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Browsing by Subject "Hepatic stellate cells"
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Item Activin B Promotes Hepatic Fibrogenesis(2019-08) Wang, Yan; Dai, Guoli; Berbari, Nicolas; Yaden, Benjamin; Liangpunsakul, Suthat; Skalnik, David G.Liver fibrosis is a common consequence of various chronic liver diseases. Although transforming growth factor β 1 (TGFβ1) expression is known to be associated with liver fibrosis, the reduced clinical efficacy of TGFβ1 inhibition or the inefficiency to completely prevent liver fibrosis in mice with liver-specific knockout of TGF receptor II suggests that other factors can mediate liver fibrogenesis. As a TGFβ superfamily ligand, activin A signaling modulates liver injury by prohibiting hepatocyte proliferation, mediating hepatocyte apoptosis, promoting Kupffer cell activation, and inducing hepatic stellate cell (HSC) activation in vitro. However, the mechanism of action and in vivo functional significance of activin A in liver fibrosis models remain uncertain. Moreover, whether activin B, another ligand structurally related to activin A, is involved in liver fibrogenesis is not yet known. This study aimed to investigate the role of activin A and B in liver fibrosis initiation and progression. The levels of hepatic and circulating activin B and A were analyzed in patients with various chronic liver diseases, including end-stage liver diseases (ESLD), non-alcoholic steatohepatitis (NASH), and alcoholic liver disease (ALD). In addition, their levels were measured in mouse carbon tetrachloride (CCl4), bile duct ligation (BDL), and ALD liver injury models. Mouse primary hepatocytes, RAW264.7 cells, and LX-2 cells were used as in vitro models of hepatocytes, macrophages, and HSCs, respectively. The specificity and potency of anti-activin B monoclonal antibody (mAb) and anti-activin A mAb were evaluated using Smad2/3 luciferase assay. Activin A, activin B, or their combination were immunologically inactivated by the neutralizing mAbs in mice with progressive or established liver fibrosis induced by CCl4 or with developing cholestatic liver fibrosis induced by BDL surgery. In patients with ESLD, NASH, and ALD, increases in hepatic and circulating activin B, but not activin A, were associated with liver fibrosis, irrespective of etiology. In mice with CCl4-, BDL-, or alcohol-induced liver injury, activin B was persistently elevated in the liver and circulation, whereas activin A showed only transient increases. Activin B was expressed and secreted mainly by the hepatocytes and other cells, including cholangiocytes, activated HSCs, and immune cells. Exogenous administration of activin B promoted hepatocyte injury, activated macrophages to release cytokines, and induced a pro-fibrotic expression profile and septa formation in HSCs. Co-treatment of activin A and B interdependently activated the chemokine (C-X-C motif) ligand 1 (CXCL1)/inducible nitric oxide synthase (iNOS) pathway in macrophages and additively upregulated connective tissue growth factor expression in HSCs. Activin B and A had redundant, unique, and interactive effects on the transcripts related to HSC activation. The neutralization of activin B attenuated the development of liver fibrosis and improved liver function in mice with CCl4- or BDL-induced liver fibrosis and largely reversed the already established liver fibrosis in the CCl4 mouse model. These effects were improved by the administration of additional anti-activin A antibody. Combination of both antibodies also inhibited hepatic and circulating inflammatory cytokine production in the BDL mouse model. In conclusion, activin B is a potential circulating biomarker and potent promotor of liver fibrosis. Its levels in the liver and circulation increase significantly in both acute and chronic states of liver injury. Activin B might additively or interdependently cooperate with activin A, which directly acts on multiple liver cell populations during liver injury and fibrosis, as the combination of both proteins increases pro-inflammatory and pro-fibrotic responses in vitro. In addition, the neutralization of both activin A and activin B in vivo enhances the preventive and reversible effects of liver injury and fibrosis compared to that when activin B alone is neutralized. Our data reveal a novel target of liver fibrosis and the mechanism of activin B-mediated initiation of this process by damaging hepatocytes and activating macrophages and HSCs. Our findings show that activin B promotes hepatic fibrogenesis, and that targeting of activin B has anti-inflammatory and anti-fibrotic effects, which ameliorate liver injury by preventing or regressing liver fibrosis. Antagonizing either activin B alone or in combination with activin A prevents and regresses liver fibrosis in multiple animal studies, paving way for future clinical studies.Item Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis(Elsevier, 2024) Ceci, Ludovica; Gaudio, Eugenio; Kennedy, Lindsey; Medicine, School of MedicineBiliary fibrosis is seen in cholangiopathies, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In PBC and PSC, biliary fibrosis is associated with worse outcomes and histologic scores. Within the liver, both hepatic stellate cells (HSCs) and portal fibroblasts (PFs) contribute to biliary fibrosis, but their roles can differ. PFs reside near the bile ducts and may be the first responders to biliary damage, whereas HSCs may be recruited later and initiate bridging fibrosis. Indeed, different models of biliary fibrosis can activate PFs and HSCs to varying degrees. The portal niche can be composed of cholangiocytes, HSCs, PFs, endothelial cells, and various immune cells, and interactions between these cell types drive biliary fibrosis. In this review, we discuss the mechanisms of biliary fibrosis and the roles of PFs and HSCs in this process. We will also evaluate cellular interactions and mechanisms that contribute to biliary fibrosis in different models and highlight future perspectives and potential therapeutics.Item Current Perspectives of Neuroendocrine Regulation in Liver Fibrosis(MDPI, 2022-11-26) Li, Bowen; Wang, Hui; Zhang, Yudian; Liu, Ying; Zhou, Tiejun; Zhou, Bingru; Zhang, Ying; Chen, Rong; Xing, Juan; He, Longfei; Salinas, Jennifer Mata; Koyama, Sachiko; Meng, Fanyin; Wan, Ying; Medicine, School of MedicineLiver fibrosis is a complicated process that involves different cell types and pathological factors. The excessive accumulation of extracellular matrix (ECM) and the formation of fibrotic scar disrupt the tissue homeostasis of the liver, eventually leading to cirrhosis and even liver failure. Myofibroblasts derived from hepatic stellate cells (HSCs) contribute to the development of liver fibrosis by producing ECM in the area of injuries. It has been reported that the secretion of the neuroendocrine hormone in chronic liver injury is different from a healthy liver. Activated HSCs and cholangiocytes express specific receptors in response to these neuropeptides released from the neuroendocrine system and other neuroendocrine cells. Neuroendocrine hormones and their receptors form a complicated network that regulates hepatic inflammation, which controls the progression of liver fibrosis. This review summarizes neuroendocrine regulation in liver fibrosis from three aspects. The first part describes the mechanisms of liver fibrosis. The second part presents the neuroendocrine sources and neuroendocrine compartments in the liver. The third section discusses the effects of various neuroendocrine factors, such as substance P (SP), melatonin, as well as α-calcitonin gene-related peptide (α-CGRP), on liver fibrosis and the potential therapeutic interventions for liver fibrosis.Item Kupffer Cells: Inflammation Pathways and Cell-Cell Interactions in Alcohol-Associated Liver Disease(Elsevier, 2020) Slevin, Elise; Baiocchi, Leonardo; Wu, Nan; Ekser, Burcin; Sato, Keisaku; Lin, Emily; Ceci, Ludovica; Chen, Lixian; Lorenzo, Sugeily R.; Xu, Wenjuan; Kyritsi, Konstantina; Meadows, Victoria; Zhou, Tianhao; Kundu, Debiyoti; Han, Yuyan; Kennedy, Lindsey; Glaser, Shannon; Francis, Heather; Alpini, Gianfranco; Meng, Fanyin; Surgery, School of MedicineChronic alcohol consumption is linked to the development of alcohol-associated liver disease (ALD). This disease is characterized by a clinical spectrum ranging from steatosis to hepatocellular carcinoma. Several cell types are involved in ALD progression, including hepatic macrophages. Kupffer cells (KCs) are the resident macrophages of the liver involved in the progression of ALD by activating pathways that lead to the production of cytokines and chemokines. In addition, KCs are involved in the production of reactive oxygen species. Reactive oxygen species are linked to the induction of oxidative stress and inflammation in the liver. These events are activated by the bacterial endotoxin, lipopolysaccharide, that is released from the gastrointestinal tract through the portal vein to the liver. Lipopolysaccharide is recognized by receptors on KCs that are responsible for triggering several pathways that activate proinflammatory cytokines involved in alcohol-induced liver injury. In addition, KCs activate hepatic stellate cells that are involved in liver fibrosis. Novel strategies to treat ALD aim at targeting Kupffer cells. These interventions modulate Kupffer cell activation or macrophage polarization. Evidence from mouse models and early clinical studies in patients with ALD injury supports the notion that pathogenic macrophage subsets can be successfully translated into novel treatment options for patients with this disease.Item Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma(Wolters Kluwer, 2021) Sato, Keisaku; Zhang, Wenjun; Safarikia, Samira; Isidan, Abdulkadir; Chen, Angela M.; Li, Ping; Francis, Heather; Kennedy, Lindsey; Baiocchi, Leonardo; Alvaro, Domenico; Glaser, Shannon; Ekser, Burcin; Alpini, Gianfranco; Medicine, School of MedicineCholangiopathies, such as primary sclerosing cholangitis, biliary atresia, and cholangiocarcinoma, have limited experimental models. Not only cholangiocytes but also other hepatic cells including hepatic stellate cells and macrophages are involved in the pathophysiology of cholangiopathies, and these hepatic cells orchestrate the coordinated response against diseased conditions. Classic two-dimensional monolayer cell cultures do not resemble intercellular cell-to-cell interaction and communication; however, three-dimensional cell culture systems, such as organoids and spheroids, can mimic cellular interaction and architecture between hepatic cells. Previous studies have demonstrated the generation of hepatic or biliary organoids/spheroids using various cell sources including pluripotent stem cells, hepatic progenitor cells, primary cells from liver biopsies, and immortalized cell lines. Gene manipulation, such as transfection and transduction can be performed in organoids, and established organoids have functional characteristics which can be suitable for drug screening. This review summarizes current methodologies for organoid/spheroid formation and a potential for three-dimensional hepatic cell cultures as in vitro models of cholangiopathies.Item Stress and Liver Fibrogenesis: Understanding the Role and Regulation of Stress Response Pathways in Hepatic Stellate Cells(Elsevier, 2023) Hanquier, Zachary; Misra, Jagannath; Baxter, Reese; Maiers, Jessica L.; Medical and Molecular Genetics, School of MedicineStress response pathways are crucial for cells to adapt to physiological and pathologic conditions. Increased transcription and translation in response to stimuli place a strain on the cell, necessitating increased amino acid supply, protein production and folding, and disposal of misfolded proteins. Stress response pathways, such as the unfolded protein response (UPR) and the integrated stress response (ISR), allow cells to adapt to stress and restore homeostasis; however, their role and regulation in pathologic conditions, such as hepatic fibrogenesis, are unclear. Liver injury promotes fibrogenesis through activation of hepatic stellate cells (HSCs), which produce and secrete fibrogenic proteins to promote tissue repair. This process is exacerbated in chronic liver disease, leading to fibrosis and, if unchecked, cirrhosis. Fibrogenic HSCs exhibit activation of both the UPR and ISR, due in part to increased transcriptional and translational demands, and these stress responses play important roles in fibrogenesis. Targeting these pathways to limit fibrogenesis or promote HSC apoptosis is a potential antifibrotic strategy, but it is limited by our lack of mechanistic understanding of how the UPR and ISR regulate HSC activation and fibrogenesis. This article explores the role of the UPR and ISR in the progression of fibrogenesis, and highlights areas that require further investigation to better understand how the UPR and ISR can be targeted to limit hepatic fibrosis progression.