous mice using real-time quantitative RT-PCR. KEY FINDINGS The effect of reduced Per1 expression on levels of mRNAs and the time-dependent regulation of expression of the endothelin axis genes appeared to be tissue-specific. In the renal inner medulla and the liver, ETA and ETB exhibited peaks of expression in opposite circadian phases. In contrast, expressions of ET-1, ETA and ETB in the lung did not appear to vary with time, but ET-1 expression was dramatically decreased in this tissue in Per1 heterozygous mice. Interestingly, ET-1 and ETA, but not ETB, were expressed in a time-dependent manner in the heart. SIGNIFICANCE Per1 appears to regulate expression of the endothelin axis genes in a tissue-specific and time-dependent manner. These observations have important implications for our understanding of the best time of day to deliver endothelin receptor antagonists.
Collapse
Affiliation(s)
- Jacob Richards
- Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA
| | - Amanda K Welch
- Department of Medicine, University of Florida, USA; North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - Sarah J Barilovits
- Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA
| | - Sean All
- Department of Medicine, University of Florida, USA
| | | | - Charles S Wingo
- Department of Medicine, University of Florida, USA; North Florida/South Georgia Veterans Health System, Gainesville, FL, USA
| | - Brian D Cain
- Department of Biochemistry and Molecular Biology, University of Florida, USA
| | - Michelle L Gumz
- Department of Medicine, University of Florida, USA; Department of Biochemistry and Molecular Biology, University of Florida, USA.
| |
Collapse
|
|
16
|
Wang J, Wang L, Song G, Han B. The mechanism through which octreotide inhibits hepatic stellate cell activity. Mol Med Rep 2013; 7:1559-64. [PMID: 23525276 DOI: 10.3892/mmr.2013.1385] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 02/13/2013] [Indexed: 12/13/2022] Open
Abstract
Hepatic stellate cells (HSCs) are important in the development of liver fibrosis and in the pathogenesis of portal hypertension. Octreotide, an analogue of somatostatin, has been demonstrated to effectively treat fibrosis and portal hypertension; however, its relative mechanism in HSCs remains unknown. LX‑2, the immortalized HSC line, was used to study the mechanism whereby octreotide functions at different concentrations. Real‑time polymerase chain reaction (PCR) and western blot analysis were used to analyze the expression of fibrosis markers and transcription factors following treatment with octreotide. Soluble secreted endothelin‑1 (ET‑1), collagen I and vascular endothelial growth factor (VEGF) were assessed in the supernatants of cultured cells by enzyme-linked immunosorbent assay (ELISA). In the present study, it was shown that octreotide was able to inhibit the proliferative ability of the LX‑2 cells and decrease the expression of transforming growth factor β (TGF‑β), α‑smooth muscle actin (α‑SMA) and smad‑4a. The transcription factors, including c‑Jun and sp‑1, were downregulated in a dose‑dependent manner following treatment with octreotide. The levels of ET‑1 and collagen I in the supernatant decreased significantly in contrast with the normal levels, whereas the levels of VEGF in the LX‑2 cells and the supernatant increased at a high octreotide concentration (10‑5 nM). Octreotide may exert its effects on ET‑1 or other targeting genes in HSCs through the downregulation of c‑Jun and specificity protein 1 (sp‑1), and the increased levels of VEGF may be the reason for the side effects observed at high concentrations of octreotide.
Collapse
Affiliation(s)
- Jingjing Wang
- Clinical Test Department of Shandong Qianfoshan Hospital, and Department of Pathology,Shandong University Medical School, Jinan, Shandong 250014, PR China
| | | | | | | |
Collapse
|
|
17
|
|