TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019
<p>Activation of hepatic stellate cells (HSCs) and origin of myofibroblasts (MFBs) in chronic liver diseases. During activation, HSCs lose intracellular lipid droplets, acquire a fibroblast-like shape, and express a large amount of alpha-smooth muscle actin (α-SMA) and extracellular matrix proteins (ECM). Beside HSCs, which represent a major source of MFBs, other cells such as pericytes, portal fibroblasts can differentiate into MFBs. Also, endothelial cells (ECs) and epithelial cells, i.e., hepatocytes and cholangiocytes, might contribute to liver MFBs pool through an endothelial-mesenchymal transition (EndMT) and epithelial-mesenchymal transition (EMT), respectively. However, unequivocal in vivo evidence of EMT during liver fibrosis is still missing.</p> "> Figure 2
<p>SMAD- and Non-SMAD-dependent TGF-β signaling. Upon liver damage associated signaling, TGF-β molecules are freed from the large latent complex (LLC) through the interaction of integrins with the latent association protein (LAP). Binding of released TGF-β to TβRII results in the formation of a heterotetramer with TβRI, which then initiates the canonical signaling pathway through phosphorylation of R-SMADs, i.e., SMAD2 (S2) and SMAD3 (S3). TGF-β can also activate non-canonical SMAD-independent pathways, as exemplified here by MAPK, mTOR, PI3K/AKT, and Rho/GTPase pathways. Alongside other mechanisms, SMAD7 negatively regulates TGF-β signaling through competing with R-SMADs for TβRI binding. TF: Transcription factors, P: phosphate group, LTBP: latent TGF-β binding protein.</p> ">
Abstract
:1. Introduction
1.1. Liver Fibrosis and Hepatic Stellate Cell (HSC) Activation
1.2. TGF-β Family
1.3. TGF-β Signaling
1.3.1. SMAD2 vs. SMAD3
1.3.2. SMAD Phosphorylation Dynamics
2. Regulation of the TGF-β Pathway
New Targets and Regulators of the TGF-β Pathway in Liver Fibrosis
3. TGF-β Activity and the Microenvironment in Liver Fibrosis
3.1. Composition of the ECM
3.2. Matrix Stiffness
3.3. TGF-β and Inflammatory Cells
3.4. TGF-β and Pathophysiological Blood Flow in Liver Fibrosis
3.5. Dynamics of TGF-β Ligand Availability
4. TGF-β Signaling, Cell Damage and Oxidative Stress in Liver Fibrosis
5. TGF-β Signaling and Epigenetics in Liver Fibrosis
6. TGF-β and Mesenchymal Transition in Liver Fibrosis
7. TGF-β and Metabolic Fate Changes in Liver Fibrosis
8. Circadian Rhythm, TGF-β Signaling, and Liver Fibrosis
9. TGF-β, Autophagy, and Senescence in Liver Fibrosis
10. Targeting TGF-β in Liver Fibrosis
11. Conclusions and Outlook
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Chen, J.Y.; Thakar, D.; Chang, T.T. Liver Fibrosis: Current Approaches and Future Directions for Diagnosis and Treatment. In Fibrosis in Disease: An Organ-Based Guide to Disease Pathophysiology and Therapeutic Considerations; Willis, M.S., Yates, C.C., Schisler, J.C., Eds.; Springer: Cham, Germany, 2019; pp. 387–417. [Google Scholar]
- Hernandez-Gea, V.; Friedman, S.L. Pathogenesis of liver fibrosis. Annu. Rev. Pathol. 2011, 6, 425–456. [Google Scholar] [CrossRef] [PubMed]
- Ni, Y.; Li, J.-M.; Liu, M.-K.; Zhang, T.-T.; Wang, D.-P.; Zhou, W.-H.; Hu, L.-Z.; Lv, W.-L. Pathological process of liver sinusoidal endothelial cells in liver diseases. World J. Gastroenterol. 2017, 23, 7666–7677. [Google Scholar] [CrossRef] [PubMed]
- Elpek, G.Ö. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J. Gastroenterol. 2014, 20, 7260–7276. [Google Scholar] [CrossRef] [PubMed]
- Seki, E.; Brenner, D.A. Recent advancement of molecular mechanisms of liver fibrosis. J. Hepato-Biliary-Pancreat. Sci. 2015, 22, 512–518. [Google Scholar] [CrossRef] [PubMed]
- Pellicoro, A.; Ramachandran, P.; Iredale, J.P.; Fallowfield, J.A. Liver fibrosis and repair: Immune regulation of wound healing in a solid organ. Nat. Rev. Immunol. 2014, 14, 181–194. [Google Scholar] [CrossRef] [PubMed]
- Zhao, Y.-L.; Zhu, R.-T.; Sun, Y.-L. Epithelial-mesenchymal transition in liver fibrosis. Biomed. Rep. 2016, 4, 269–274. [Google Scholar] [CrossRef] [PubMed]
- Fabregat, I.; Caballero-Díaz, D. Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front. Oncol. 2018, 8, 357. [Google Scholar] [CrossRef] [PubMed]
- Tsuchida, T.; Friedman, S.L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 2017, 14, 397–411. [Google Scholar] [CrossRef] [PubMed]
- Dewidar, B.; Soukupova, J.; Fabregat, I.; Dooley, S. TGF-β in hepatic stellate cell activation and liver fibrogenesis: Updated. Curr. Pathobiol. Rep. 2015, 3, 291–305. [Google Scholar] [CrossRef]
- Schon, H.-T.; Weiskirchen, R. Immunomodulatory effects of transforming growth factor-β in the liver. Hepatobiliary Surg. Nutr. 2014, 3, 386–406. [Google Scholar] [PubMed]
- Ghafoory, S.; Varshney, R.; Robison, T.; Kouzbari, K.; Woolington, S.; Murphy, B.; Xia, L.; Ahamed, J. Platelet TGF-β1 deficiency decreases liver fibrosis in a mouse model of liver injury. Blood Adv. 2018, 2, 470–480. [Google Scholar] [CrossRef] [PubMed]
- Derynck, R.; Budi, E.H. Specificity, versatility, and control of TGF-β family signaling. Sci. Signal. 2019, 12, eaav5183. [Google Scholar] [CrossRef] [PubMed]
- Dickson, M.C.; Martin, J.S.; Cousins, F.M.; Kulkarni, A.B.; Karlsson, S.; Akhurst, R.J. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development 1995, 121, 1845–1854. [Google Scholar] [PubMed]
- Kaartinen, V.; Voncken, J.W.; Shuler, C.; Warburton, D.; Bu, D.; Heisterkamp, N.; Groffen, J. Abnormal lung development and cleft palate in mice lacking TGF-beta 3 indicates defects of epithelial-mesenchymal interaction. Nat. Genet. 1995, 11, 415–421. [Google Scholar] [CrossRef] [PubMed]
- Sanford, L.P.; Ormsby, I.; Gittenberger-de Groot, A.C.; Sariola, H.; Friedman, R.; Boivin, G.P.; Cardell, E.L.; Doetschman, T. TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 1997, 124, 2659–2670. [Google Scholar] [PubMed]
- Fabregat, I.; Moreno-Càceres, J.; Sánchez, A.; Dooley, S.; Dewidar, B.; Giannelli, G.; Ten Dijke, P. IT-LIVER Consortium TGF-β signalling and liver disease. FEBS J. 2016, 283, 2219–2232. [Google Scholar] [CrossRef] [PubMed]
- Dropmann, A.; Dediulia, T.; Breitkopf-Heinlein, K.; Korhonen, H.; Janicot, M.; Weber, S.N.; Thomas, M.; Piiper, A.; Bertran, E.; Fabregat, I.; et al. TGF-β1 and TGF-β2 abundance in liver diseases of mice and men. Oncotarget 2016, 7, 19499–19518. [Google Scholar] [CrossRef] [PubMed]
- Abd El-Meguid, M.; Dawood, R.M.; Mokhles, M.A.; El Awady, M.K. Extrahepatic upregulation of transforming growth factor beta 2 in HCV genotype 4-induced liver fibrosis. J. Int. Soc. Interferon Cytokine Res. 2018, 38, 341–347. [Google Scholar] [CrossRef] [PubMed]
- Chida, T.; Ito, M.; Nakashima, K.; Kanegae, Y.; Aoshima, T.; Takabayashi, S.; Kawata, K.; Nakagawa, Y.; Yamamoto, M.; Shimano, H.; et al. Critical role of CREBH-mediated induction of transforming growth factor β2 by hepatitis C virus infection in fibrogenic responses in hepatic stellate cells. Hepatology. 2017, 66, 1430–1443. [Google Scholar] [CrossRef] [PubMed]
- Shi, M.; Zhu, J.; Wang, R.; Chen, X.; Mi, L.; Walz, T.; Springer, T.A. Latent TGF-β structure and activation. Nature 2011, 474, 343–349. [Google Scholar] [CrossRef] [PubMed]
- Robertson, I.B.; Rifkin, D.B. Regulation of the Bioavailability of TGF-β and TGF-β-Related Proteins. Cold Spring Harb. Perspect. Biol. 2016, 8, a021907. [Google Scholar] [CrossRef] [PubMed]
- Khan, Z.; Marshall, J.F. The role of integrins in TGFβ activation in the tumour stroma. Cell Tissue Res. 2016, 365, 657–673. [Google Scholar] [CrossRef] [PubMed]
- Nishimura, S.L. Integrin-mediated transforming growth factor-beta activation, a potential therapeutic target in fibrogenic disorders. Am. J. Pathol. 2009, 175, 1362–1370. [Google Scholar] [CrossRef] [PubMed]
- Fan, W.; Liu, T.; Chen, W.; Hammad, S.; Longerich, T.; Fu, Y.; Li, N.; He, Y.; Liu, C.; Zhang, Y.; et al. ECM1 Prevents activation of transforming growth factor beta, hepatic stellate cells, and fibrogenesis in mice. Gastroenterology 2019, 157, 1352–1367. [Google Scholar] [CrossRef] [PubMed]
- Carthy, J.M. TGFβ signaling and the control of myofibroblast differentiation: Implications for chronic inflammatory disorders. J. Cell. Physiol. 2018, 233, 98–106. [Google Scholar] [CrossRef] [PubMed]
- Heldin, C.-H. Transforming Growth Factor-β Signaling. In TGF-β in Human Disease; Moustakas, A., Miyazawa, K., Eds.; Springer: Tokyo, Japan, 2013; pp. 3–32. [Google Scholar]
- Levy, L.; Hill, C.S. Smad4 dependency defines two classes of transforming growth factor β (TGF-β) target genes and distinguishes TGF-β-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol. Cell. Biol. 2005, 25, 8108–8125. [Google Scholar] [CrossRef] [PubMed]
- Moustakas, A.; Heldin, C.-H. Non-Smad TGF-beta signals. J. Cell Sci. 2005, 118, 3573–3584. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.E. Non-Smad pathways in TGF-beta signaling. Cell Res. 2009, 19, 128–139. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.E. Non-Smad Signaling Pathways of the TGF-β Family. Cold Spring Harb. Perspect. Biol. 2017, 9, a022129. [Google Scholar] [CrossRef] [PubMed]
- Lee, M.-S.; Ko, S.-G.; Kim, H.-P.; Kim, Y.-B.; Lee, S.-Y.; Kim, S.-G.; Jong, H.-S.; Kim, T.-Y.; Lee, J.W.; Bang, Y.-J. Smad2 mediates Erk1/2 activation by TGF-beta1 in suspended, but not in adherent, gastric carcinoma cells. Int. J. Oncol. 2004, 24, 1229–1234. [Google Scholar] [PubMed]
- Zhang, L.; Duan, C.J.; Binkley, C.; Li, G.; Uhler, M.D.; Logsdon, C.D.; Simeone, D.M. A transforming growth factor beta-induced Smad3/Smad4 complex directly activates protein kinase A. Mol. Cell. Biol. 2004, 24, 2169–2180. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Perlman, R.; Schiemann, W.P.; Brooks, M.W.; Lodish, H.F.; Weinberg, R.A. TGF-beta-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation. Nat. Cell Biol. 2001, 3, 708–714. [Google Scholar] [CrossRef] [PubMed]
- Kretzschmar, M.; Doody, J.; Massagué, J. Opposing BMP and EGF signalling pathways converge on the TGF-beta family mediator Smad1. Nature 1997, 389, 618–622. [Google Scholar] [CrossRef] [PubMed]
- Yang, L.; Moses, H.L. Transforming growth factor β: Tumor suppressor or promoter? Are host immune cells the answer? Cancer Res. 2008, 68, 9107–9111. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, K.; Matsuzaki, K.; Murata, M.; Yamaguchi, T.; Suwa, K.; Okazaki, K. Clinico-Pathological importance of TGF-β/phospho-smad signaling during human hepatic fibrocarcinogenesis. Cancers 2018, 10, 183. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Simeone, D.M.; Zhang, L.; Graziano, K.; Nicke, B.; Pham, T.; Schaefer, C.; Logsdon, C.D. Smad4 mediates activation of mitogen-activated protein kinases by TGF-beta in pancreatic acinar cells. Am. J. Physiol. Cell Physiol. 2001, 281, C311–C319. [Google Scholar] [CrossRef] [PubMed]
- Olsson, N.; Piek, E.; Sundström, M.; ten Dijke, P.; Nilsson, G. Transforming growth factor-beta-mediated mast cell migration depends on mitogen-activated protein kinase activity. Cell. Signal. 2001, 13, 483–490. [Google Scholar] [CrossRef]
- Lee, M.K.; Pardoux, C.; Hall, M.C.; Lee, P.S.; Warburton, D.; Qing, J.; Smith, S.M.; Derynck, R. TGF-β activates Erk MAP kinase signalling through direct phosphorylation of ShcA. Embo J. 2007, 26, 3957–3967. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xu, F.; Liu, C.; Zhou, D.; Zhang, L. TGF-β/SMAD Pathway and Its Regulation in Hepatic Fibrosis. J. Histochem. Cytochem. 2016, 64, 157–167. [Google Scholar] [CrossRef] [PubMed]
- Xu, F.; Zhou, D.; Meng, X.; Wang, X.; Liu, C.; Huang, C.; Li, J.; Zhang, L. Smad2 increases the apoptosis of activated human hepatic stellate cells induced by TRAIL. Int. Immunopharmacol. 2016, 32, 76–86. [Google Scholar] [CrossRef] [PubMed]
- Khalil, H.; Kanisicak, O.; Prasad, V.; Correll, R.N.; Fu, X.; Schips, T.; Vagnozzi, R.J.; Liu, R.; Huynh, T.; Lee, S.-J.; et al. Fibroblast-specific TGF-β-Smad2/3 signaling underlies cardiac fibrosis. J. Clin. Investig. 2017, 127, 3770–3783. [Google Scholar] [CrossRef] [PubMed]
- Carthy, J.M.; Sundqvist, A.; Heldin, A.; van Dam, H.; Kletsas, D.; Heldin, C.-H.; Moustakas, A. Tamoxifen inhibits TGF-β-mediated activation of myofibroblasts by blocking non-smad signaling through ERK1/2. J. Cell. Physiol. 2015, 230, 3084–3092. [Google Scholar] [CrossRef] [PubMed]
- Ard, S.; Reed, E.B.; Smolyaninova, L.V.; Orlov, S.N.; Mutlu, G.M.; Guzy, R.D.; Dulin, N.O. Sustained smad2 phosphorylation is required for myofibroblast transformation in response to TGF-β. Am. J. Respir. Cell Mol. Biol. 2019, 60, 367–369. [Google Scholar] [CrossRef] [PubMed]
- Park, S.H. Fine tuning and cross-talking of TGF-beta signal by inhibitory Smads. J. Biochem. Mol. Biol. 2005, 38, 9–16. [Google Scholar] [PubMed] [Green Version]
- Goto, K.; Kamiya, Y.; Imamura, T.; Miyazono, K.; Miyazawa, K. Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors. J. Biol. Chem. 2007, 282, 20603–20611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, W.; Sun, C.; He, B.; Xiong, W.; Shi, X.; Yao, D.; Cao, X. GADD34–PP1c recruited by Smad7 dephosphorylates TGFβ type I receptor. J. Cell Biol. 2004, 164, 291–300. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kavsak, P.; Rasmussen, R.K.; Causing, C.G.; Bonni, S.; Zhu, H.; Thomsen, G.H.; Wrana, J.L. Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol. Cell 2000, 6, 1365–1375. [Google Scholar] [CrossRef]
- Malonis, R.J.; Fu, W.; Jelcic, M.J.; Thompson, M.; Canter, B.S.; Tsikitis, M.; Esteva, F.J.; Sánchez, I. RNF11 sequestration of the E3 ligase SMURF2 on membranes antagonizes SMAD7 down-regulation of transforming growth factor β signaling. J. Biol. Chem. 2017, 292, 7435–7451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Z.; Fan, Y.; Xie, F.; Zhou, H.; Jin, K.; Shao, L.; Shi, W.; Fang, P.; Yang, B.; van Dam, H.; et al. Breast cancer metastasis suppressor OTUD1 deubiquitinates SMAD7. Nat. Commun. 2017, 8, 2116. [Google Scholar] [CrossRef] [PubMed]
- Chandhoke, A.S.; Karve, K.; Dadakhujaev, S.; Netherton, S.; Deng, L.; Bonni, S. The ubiquitin ligase Smurf2 suppresses TGFβ-induced epithelial–mesenchymal transition in a sumoylation-regulated manner. Cell Death Differ. 2016, 23, 876–888. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shihata, W.A.; Putra, M.R.A.; Chin-Dusting, J.P.F. Is there a potential therapeutic role for caveolin-1 in fibrosis? Front. Pharm. 2017, 8, 567. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Le Roy, C.; Wrana, J.L. Clathrin- and non-clathrin-mediated endocytic regulation of cell signalling. Nat. Rev. Mol. Cell Biol. 2005, 6, 112–126. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.-G. Endocytic regulation of TGF-beta signaling. Cell Res. 2009, 19, 58–70. [Google Scholar] [CrossRef] [PubMed]
- Meyer, C.; Godoy, P.; Bachmann, A.; Liu, Y.; Barzan, D.; Ilkavets, I.; Maier, P.; Herskind, C.; Hengstler, J.G.; Dooley, S. Distinct role of endocytosis for Smad and non-Smad TGF-β signaling regulation in hepatocytes. J. Hepatol. 2011, 55, 369–378. [Google Scholar] [CrossRef] [PubMed]
- Ji, D.-G.; Zhang, Y.; Yao, S.-M.; Zhai, X.-J.; Zhang, L.-R.; Zhang, Y.-Z.; Li, H. Cav-1 deficiency promotes liver fibrosis in carbon tetrachloride (CCl4)-induced mice by regulation of oxidative stress and inflammation responses. Biomed. Pharm. Biomed. Pharm. 2018, 102, 26–33. [Google Scholar] [CrossRef] [PubMed]
- Lu, J.; Zhang, J.; Wang, Y.; Sun, Q. Caveolin-1 scaffolding domain peptides alleviate liver fibrosis by inhibiting tgf-β1/smad signaling in mice. Int. J. Mol. Sci. 2018, 19, 1729. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meyer, C.; Liu, Y.; Kaul, A.; Peipe, I.; Dooley, S. Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis. Cell Death Dis. 2013, 4, e466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Meyer, C.; Dzieran, J.; Liu, Y.; Schindler, F.; Munker, S.; Müller, A.; Coulouarn, C.; Dooley, S. Distinct dedifferentiation processes affect caveolin-1 expression in hepatocytes. Cell Commun. Signal. 2013, 11, 6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, M.; Chen, D.; Huang, H.; Wang, J.; Wan, X.; Xu, C.; Li, C.; Ma, H.; Yu, C.; Li, Y. Caveolin1 protects against diet induced hepatic lipid accumulation in mice. PLoS ONE 2017, 12, e0178748. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, Y.M.; Noureddin, M.; Liu, C.; Ohashi, K.; Kim, S.Y.; Ramnath, D.; Powell, E.E.; Sweet, M.J.; Roh, Y.S.; Hsin, I.-F.; et al. Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis. Sci. Transl. Med. 2019, 11, eaat9284. [Google Scholar] [CrossRef] [PubMed]
- Zhang, D.-W.; Zhao, Y.-X.; Wei, D.; Li, Y.-L.; Zhang, Y.; Wu, J.; Xu, J.; Chen, C.; Tang, H.; Zhang, W.; et al. HAb18G/CD147 promotes activation of hepatic stellate cells and is a target for antibody therapy of liver fibrosis. J. Hepatol. 2012, 57, 1283–1291. [Google Scholar] [CrossRef] [PubMed]
- Li, H.-Y.; Ju, D.; Zhang, D.-W.; Li, H.; Kong, L.-M.; Guo, Y.; Li, C.; Wang, X.-L.; Chen, Z.-N.; Bian, H. Activation of TGF-β1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Sci. Rep. 2015, 5, 16552. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shibanuma, M.; Mashimo, J.; Kuroki, T.; Nose, K. Characterization of the TGF beta 1-inducible hic-5 gene that encodes a putative novel zinc finger protein and its possible involvement in cellular senescence. J. Biol. Chem. 1994, 269, 26767–26774. [Google Scholar] [PubMed]
- Varney, S.D.; Betts, C.B.; Zheng, R.; Wu, L.; Hinz, B.; Zhou, J.; Van De Water, L. Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation. J. Cell Sci. 2016, 129, 774–787. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lei, X.-F.; Fu, W.; Kim-Kaneyama, J.-R.; Omoto, T.; Miyazaki, T.; Li, B.; Miyazaki, A. Hic-5 deficiency attenuates the activation of hepatic stellate cells and liver fibrosis through upregulation of Smad7 in mice. J. Hepatol. 2016, 64, 110–117. [Google Scholar] [CrossRef] [PubMed]
- Kladney, R.D.; Cui, X.; Bulla, G.A.; Brunt, E.M.; Fimmel, C.J. Expression of GP73, a resident Golgi membrane protein, in viral and nonviral liver disease. Hepatology 2002, 35, 1431–1440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yang, X.; Wei, C.; Liu, N.; Wu, F.; Chen, J.; Wang, C.; Sun, Z.; Wang, Y.; Liu, L.; Zhang, X.; et al. GP73, a novel TGF-β target gene, provides selective regulation on Smad and non-Smad signaling pathways. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 588–597. [Google Scholar] [CrossRef] [PubMed]
- Earl, L.A.; Bi, S.; Baum, L.G. Galectin multimerization and lattice formation are regulated by linker region structure. Glycobiology 2011, 21, 6–12. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, M.-H.; Hong, H.-C.; Hong, T.-M.; Chiang, W.-F.; Jin, Y.-T.; Chen, Y.-L. Targeting galectin-1 in carcinoma-associated fibroblasts inhibits oral squamous cell carcinoma metastasis by downregulating MCP-1/CCL2 expression. Clin. Cancer Res. 2011, 17, 1306–1316. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tsutsumi, T.; Suzuki, T.; Moriya, K.; Shintani, Y.; Fujie, H.; Miyoshi, H.; Matsuura, Y.; Koike, K.; Miyamura, T. Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology 2003, 38, 820–828. [Google Scholar] [CrossRef] [PubMed]
- Wu, M.-H.; Chen, Y.-L.; Lee, K.-H.; Chang, C.-C.; Cheng, T.-M.; Wu, S.-Y.; Tu, C.-C.; Tsui, W.-L. Glycosylation-dependent galectin-1/neuropilin-1 interactions promote liver fibrosis through activation of TGF-β- and PDGF-like signals in hepatic stellate cells. Sci. Rep. 2017, 7, 11006. [Google Scholar] [CrossRef] [PubMed]
- Chen, Y.; Rui, B.-B.; Tang, L.-Y.; Hu, C.-M. Lipin family proteins—Key regulators in lipid metabolism. Ann. Nutr. Metab. 2015, 66, 10–18. [Google Scholar] [CrossRef] [PubMed]
- Finck, B.N.; Gropler, M.C.; Chen, Z.; Leone, T.C.; Croce, M.A.; Harris, T.E.; Lawrence, J.C.; Kelly, D.P. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 2006, 4, 199–210. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Jang, C.H.; Kim, K.M.; Yang, J.H.; Cho, S.S.; Kim, S.J.; Shin, S.M.; Cho, I.J.; Ki, S.H. The Role of Lipin-1 in the Regulation of Fibrogenesis and TGF-β Signaling in Hepatic Stellate Cells. Toxicol. Sci. 2016, 153, 28–38. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Shen, R.-W.; Han, B.; Li, Z.; Xiong, L.; Zhang, F.-Y.; Cong, B.-B.; Zhang, B. Notch signaling mediated by TGF-β/Smad pathway in concanavalin A-induced liver fibrosis in rats. World J. Gastroenterol. 2017, 23, 2330–2336. [Google Scholar] [CrossRef] [PubMed]
- Shen, Z.; Liu, Y.; Dewidar, B.; Hu, J.; Park, O.; Feng, T.; Xu, C.; Yu, C.; Li, Q.; Meyer, C.; et al. Delta-like ligand 4 modulates liver damage by down-regulating chemokine expression. Am. J. Pathol. 2016, 186, 1874–1889. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Xiong, P.; Zhang, J.; Xu, D.; Zhu, J.; Li, W.; Liu, J.; Liu, F. Positive feedback loop of YB-1 interacting with Smad2 promotes liver fibrosis. Biochem. Biophys. Res. Commun. 2017, 484, 753–761. [Google Scholar] [CrossRef] [PubMed]
- Kolliopoulos, C.; Raja, E.; Razmara, M.; Heldin, P.; Heldin, C.-H.; Moustakas, A.; van der Heide, L.P. Transforming growth factor β (TGFβ) induces NUAK kinase expression to fine-tune its signaling output. J. Biol. Chem. 2019, 294, 4119–4136. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, Y.; Liu, H.; Meyer, C.; Li, J.; Nadalin, S.; Königsrainer, A.; Weng, H.; Dooley, S.; ten Dijke, P. Transforming growth factor-β (TGF-β)-mediated connective tissue growth factor (CTGF) expression in hepatic stellate cells requires Stat3 signaling activation. J. Biol. Chem. 2013, 288, 30708–30719. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, L.-Y.; Heller, M.; Meng, Z.; Yu, L.-R.; Tang, Y.; Zhou, M.; Zhang, Y.E. Transforming growth factor-β (TGF-β) Directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway. J. Biol. Chem. 2017, 292, 4302–4312. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, G.; Yu, Y.; Sun, C.; Liu, T.; Liang, T.; Zhan, L.; Lin, X.; Feng, X.-H. STAT3 selectively interacts with Smad3 to antagonize TGF-β signalling. Oncogene 2016, 35, 4388–4398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yoon, J.-H.; Sudo, K.; Kuroda, M.; Kato, M.; Lee, I.-K.; Han, J.S.; Nakae, S.; Imamura, T.; Kim, J.; Ju, J.H.; et al. Phosphorylation status determines the opposing functions of Smad2/Smad3 as STAT3 cofactors in TH17 differentiation. Nat. Commun. 2015, 6, 7600. [Google Scholar] [CrossRef] [PubMed]
- Kim, J.-H.; Ham, S.; Lee, Y.; Suh, G.Y.; Lee, Y.-S. TTC3 contributes to TGF-β1-induced epithelial-mesenchymal transition and myofibroblast differentiation, potentially through SMURF2 ubiquitylation and degradation. Cell Death Dis. 2019, 10, 92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Iwaisako, K.; Jiang, C.; Zhang, M.; Cong, M.; Moore-Morris, T.J.; Park, T.J.; Liu, X.; Xu, J.; Wang, P.; Paik, Y.-H.; et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl. Acad. Sci. USA 2014, 111, E3297–E3305. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pastan, I.; Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 2014, 74, 2907–2912. [Google Scholar] [CrossRef] [PubMed]
- Koyama, Y.; Wang, P.; Liang, S.; Iwaisako, K.; Liu, X.; Xu, J.; Zhang, M.; Sun, M.; Cong, M.; Karin, D.; et al. Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis. J. Clin. Investig. 2017, 127, 1254–1270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Herrera, B.; Addante, A.; Sánchez, A. BMP Signalling at the crossroad of liver fibrosis and regeneration. Int. J. Mol. Sci. 2017, 19, 39. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Breitkopf-Heinlein, K.; Meyer, C.; König, C.; Gaitantzi, H.; Addante, A.; Thomas, M.; Wiercinska, E.; Cai, C.; Li, Q.; Wan, F.; et al. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut 2017, 66, 939–954. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chung, Y.-H.; Huang, Y.-H.; Chu, T.-H.; Chen, C.-L.; Lin, P.-R.; Huang, S.-C.; Wu, D.-C.; Huang, C.-C.; Hu, T.-H.; Kao, Y.-H.; et al. BMP-2 restoration aids in recovery from liver fibrosis by attenuating TGF-β1 signaling. Lab. Investig. J. Tech. Methods Pathol. 2018, 98, 999–1013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhang, Y.-Q.; Wan, L.-Y.; He, X.-M.; Ni, Y.-R.; Wang, C.; Liu, C.-B.; Wu, J.-F. Gremlin1 Accelerates Hepatic Stellate Cell Activation Through Upregulation of TGF-Beta Expression. DNA Cell Biol. 2017, 36, 603–610. [Google Scholar] [CrossRef] [PubMed]
- Navarro-Corcuera, A.; López-Zabalza, M.J.; Martínez-Irujo, J.J.; Álvarez-Sola, G.; Ávila, M.A.; Iraburu, M.J.; Ansorena, E.; Montiel-Duarte, C. Role of AGAP2 in the profibrogenic effects induced by TGFβ in LX-2 hepatic stellate cells. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 673–685. [Google Scholar] [CrossRef] [PubMed]
- Römisch, J. Factor VII activating protease (FSAP): A novel protease in hemostasis. Biol. Chem. 2002, 383, 1119–1124. [Google Scholar] [CrossRef] [PubMed]
- Leiting, S.; Seidl, S.; Martinez-Palacian, A.; Muhl, L.; Kanse, S.M. Transforming growth factor-β (TGF-β) inhibits the expression of factor vii-activating protease (FSAP) in hepatocytes. J. Biol. Chem. 2016, 291, 21020–21028. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Borkham-Kamphorst, E.; Zimmermann, H.W.; Gassler, N.; Bissels, U.; Bosio, A.; Tacke, F.; Weiskirchen, R.; Kanse, S.M. Factor VII activating protease (FSAP) exerts anti-inflammatory and anti-fibrotic effects in liver fibrosis in mice and men. J. Hepatol. 2013, 58, 104–111. [Google Scholar] [CrossRef] [PubMed]
- Wasmuth, H.E.; Tag, C.G.; Van de Leur, E.; Hellerbrand, C.; Mueller, T.; Berg, T.; Puhl, G.; Neuhaus, P.; Samuel, D.; Trautwein, C.; et al. The Marburg I variant (G534E) of the factor VII-activating protease determines liver fibrosis in hepatitis C infection by reduced proteolysis of platelet-derived growth factor BB. Hepatology 2009, 49, 775–780. [Google Scholar] [CrossRef] [PubMed]
- Spanjer, A.I.R.; Baarsma, H.A.; Oostenbrink, L.M.; Jansen, S.R.; Kuipers, C.C.; Lindner, M.; Postma, D.S.; Meurs, H.; Heijink, I.H.; Gosens, R.; et al. TGF-β-induced profibrotic signaling is regulated in part by the WNT receptor Frizzled-8. FASEB J. 2016, 30, 1823–1835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beljaars, L.; Daliri, S.; Dijkhuizen, C.; Poelstra, K.; Gosens, R. WNT-5A regulates TGF-β-related activities in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2017, 312, G219–G227. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Augustin, H.G.; Koh, G.Y. Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science 2017, 357, eaal2379. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Karin, D.; Koyama, Y.; Brenner, D.; Kisseleva, T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differ. Res. Biol. Divers. 2016, 92, 84–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sun, M.; Kisseleva, T. Reversibility of liver fibrosis. Clin. Res. Hepatol. Gastroenterol. 2015, 39, S60–S63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bataller, R.; Brenner, D.A. Liver fibrosis. J. Clin. Investig. 2005, 115, 209–218. [Google Scholar] [CrossRef] [PubMed]
- Puche, J.E.; Saiman, Y.; Friedman, S.L. Hepatic stellate cells and liver fibrosis. Compr. Physiol. 2013, 3, 1473–1492. [Google Scholar] [PubMed]
- Heymann, F.; Trautwein, C.; Tacke, F. Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm. Allergy Drug Targets 2009, 8, 307–318. [Google Scholar] [CrossRef] [PubMed]
- Krenkel, O.; Tacke, F. Liver macrophages in tissue homeostasis and disease. Nat. Rev. Immunol. 2017, 17, 306–321. [Google Scholar] [CrossRef] [PubMed]
- Schuppan, D.; Ruehl, M.; Somasundaram, R.; Hahn, E.G. Matrix as a modulator of hepatic fibrogenesis. Semin. Liver Dis. 2001, 21, 351–372. [Google Scholar] [CrossRef] [PubMed]
- Henderson, N.C.; Arnold, T.D.; Katamura, Y.; Giacomini, M.M.; Rodriguez, J.D.; McCarty, J.H.; Pellicoro, A.; Raschperger, E.; Betsholtz, C.; Ruminski, P.G.; et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 2013, 19, 1617–1624. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Olaso, E.; Ikeda, K.; Eng, F.J.; Xu, L.; Wang, L.H.; Lin, H.C.; Friedman, S.L. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J. Clin. Investig. 2001, 108, 1369–1378. [Google Scholar] [CrossRef] [PubMed]
- Bansal, R.; Nakagawa, S.; Yazdani, S.; van Baarlen, J.; Venkatesh, A.; Koh, A.P.; Song, W.-M.; Goossens, N.; Watanabe, H.; Beasley, M.B.; et al. Integrin alpha 11 in the regulation of the myofibroblast phenotype: Implications for fibrotic diseases. Exp. Mol. Med. 2017, 49, e396. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Greenhalgh, S.N.; Matchett, K.P.; Taylor, R.S.; Huang, K.; Li, J.T.; Saeteurn, K.; Donnelly, M.C.; Simpson, E.E.M.; Pollack, J.L.; Atakilit, A.; et al. Loss of integrin αvβ8 in murine hepatocytes accelerates liver regeneration. Am. J. Pathol. 2019, 189, 258–271. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rognoni, E.; Ruppert, R.; Fässler, R. The kindlin family: Functions, signaling properties and implications for human disease. J. Cell Sci. 2016, 129, 17–27. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, J.; Hu, Y.; Gao, Y.; Li, Q.; Zeng, Z.; Li, Y.; Chen, H. Kindlin-2 regulates hepatic stellate cells activation and liver fibrogenesis. Cell Death Discov. 2018, 4, 34. [Google Scholar] [CrossRef] [PubMed]
- Zollinger, A.J.; Smith, M.L. Fibronectin, the extracellular glue. Matrix Biol. J. Int. Soc. Matrix Biol. 2017, 60–61, 27–37. [Google Scholar] [CrossRef] [PubMed]
- Klingberg, F.; Chau, G.; Walraven, M.; Boo, S.; Koehler, A.; Chow, M.L.; Olsen, A.L.; Im, M.; Lodyga, M.; Wells, R.G.; et al. The fibronectin ED-A domain enhances recruitment of latent TGF-β-binding protein-1 to the fibroblast matrix. J. Cell Sci. 2018, 131, jcs201293. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Peters, J.H.; Hynes, R.O. Fibronectin isoform distribution in the mouse. I. The alternatively spliced EIIIB, EIIIA, and V segments show widespread codistribution in the developing mouse embryo. Cell Adhes. Commun. 1996, 4, 103–125. [Google Scholar] [CrossRef] [PubMed]
- Zent, J.; Guo, L.-W. Signaling Mechanisms of Myofibroblastic Activation: Outside-in and Inside-Out. Cell. Physiol. Biochem. 2018, 49, 848–868. [Google Scholar] [CrossRef] [PubMed]
- Muro, A.F.; Moretti, F.A.; Moore, B.B.; Yan, M.; Atrasz, R.G.; Wilke, C.A.; Flaherty, K.R.; Martinez, F.J.; Tsui, J.L.; Sheppard, D.; et al. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2008, 177, 638–645. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kawelke, N.; Vasel, M.; Sens, C.; von Au, A.; Dooley, S.; Nakchbandi, I.A. Fibronectin protects from excessive liver fibrosis by modulating the availability of and responsiveness of stellate cells to active TGF-β. PLoS ONE 2011, 6, e28181. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Altrock, E.; Sens, C.; Wuerfel, C.; Vasel, M.; Kawelke, N.; Dooley, S.; Sottile, J.; Nakchbandi, I.A. Inhibition of fibronectin deposition improves experimental liver fibrosis. J. Hepatol. 2015, 62, 625–633. [Google Scholar] [CrossRef] [PubMed]
- Phanish, M.K.; Heidebrecht, F.; Nabi, M.E.; Shah, N.; Niculescu-Duvaz, I.; Dockrell, M.E.C. The regulation of TGFβ1 Induced fibronectin eda exon alternative splicing in human renal proximal tubule epithelial cells. J. Cell. Physiol. 2015, 230, 286–295. [Google Scholar] [CrossRef] [PubMed]
- Li, J.; Wang, Y.; Ma, M.; Jiang, S.; Zhang, X.; Zhang, Y.; Yang, X.; Xu, C.; Tian, G.; Li, Q.; et al. Autocrine CTHRC1 activates hepatic stellate cells and promotes liver fibrosis by activating TGF-β signaling. EBioMedicine 2019, 40, 43–55. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Santos, A.; Lagares, D. Matrix stiffness: The conductor of organ fibrosis. Curr. Rheumatol. Rep. 2018, 20, 2. [Google Scholar] [CrossRef] [PubMed]
- Lampi, M.C.; Reinhart-King, C.A. Targeting extracellular matrix stiffness to attenuate disease: From molecular mechanisms to clinical trials. Sci. Transl. Med. 2018, 10, eaao0475. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Caliari, S.R.; Perepelyuk, M.; Soulas, E.M.; Lee, G.Y.; Wells, R.G.; Burdick, J.A. Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression. Integr. Biol. Quant. Biosci. Nano Macro 2016, 8, 720–728. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Peterová, E.; Mrkvicová, A.; Podmolíková, L.; Řezáčová, M.; Kanta, J. The role of cytokines TGF-beta1 and FGF-1 in the expression of characteristic markers of rat liver myofibroblasts cultured in three-dimensional collagen gel. Physiol. Res. 2016, 65, 661–672. [Google Scholar] [PubMed]
- Siegel, R.C.; Pinnell, S.R.; Martin, G.R. Cross-linking of collagen and elastin. Properties of lysyl oxidase. Biochemistry 1970, 9, 4486–4492. [Google Scholar] [CrossRef] [PubMed]
- Liu, S.B.; Ikenaga, N.; Peng, Z.-W.; Sverdlov, D.Y.; Greenstein, A.; Smith, V.; Schuppan, D.; Popov, Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J. 2016, 30, 1599–1609. [Google Scholar] [CrossRef] [PubMed]
- Ma, L.; Zeng, Y.; Wei, J.; Yang, D.; Ding, G.; Liu, J.; Shang, J.; Kang, Y.; Ji, X. Knockdown of LOXL1 inhibits TGF-β1-induced proliferation and fibrogenesis of hepatic stellate cells by inhibition of Smad2/3 phosphorylation. Biomed. Pharm. Biomed. Pharm. 2018, 107, 1728–1735. [Google Scholar] [CrossRef] [PubMed]
- Mesarwi, O.A.; Shin, M.-K.; Drager, L.F.; Bevans-Fonti, S.; Jun, J.C.; Putcha, N.; Torbenson, M.S.; Pedrosa, R.P.; Lorenzi-Filho, G.; Steele, K.E.; et al. Lysyl Oxidase as a serum biomarker of liver fibrosis in patients with severe obesity and obstructive sleep apnea. Sleep 2015, 38, 1583–1591. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Z.; Perez, M.; Lee, E.-S.; Kojima, S.; Griffin, M. The functional relationship between transglutaminase 2 and transforming growth factor β1 in the regulation of angiogenesis and endothelial-mesenchymal transition. Cell Death Dis. 2017, 8, e3032. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Verderio, E.; Gaudry, C.; Gross, S.; Smith, C.; Downes, S.; Griffin, M. Regulation of cell surface tissue transglutaminase: Effects on matrix storage of latent transforming growth factor-beta binding protein-1. J. Histochem. Cytochem. 1999, 47, 1417–1432. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Weiskirchen, R.; Tacke, F. Liver fibrosis: From pathogenesis to novel therapies. Dig. Dis. 2016, 34, 410–422. [Google Scholar] [CrossRef] [PubMed]
- Lodyga, M.; Cambridge, E.; Karvonen, H.M.; Pakshir, P.; Wu, B.; Boo, S.; Kiebalo, M.; Kaarteenaho, R.; Glogauer, M.; Kapoor, M.; et al. Cadherin-11-mediated adhesion of macrophages to myofibroblasts establishes a profibrotic niche of active TGF-β. Sci. Signal. 2019, 12, e3469. [Google Scholar] [CrossRef] [PubMed]
- Cai, X.; Li, Z.; Zhang, Q.; Qu, Y.; Xu, M.; Wan, X.; Lu, L. CXCL6-EGFR-induced Kupffer cells secrete TGF-β1 promoting hepatic stellate cell activation via the SMAD2/BRD4/C-MYC/EZH2 pathway in liver fibrosis. J. Cell. Mol. Med. 2018, 22, 5050–5061. [Google Scholar] [CrossRef] [PubMed]
- Fabre, T.; Molina, M.F.; Soucy, G.; Goulet, J.-P.; Willems, B.; Villeneuve, J.-P.; Bilodeau, M.; Shoukry, N.H. Type 3 cytokines IL-17A and IL-22 drive TGF-β-dependent liver fibrosis. Sci. Immunol. 2018, 3, e7754. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Shi, J.; Zhao, J.; Zhang, X.; Cheng, Y.; Hu, J.; Li, Y.; Zhao, X.; Shang, Q.; Sun, Y.; Tu, B.; et al. Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients. Sci. Rep. 2017, 7, 44544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ng, C.P.; Hinz, B.; Swartz, M.A. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J. Cell Sci. 2005, 118, 4731–4739. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nithiananthan, S.; Crawford, A.; Knock, J.C.; Lambert, D.W.; Whawell, S.A. Physiological fluid flow moderates fibroblast responses to TGF-β1. J. Cell. Biochem. 2017, 118, 878–890. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ansorge, M.; Sapudom, J.; Chkolnikov, M.; Wilde, M.; Anderegg, U.; Möller, S.; Schnabelrauch, M.; Pompe, T. Mimicking paracrine TGFβ1 Signals during myofibroblast differentiation in 3D Collagen networks. Sci. Rep. 2017, 7, 5664. [Google Scholar] [CrossRef] [PubMed]
- Zi, Z.; Feng, Z.; Chapnick, D.A.; Dahl, M.; Deng, D.; Klipp, E.; Moustakas, A.; Liu, X. Quantitative analysis of transient and sustained transforming growth factor-β signaling dynamics. Mol. Syst. Biol. 2011, 7, 492. [Google Scholar] [CrossRef] [PubMed]
- Feng, Z.; Zi, Z.; Liu, X. Measuring TGF-β ligand dynamics in culture medium. Methods Mol. Biol. 2016, 1344, 379–389. [Google Scholar] [PubMed]
- Hara, M.; Kirita, A.; Kondo, W.; Matsuura, T.; Nagatsuma, K.; Dohmae, N.; Ogawa, S.; Imajoh-Ohmi, S.; Friedman, S.L.; Rifkin, D.B.; et al. LAP degradation product reflects plasma kallikrein-dependent TGF-β activation in patients with hepatic fibrosis. SpringerPlus 2014, 3, 221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hara, M.; Inoue, I.; Yamazaki, Y.; Kirita, A.; Matsuura, T.; Friedman, S.L.; Rifkin, D.B.; Kojima, S. L59 TGF-β LAP degradation products serve as a promising blood biomarker for liver fibrogenesis in mice. Fibrogenesis Tissue Repair 2015, 8, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Novo, E.; Parola, M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 2008, 1, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Richter, K.; Kietzmann, T. Reactive oxygen species and fibrosis: Further evidence of a significant liaison. Cell Tissue Res. 2016, 365, 591–605. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Liu, R.-M.; Desai, L.P. Reciprocal regulation of TGF-β and reactive oxygen species: A perverse cycle for fibrosis. Redox Biol. 2015, 6, 565–577. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, Y.; Wang, W.; Peng, X.-M.; He, Y.; Xiong, Y.-X.; Liang, H.-F.; Chu, L.; Zhang, B.-X.; Ding, Z.-Y.; Chen, X.-P. Rapamycin Upregulates connective tissue growth factor expression in hepatic progenitor cells through TGF-β-Smad2 dependent signaling. Front. Pharm. 2018, 9, 877. [Google Scholar] [CrossRef] [PubMed]
- Liang, S.; Kisseleva, T.; Brenner, D.A. The role of NADPH oxidases (NOXs) in liver fibrosis and the activation of myofibroblasts. Front. Physiol. 2016, 7, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Paik, Y.-H.; Iwaisako, K.; Seki, E.; Inokuchi, S.; Schnabl, B.; Osterreicher, C.H.; Kisseleva, T.; Brenner, D.A. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology 2011, 53, 1730–1741. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Matsumoto, M.; Zhang, J.; Zhang, X.; Liu, J.; Jiang, J.X.; Yamaguchi, K.; Taruno, A.; Katsuyama, M.; Iwata, K.; Ibi, M.; et al. The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. Free Radic. Biol. Med. 2018, 115, 412–420. [Google Scholar] [CrossRef] [PubMed]
- Sancho, P.; Mainez, J.; Crosas-Molist, E.; Roncero, C.; Fernández-Rodriguez, C.M.; Pinedo, F.; Huber, H.; Eferl, R.; Mikulits, W.; Fabregat, I. NADPH oxidase NOX4 mediates stellate cell activation and hepatocyte cell death during liver fibrosis development. PLoS ONE 2012, 7, e45285. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Andueza, A.; Garde, N.; García-Garzón, A.; Ansorena, E.; López-Zabalza, M.J.; Iraburu, M.J.; Zalba, G.; Martínez-Irujo, J.J. NADPH oxidase 5 promotes proliferation and fibrosis in human hepatic stellate cells. Free Radic. Biol. Med. 2018, 126, 15–26. [Google Scholar] [CrossRef] [PubMed]
- Latella, G. Redox Imbalance in intestinal fibrosis: Beware of the TGFβ-1, ROS, and Nrf2 connection. Dig. Dis. Sci. 2018, 63, 312–320. [Google Scholar] [CrossRef] [PubMed]
- Xu, W.; Hellerbrand, C.; Köhler, U.A.; Bugnon, P.; Kan, Y.-W.; Werner, S.; Beyer, T.A. The Nrf2 transcription factor protects from toxin-induced liver injury and fibrosis. Lab. Investig. J. Tech. Methods Pathol. 2008, 88, 1068–1078. [Google Scholar] [CrossRef] [PubMed]
- Oh, C.J.; Kim, J.-Y.; Min, A.-K.; Park, K.-G.; Harris, R.A.; Kim, H.-J.; Lee, I.-K. Sulforaphane attenuates hepatic fibrosis via NF-E2-related factor 2-mediated inhibition of transforming growth factor-β/Smad signaling. Free Radic. Biol. Med. 2012, 52, 671–682. [Google Scholar] [CrossRef] [PubMed]
- Prestigiacomo, V.; Suter-Dick, L. Nrf2 protects stellate cells from Smad-dependent cell activation. PLoS ONE 2018, 13, e0201044. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Guan, Y.; Tan, Y.; Liu, W.; Yang, J.; Wang, D.; Pan, D.; Sun, Y.; Zheng, C. NF-E2-related factor 2 suppresses intestinal fibrosis by inhibiting reactive oxygen species-dependent TGF-β1/SMADs pathway. Dig. Dis. Sci. 2018, 63, 366–380. [Google Scholar] [CrossRef] [PubMed]
- Chen, Q.; Zhang, H.; Cao, Y.; Li, Y.; Sun, S.; Zhang, J.; Zhang, G. Schisandrin B attenuates CCl4-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-β/Smad signaling pathways. Drug Des. Dev. 2017, 11, 2179–2191. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Piersma, B.; Wouters, O.Y.; de Rond, S.; Boersema, M.; Gjaltema, R.A.F.; Bank, R.A. Ascorbic acid promotes a TGFβ1-induced myofibroblast phenotype switch. Physiol. Rep. 2017, 5, e13324. [Google Scholar] [CrossRef] [PubMed]
- Jung, B.-J.; Yoo, H.-S.; Shin, S.; Park, Y.-J.; Jeon, S.-M. Dysregulation of NRF2 in cancer: From Molecular mechanisms to therapeutic opportunities. Biomology 2018, 26, 57–68. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Camarena, V.; Wang, G. The epigenetic role of vitamin C in health and disease. Cell. Mol. Life Sci. 2016, 73, 1645–1658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Argemi, J.; Latasa, M.U.; Atkinson, S.R.; Blokhin, I.O.; Massey, V.; Gue, J.P.; Cabezas, J.; Lozano, J.J.; Van Booven, D.; Bell, A.; et al. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat. Commun. 2019, 10, 3126. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Berger, S.L.; Kouzarides, T.; Shiekhattar, R.; Shilatifard, A. An operational definition of epigenetics. Genes Dev. 2009, 23, 781–783. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yu, F.; Chen, B.; Fan, X.; Li, G.; Dong, P.; Zheng, J. Epigenetically-regulated MicroRNA-9-5p suppresses the activation of hepatic stellate cells via TGFBR1 and TGFBR2. Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharm. 2017, 43, 2242–2252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Davoodian, P.; Ravanshad, M.; Hosseini, S.Y.; Khanizadeh, S.; Almasian, M.; Nejati Zadeh, A.; Esmaiili Lashgarian, H. Effect of TGF-β/smad signaling pathway blocking on expression profiles of miR-335, miR-150, miR-194, miR-27a, and miR-199a of hepatic stellate cells (HSCs). Gastroenterol. Hepatol. Bed Bench 2017, 10, 112–117. [Google Scholar] [PubMed]
- Bowen, T.; Jenkins, R.H.; Fraser, D.J. MicroRNAs, transforming growth factor beta-1, and tissue fibrosis. J. Pathol. 2013, 229, 274–285. [Google Scholar] [CrossRef] [PubMed]
- Coll, M.; El Taghdouini, A.; Perea, L.; Mannaerts, I.; Vila-Casadesús, M.; Blaya, D.; Rodrigo-Torres, D.; Affò, S.; Morales-Ibanez, O.; Graupera, I.; et al. Integrative miRNA and Gene expression profiling analysis of human quiescent hepatic stellate cells. Sci. Rep. 2015, 5, 11549. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Roderburg, C.; Luedde, M.; Vargas Cardenas, D.; Vucur, M.; Mollnow, T.; Zimmermann, H.W.; Koch, A.; Hellerbrand, C.; Weiskirchen, R.; Frey, N.; et al. miR-133a mediates TGF-β-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis. J. Hepatol. 2013, 58, 736–742. [Google Scholar] [CrossRef] [PubMed]
- Roy, S.; Benz, F.; Vargas Cardenas, D.; Vucur, M.; Gautheron, J.; Schneider, A.; Hellerbrand, C.; Pottier, N.; Alder, J.; Tacke, F.; et al. miR-30c and miR-193 are a part of the TGF-β-dependent regulatory network controlling extracellular matrix genes in liver fibrosis. J. Dig. Dis. 2015, 16, 513–524. [Google Scholar] [CrossRef] [PubMed]
- Brandon-Warner, E.; Benbow, J.H.; Swet, J.H.; Feilen, N.A.; Culberson, C.R.; McKillop, I.H.; deLemos, A.S.; Russo, M.W.; Schrum, L.W. Adeno-associated virus serotype 2 vector-mediated reintroduction of microrna-19b attenuates hepatic fibrosis. Hum. Gene Ther. 2018, 29, 674–686. [Google Scholar] [CrossRef] [PubMed]
- Feili, X.; Wu, S.; Ye, W.; Tu, J.; Lou, L. MicroRNA-34a-5p inhibits liver fibrosis by regulating TGF-β1/Smad3 pathway in hepatic stellate cells. Cell Biol. Int. 2018, 42, 1370–1376. [Google Scholar] [CrossRef] [PubMed]
- Zou, Y.; Li, S.; Li, Z.; Song, D.; Zhang, S.; Yao, Q. MiR-146a attenuates liver fibrosis by inhibiting transforming growth factor-β1 mediated epithelial-mesenchymal transition in hepatocytes. Cell. Signal. 2019, 58, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Zou, Y.; Cai, Y.; Lu, D.; Zhou, Y.; Yao, Q.; Zhang, S. MicroRNA-146a-5p attenuates liver fibrosis by suppressing profibrogenic effects of TGFβ1 and lipopolysaccharide. Cell. Signal. 2017, 39, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Wang, P.; Lei, S.; Wang, X.; Xu, W.; Hu, P.; Chen, F.; Zhang, X.; Yin, C.; Xie, W. MicroRNA-134 deactivates hepatic stellate cells by targeting tgf-β activated kinase 1-binding protein 1. Biochem. Cell Biol. 2019, 97, 505–512. [Google Scholar] [CrossRef] [PubMed]
- Tao, L.; Xue, D.; Shen, D.; Ma, W.; Zhang, J.; Wang, X.; Zhang, W.; Wu, L.; Pan, K.; Yang, Y.; et al. MicroRNA-942 mediates hepatic stellate cell activation by regulating BAMBI expression in human liver fibrosis. Arch. Toxicol. 2018, 92, 2935–2946. [Google Scholar] [CrossRef] [PubMed]
- You, K.; Li, S.-Y.; Gong, J.; Fang, J.-H.; Zhang, C.; Zhang, M.; Yuan, Y.; Yang, J.; Zhuang, S.-M. MicroRNA-125b promotes hepatic stellate cell activation and liver fibrosis by activating rhoa signaling. Mol. Nucleic Acids 2018, 12, 57–66. [Google Scholar] [CrossRef] [PubMed]
- Yu, F.; Guo, Y.; Chen, B.; Dong, P.; Zheng, J. MicroRNA-17-5p activates hepatic stellate cells through targeting of Smad7. Lab. Investig. J. Tech. Methods Pathol. 2015, 95, 781–789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zhu, J.; Zhang, Z.; Zhang, Y.; Li, W.; Zheng, W.; Yu, J.; Wang, B.; Chen, L.; Zhuo, Q.; Chen, L.; et al. MicroRNA-212 activates hepatic stellate cells and promotes liver fibrosis via targeting SMAD7. Biochem. Biophys. Res. Commun. 2018, 496, 176–183. [Google Scholar] [CrossRef] [PubMed]
- Tu, X.; Zheng, X.; Li, H.; Cao, Z.; Chang, H.; Luan, S.; Zhu, J.; Chen, J.; Zang, Y.; Zhang, J. MicroRNA-30 Protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor beta signaling in hepatic stellate cells. Toxicol. Sci. 2015, 146, 157–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gupta, P.; Sata, T.N.; Yadav, A.K.; Mishra, A.; Vats, N.; Hossain, M.M.; Sanal, M.G.; Venugopal, S.K. TGF-β induces liver fibrosis via miRNA-181a-mediated down regulation of augmenter of liver regeneration in hepatic stellate cells. PLoS ONE 2019, 14, e0214534. [Google Scholar] [CrossRef] [PubMed]
- Yang, X.; Dan, X.; Men, R.; Ma, L.; Wen, M.; Peng, Y.; Yang, L. MiR-142-3p blocks TGF-β-induced activation of hepatic stellate cells through targeting TGFβRI. Life Sci. 2017, 187, 22–30. [Google Scholar] [CrossRef] [PubMed]
- Wei, S.; Wang, Q.; Zhou, H.; Qiu, J.; Li, C.; Shi, C.; Zhou, S.; Liu, R.; Lu, L. miR-455-3p Alleviates Hepatic Stellate Cell Activation and Liver Fibrosis by Suppressing HSF1 Expression. Mol. Nucleic Acids 2019, 16, 758–769. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Fan, Z.; Hao, C.; Li, M.; Dai, X.; Qin, H.; Li, J.; Xu, H.; Wu, X.; Zhang, L.; Fang, M.; et al. MKL1 is an epigenetic modulator of TGF-β induced fibrogenesis. Biochim. Biophys. Acta 2015, 1849, 1219–1228. [Google Scholar] [CrossRef] [PubMed]
- Hu, J.; Chen, C.; Liu, Q.; Liu, B.; Song, C.; Zhu, S.; Wu, C.; Liu, S.; Yu, H.; Yao, D.; et al. The role of the miR-31/FIH1 pathway in TGF-β-induced liver fibrosis. Clin. Sci. 2015, 129, 305–317. [Google Scholar] [CrossRef] [PubMed]
- Genz, B.; Coleman, M.A.; Irvine, K.M.; Kutasovic, J.R.; Miranda, M.; Gratte, F.D.; Tirnitz-Parker, J.E.E.; Olynyk, J.K.; Calvopina, D.A.; Weis, A.; et al. Overexpression of miRNA-25-3p inhibits Notch1 signaling and TGF-β-induced collagen expression in hepatic stellate cells. Sci. Rep. 2019, 9, 8541. [Google Scholar] [CrossRef] [PubMed]
- Peng, H.; Wan, L.-Y.; Liang, J.-J.; Zhang, Y.-Q.; Ai, W.-B.; Wu, J.-F. The roles of lncRNA in hepatic fibrosis. Cell Biosci. 2018, 8, 63. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tang, P.M.-K.; Zhang, Y.-Y.; Lan, H.-Y. LncRNAs in TGF-β-driven tissue fibrosis. Non-Coding RNA 2018, 4, 26. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Tu, X.; Zhang, Y.; Zheng, X.; Deng, J.; Li, H.; Kang, Z.; Cao, Z.; Huang, Z.; Ding, Z.; Dong, L.; et al. TGF-β-induced hepatocyte lincRNA-p21 contributes to liver fibrosis in mice. Sci. Rep. 2017, 7, 2957. [Google Scholar] [CrossRef] [PubMed]
- Zhang, Y.; Liu, C.; Barbier, O.; Smalling, R.; Tsuchiya, H.; Lee, S.; Delker, D.; Zou, A.; Hagedorn, C.H.; Wang, L. Bcl2 is a critical regulator of bile acid homeostasis by dictating Shp and lncRNA H19 function. Sci. Rep. 2016, 6, 20559. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Yamamoto, M.; Fujii, K.; Nagahama, Y.; Ooshio, T.; Xin, B.; Okada, Y.; Furukawa, H.; Nishikawa, Y. Differential reactivation of fetal/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions. Cancer Sci. 2015, 106, 972–981. [Google Scholar] [CrossRef] [PubMed]
- Zhu, J.; Luo, Z.; Pan, Y.; Zheng, W.; Li, W.; Zhang, Z.; Xiong, P.; Xu, D.; Du, M.; Wang, B.; et al. H19/miR-148a/USP4 axis facilitates liver fibrosis by enhancing TGF-β signaling in both hepatic stellate cells and hepatocytes. J. Cell. Physiol. 2019, 234, 9698–9710. [Google Scholar] [CrossRef] [PubMed]
- Song, M.; Xia, L.; Sun, M.; Yang, C.; Wang, F. Circular RNA in Liver: Health and diseases. Adv. Exp. Med. Biol. 2018, 1087, 245–257. [Google Scholar] [PubMed]
- Chen, Y.; Yuan, B.; Wu, Z.; Dong, Y.; Zhang, L.; Zeng, Z. Microarray profiling of circular RNAs and the potential regulatory role of hsa_circ_0071410 in the activated human hepatic stellate cell induced by irradiation. Gene 2017, 629, 35–42. [Google Scholar] [CrossRef] [PubMed]
- Zhou, Y.; Lv, X.; Qu, H.; Zhao, K.; Fu, L.; Zhu, L.; Ye, G.; Guo, J. Preliminary screening and functional analysis of circular RNAs associated with hepatic stellate cell activation. Gene 2018, 677, 317–323. [Google Scholar] [CrossRef] [PubMed]
- Keene, J.D. RNA regulons: Coordination of post-transcriptional events. Nat. Rev. Genet. 2007, 8, 533–543. [Google Scholar] [CrossRef] [PubMed]
- Wang, S.; Jung, Y.; Hyun, J.; Friedersdorf, M.; Oh, S.-H.; Kim, J.; Premont, R.T.; Keene, J.D.; Diehl, A.M. RNA binding proteins control transdifferentiation of hepatic stellate cells into myofibroblasts. Cell. Physiol. Biochem. 2018, 48, 1215–1229. [Google Scholar] [CrossRef] [PubMed]
- Chen, P.-J.; Huang, C.; Meng, X.-M.; Li, J. Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis. Biochimie 2015, 116, 61–69. [Google Scholar] [CrossRef] [PubMed]
- Hardy, T.; Mann, D.A. Epigenetics in liver disease: From biology to therapeutics. Gut 2016, 65, 1895–1905. [Google Scholar] [CrossRef] [PubMed]
- Zhou, B.; Zeng, S.; Li, L.; Fan, Z.; Tian, W.; Li, M.; Xu, H.; Wu, X.; Fang, M.; Xu, Y. Angiogenic factor with G patch and FHA domains 1 (Aggf1) regulates liver fibrosis by modulating TGF-β signaling. Biochim. Biophys. Acta 2016, 1862, 1203–1213. [Google Scholar] [CrossRef] [PubMed]
- Zeybel, M.; Luli, S.; Sabater, L.; Hardy, T.; Oakley, F.; Leslie, J.; Page, A.; Moran Salvador, E.; Sharkey, V.; Tsukamoto, H.; et al. A proof-of-concept for epigenetic therapy of tissue fibrosis: Inhibition of liver fibrosis progression by 3-deazaneplanocin A. Mol. J. Am. Soc. Gene 2017, 25, 218–231. [Google Scholar] [CrossRef] [PubMed]
- Martin-Mateos, R.; De Assuncao, T.M.; Arab, J.P.; Jalan-Sakrikar, N.; Yaqoob, U.; Greuter, T.; Verma, V.K.; Mathison, A.J.; Cao, S.; Lomberk, G.; et al. Enhancer of zeste homologue 2 inhibition attenuates TGF-β dependent hepatic stellate cell activation and liver fibrosis. Cell. Mol. Gastroenterol. Hepatol. 2019, 7, 197–209. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lin, T.; Wang, S.; Shao, C.; Yuan, X.; Wandrer, F.; Bantel, H.; Marx, A.; Ebert, M.; Ding, H.; Dooley, S.; et al. THU-375-Transcription factor TRIM33 controls liver progenitor cell towards hepatocyte differentiation through synergizing with SMAD2/3 following massive parenchymal loss. J. Hepatol. 2019, 70, e318–e319. [Google Scholar] [CrossRef]
- Wang, Y.; Zhao, L.; Jiao, F.-Z.; Zhang, W.-B.; Chen, Q.; Gong, Z.-J. Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway. Hepatobiliary Pancreat. Dis. Int. 2018, 17, 423–429. [Google Scholar] [CrossRef] [PubMed]
- Tu, A.W.; Luo, K. Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response. J. Biol. Chem. 2007, 282, 21187–21196. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Inoue, Y.; Itoh, Y.; Abe, K.; Okamoto, T.; Daitoku, H.; Fukamizu, A.; Onozaki, K.; Hayashi, H. Smad3 is acetylated by p300/CBP to regulate its transactivation activity. Oncogene 2007, 26, 500–508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Janknecht, R.; Wells, N.J.; Hunter, T. TGF-beta-stimulated cooperation of smad proteins with the coactivators CBP/p300. Genes Dev. 1998, 12, 2114–2119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, Y.; Tu, K.; Liu, D.; Guo, L.; Chen, Y.; Li, Q.; Maiers, J.L.; Liu, Z.; Shah, V.H.; Dou, C.; et al. p300 acetyltransferase is a cytoplasm-to-nucleus shuttle for SMAD2/3 and TAZ nuclear transport in transforming growth factor β-stimulated hepatic stellate cells. Hepatology 2019, 70, 1409–1423. [Google Scholar] [CrossRef] [PubMed]
- Jiang, R.; Zhou, Y.; Wang, S.; Pang, N.; Huang, Y.; Ye, M.; Wan, T.; Qiu, Y.; Pei, L.; Jiang, X.; et al. Nicotinamide riboside protects against liver fibrosis induced by CCl4 via regulating the acetylation of Smads signaling pathway. Life Sci. 2019, 225, 20–28. [Google Scholar] [CrossRef] [PubMed]
- Alonso-Merino, E.; Martín Orozco, R.; Ruíz-Llorente, L.; Martínez-Iglesias, O.A.; Velasco-Martín, J.P.; Montero-Pedrazuela, A.; Fanjul-Rodríguez, L.; Contreras-Jurado, C.; Regadera, J.; Aranda, A. Thyroid hormones inhibit TGF-β signaling and attenuate fibrotic responses. Proc. Natl. Acad. Sci. USA 2016, 113, E3451–E3460. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Munker, S.; Wu, Y.-L.; Ding, H.-G.; Liebe, R.; Weng, H.-L. Can a fibrotic liver afford epithelial-mesenchymal transition? World J. Gastroenterol. 2017, 23, 4661–4668. [Google Scholar] [CrossRef] [PubMed]
- Taura, K.; Iwaisako, K.; Hatano, E.; Uemoto, S. Controversies over the epithelial-to-mesenchymal transition in liver fibrosis. J. Clin. Med. 2016, 5, 9. [Google Scholar] [CrossRef] [PubMed]
- Choi, S.S.; Diehl, A.M. Epithelial-to-mesenchymal transitions in the liver. Hepatology 2009, 50, 2007–2013. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kisseleva, T. The origin of fibrogenic myofibroblasts in fibrotic liver. Hepatology 2017, 65, 1039–1043. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Zeisberg, M.; Kalluri, R. Cellular mechanisms of tissue fibrosis. 1. Common and organ-specific mechanisms associated with tissue fibrosis. Am. J. Physiol. Cell Physiol. 2013, 304, C216–C225. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wu, Y.; Ding, Z.-Y.; Jin, G.-N.; Xiong, Y.-X.; Yu, B.; Sun, Y.-M.; Wang, W.; Liang, H.-F.; Zhang, B.; Chen, X.-P. Autocrine transforming growth factor-β/activin A-Smad signaling induces hepatic progenitor cells undergoing partial epithelial-mesenchymal transition states. Biochimie 2018, 148, 87–98. [Google Scholar] [CrossRef] [PubMed]
- Katsuno, Y.; Meyer, D.S.; Zhang, Z.; Shokat, K.M.; Akhurst, R.J.; Miyazono, K.; Derynck, R. Chronic TGF-β exposure drives stabilized EMT, tumor stemness, and cancer drug resistance with vulnerability to bitopic mTOR inhibition. Sci. Signal. 2019, 12, eaau8544. [Google Scholar] [CrossRef] [PubMed]
- Sun, S.; Xie, F.; Zhang, Q.; Cui, Z.; Cheng, X.; Zhong, F.; He, K.; Zhou, J. Advanced oxidation protein products induce hepatocyte epithelial-mesenchymal transition via a ROS-dependent, TGF-β/Smad signaling pathway. Cell Biol. Int. 2017, 41, 842–853. [Google Scholar] [CrossRef] [PubMed]
- Asahina, K.; Zhou, B.; Pu, W.T.; Tsukamoto, H. Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 2011, 53, 983–995. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, Y.; Lua, I.; French, S.W.; Asahina, K. Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 2016, 310, G262–G272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adams, D.H.; Shepherd, E.L.; Lalor, P.F. Could endothelial TGFβ signaling be a promising new target for liver disease? Expert Rev. Gastroenterol. Hepatol. 2018, 12, 637–639. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ribera, J.; Pauta, M.; Melgar-Lesmes, P.; Córdoba, B.; Bosch, A.; Calvo, M.; Rodrigo-Torres, D.; Sancho-Bru, P.; Mira, A.; Jiménez, W.; et al. A small population of liver endothelial cells undergoes endothelial-to-mesenchymal transition in response to chronic liver injury. Am. J. Physiol. Gastrointest. Liver Physiol. 2017, 313, G492–G504. [Google Scholar] [CrossRef] [PubMed]
- Dufton, N.P.; Peghaire, C.R.; Osuna-Almagro, L.; Raimondi, C.; Kalna, V.; Chuahan, A.; Webb, G.; Yang, Y.; Birdsey, G.M.; Lalor, P.; et al. Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis. Nat. Commun. 2017, 8, 895. [Google Scholar] [CrossRef] [PubMed]
- Vallée, A.; Lecarpentier, Y.; Vallée, J.-N. Thermodynamic Aspects and Reprogramming Cellular Energy Metabolism during the Fibrosis Process. Int. J. Mol. Sci. 2017, 18, 2537. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Vander Heiden, M.G.; Cantley, L.C.; Thompson, C.B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 2009, 324, 1029–1033. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Pfeiffer, T.; Schuster, S.; Bonhoeffer, S. Cooperation and competition in the evolution of ATP-producing pathways. Science 2001, 292, 504–507. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Kottmann, R.M.; Kulkarni, A.A.; Smolnycki, K.A.; Lyda, E.; Dahanayake, T.; Salibi, R.; Honnons, S.; Jones, C.; Isern, N.G.; Hu, J.Z.; et al. Lactic acid is elevated in idiopathic pulmonary fibrosis and induces myofibroblast differentiation via pH-dependent activation of transforming growth factor-β. Am. J. Respir. Crit. Care Med. 2012, 186, 740–751. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Li, J.; Ghazwani, M.; Liu, K.; Huang, Y.; Chang, N.; Fan, J.; He, F.; Li, L.; Bu, S.; Xie, W.; et al. Regulation of hepatic stellate cell proliferation and activation by glutamine metabolism. PLoS ONE 2017, 12, e0182679. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bernard, K.; Logsdon, N.J.; Benavides, G.A.; Sanders, Y.; Zhang, J.; Darley-Usmar, V.M.; Thannickal, V.J. Glutaminolysis is required for transforming growth factor-β1-induced myofibroblast differentiation and activation. J. Biol. Chem. 2018, 293, 1218–1228. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Altman, B.J.; Stine, Z.E.; Dang, C.V. From Krebs to clinic: Glutamine metabolism to cancer therapy. Nat. Rev. Cancer 2016, 16, 619–634. [Google Scholar] [CrossRef] [PubMed]
- Takahashi, H.; Alves, C.R.R.; Stanford, K.I.; Middelbeek, R.J.W.; Nigro, P.; Ryan, R.E.; Xue, R.; Sakaguchi, M.; Lynes, M.D.; So, K.; et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 2019, 1, 291–303. [Google Scholar] [CrossRef] [PubMed]
- Starling, S. A new metabolic role for TGFβ2. Nat. Rev. Endocrinol. 2019, 15, 191. [Google Scholar] [CrossRef] [PubMed]
- Qin, G.; Wang, G.Z.; Guo, D.D.; Bai, R.X.; Wang, M.; Du, S.Y. Deletion of Smad4 reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression. J. Dig. Dis. 2018, 19, 301–313. [Google Scholar] [CrossRef] [PubMed]
- Ko, C.H.; Takahashi, J.S. Molecular components of the mammalian circadian clock. Hum. Mol. Genet. 2006, 15, R271–R277. [Google Scholar] [CrossRef] [PubMed]
- Gekakis, N.; Staknis, D.; Nguyen, H.B.; Davis, F.C.; Wilsbacher, L.D.; King, D.P.; Takahashi, J.S.; Weitz, C.J. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998, 280, 1564–1569. [Google Scholar] [CrossRef] [PubMed]
- Chen, P.; Kakan, X.; Wang, S.; Dong, W.; Jia, A.; Cai, C.; Zhang, J. Deletion of clock gene Per2 exacerbates cholestatic liver injury and fibrosis in mice. Exp. Toxicol. Pathol. 2013, 65, 427–432. [Google Scholar] [CrossRef] [PubMed]
- Chen, P.; Han, Z.; Yang, P.; Zhu, L.; Hua, Z.; Zhang, J. Loss of clock gene mPer2 promotes liver fibrosis induced by carbon tetrachloride. Hepatol. Res. 2010, 40, 1117–1127. [Google Scholar] [CrossRef] [PubMed]
- Janich, P.; Pascual, G.; Merlos-Suárez, A.; Batlle, E.; Ripperger, J.; Albrecht, U.; Cheng, H.-Y.M.; Obrietan, K.; Di Croce, L.; Benitah, S.A. The circadian molecular clock creates epidermal stem cell heterogeneity. Nature 2011, 480, 209–214. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gast, H.; Gordic, S.; Petrzilka, S.; Lopez, M.; Müller, A.; Gietl, A.; Hock, C.; Birchler, T.; Fontana, A. Transforming growth factor-beta inhibits the expression of clock genes. Ann. N. Y. Acad. Sci. 2012, 1261, 79–87. [Google Scholar] [CrossRef] [PubMed]
- Dong, C.; Gongora, R.; Sosulski, M.L.; Luo, F.; Sanchez, C.G. Regulation of transforming growth factor-beta1 (TGF-β1)-induced pro-fibrotic activities by circadian clock gene BMAL1. Respir. Res. 2016, 17, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gibbs, J.; Ince, L.; Matthews, L.; Mei, J.; Bell, T.; Yang, N.; Saer, B.; Begley, N.; Poolman, T.; Pariollaud, M.; et al. An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat. Med. 2014, 20, 919–926. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hwang, J.-W.; Sundar, I.K.; Yao, H.; Sellix, M.T.; Rahman, I. Circadian clock function is disrupted by environmental tobacco/cigarette smoke, leading to lung inflammation and injury via a SIRT1-BMAL1 pathway. FASEB J. 2014, 28, 176–194. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dikic, I.; Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 2018, 19, 349–364. [Google Scholar] [CrossRef] [PubMed]
- Li, T.; Eheim, A.L.; Klein, S.; Uschner, F.E.; Smith, A.C.; Brandon-Warner, E.; Ghosh, S.; Bonkovsky, H.L.; Trebicka, J.; Schrum, L.W. Novel role of nuclear receptor Rev-erbα in hepatic stellate cell activation: Potential therapeutic target for liver injury. Hepatology 2014, 59, 2383–2396. [Google Scholar] [CrossRef] [PubMed]
- Kojetin, D.J.; Burris, T.P. REV-ERB and ROR nuclear receptors as drug targets. Nat. Rev. Drug Discov. 2014, 13, 197–216. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thomes, P.G.; Brandon-Warner, E.; Li, T.; Donohue, T.M.; Schrum, L.W. Rev-erb agonist and TGF-β similarly affect autophagy but differentially regulate hepatic stellate cell fibrogenic phenotype. Int. J. Biochem. Cell Biol. 2016, 81, 137–147. [Google Scholar] [CrossRef] [PubMed]
- Schrader, J.; Fallowfield, J.; Iredale, J.P. Senescence of activated stellate cells: Not just early retirement. Hepatology 2009, 49, 1045–1047. [Google Scholar] [CrossRef] [PubMed]
- Muñoz-Espín, D.; Serrano, M. Cellular senescence: From physiology to pathology. Nat. Rev. Mol. Cell Biol. 2014, 15, 482–496. [Google Scholar] [CrossRef] [PubMed]
- Krizhanovsky, V.; Yon, M.; Dickins, R.A.; Hearn, S.; Simon, J.; Miething, C.; Yee, H.; Zender, L.; Lowe, S.W. Senescence of activated stellate cells limits liver fibrosis. Cell 2008, 134, 657–667. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wiemann, S.U.; Satyanarayana, A.; Tsahuridu, M.; Tillmann, H.L.; Zender, L.; Klempnauer, J.; Flemming, P.; Franco, S.; Blasco, M.A.; Manns, M.P.; et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 2002, 16, 935–942. [Google Scholar] [CrossRef] [PubMed]
- Schafer, M.J.; White, T.A.; Iijima, K.; Haak, A.J.; Ligresti, G.; Atkinson, E.J.; Oberg, A.L.; Birch, J.; Salmonowicz, H.; Zhu, Y.; et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 2017, 8, 14532. [Google Scholar] [CrossRef] [PubMed]
- Razdan, N.; Vasilopoulos, T.; Herbig, U. Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts. Aging Cell 2018, 17, e12838. [Google Scholar] [CrossRef] [PubMed]
- Bird, T.G.; Müller, M.; Boulter, L.; Vincent, D.F.; Ridgway, R.A.; Lopez-Guadamillas, E.; Lu, W.-Y.; Jamieson, T.; Govaere, O.; Campbell, A.D.; et al. TGFβ inhibition restores a regenerative response in acute liver injury by suppressing paracrine senescence. Sci. Transl. Med. 2018, 10, eaan1230. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferreira-Gonzalez, S.; Lu, W.-Y.; Raven, A.; Dwyer, B.; Man, T.Y.; O’Duibhir, E.; Lewis, P.J.S.; Campana, L.; Kendall, T.J.; Bird, T.G.; et al. Paracrine cellular senescence exacerbates biliary injury and impairs regeneration. Nat. Commun. 2018, 9, 1020. [Google Scholar] [CrossRef] [PubMed]
- Marcellin, P.; Gane, E.; Buti, M.; Afdhal, N.; Sievert, W.; Jacobson, I.M.; Washington, M.K.; Germanidis, G.; Flaherty, J.F.; Aguilar Schall, R.; et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study. Lancet 2013, 381, 468–475. [Google Scholar] [CrossRef]
- Schuppan, D.; Ashfaq-Khan, M.; Yang, A.T.; Kim, Y.O. Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol. 2018, 68–69, 435–451. [Google Scholar] [CrossRef] [PubMed]
- Dooley, S.; ten Dijke, P. TGF-β in progression of liver disease. Cell Tissue Res. 2012, 347, 245–256. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Wang, X.; Li, Y.; Li, X.; Yan, L.; Guan, H.; Han, R.; Han, Y.; Gui, J.; Xu, X.; Dong, Y.; et al. Expression, purification, and evaluation of in vivo anti-fibrotic activity for soluble truncated TGF-β receptor II as a cleavable His-SUMO fusion protein. World J. Microbiol. Biotechnol. 2018, 34, 181. [Google Scholar] [CrossRef] [PubMed]
- Dituri, F.; Mancarella, S.; Cigliano, A.; Chieti, A.; Giannelli, G. TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives. Semin. Liver Dis. 2019, 39, 53–69. [Google Scholar] [PubMed]
- Melisi, D.; Ishiyama, S.; Sclabas, G.M.; Fleming, J.B.; Xia, Q.; Tortora, G.; Abbruzzese, J.L.; Chiao, P.J. LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol. Cancer Ther. 2008, 7, 829–840. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Luangmonkong, T.; Suriguga, S.; Bigaeva, E.; Boersema, M.; Oosterhuis, D.; de Jong, K.P.; Schuppan, D.; Mutsaers, H.A.M.; Olinga, P. Evaluating the antifibrotic potency of galunisertib in a human ex vivo model of liver fibrosis. Br. J. Pharm. 2017, 174, 3107–3117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hammad, S.; Cavalcanti, E.; Werle, J.; Caruso, M.L.; Dropmann, A.; Ignazzi, A.; Ebert, M.P.; Dooley, S.; Giannelli, G. Galunisertib modifies the liver fibrotic composition in the Abcb4Ko mouse model. Arch. Toxicol. 2018, 92, 2297–2309. [Google Scholar] [CrossRef] [PubMed]
- Ikenaga, N.; Peng, Z.-W.; Vaid, K.A.; Liu, S.B.; Yoshida, S.; Sverdlov, D.Y.; Mikels-Vigdal, A.; Smith, V.; Schuppan, D.; Popov, Y.V. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 2017, 66, 1697–1708. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ahn, J.; Son, M.K.; Jung, K.H.; Kim, K.; Kim, G.J.; Lee, S.-H.; Hong, S.-S.; Park, S.G. Aminoacyl-tRNA synthetase interacting multi-functional protein 1 attenuates liver fibrosis by inhibiting TGFβ signaling. Int. J. Oncol. 2016, 48, 747–755. [Google Scholar] [CrossRef] [PubMed]
- Zhang, H.; Ju, B.; Zhang, X.; Zhu, Y.; Nie, Y.; Xu, Y.; Lei, Q. Magnolol attenuates concanavalin a-induced hepatic fibrosis, inhibits cd4+ t helper 17 (Th17) cell differentiation and suppresses hepatic stellate cell activation: Blockade of smad3/smad4 signalling. Basic Clin. Pharm. Toxicol. 2017, 120, 560–570. [Google Scholar] [CrossRef] [PubMed]
- Ji, X.; Wang, H.; Wu, Z.; Zhong, X.; Zhu, M.; Zhang, Y.; Tan, R.; Liu, Y.; Li, J.; Wang, L. Specific Inhibitor of smad3 (SIS3) attenuates fibrosis, apoptosis, and inflammation in unilateral ureteral obstruction kidneys by inhibition of transforming growth factor β (TGF-β)/Smad3 signaling. Med. Sci. Monit. Int. 2018, 24, 1633–1641. [Google Scholar] [CrossRef] [PubMed]
- Ganai, A.A.; Husain, M. Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-β/Smad signaling pathways. Chem. Biol. Interact. 2017, 261, 80–85. [Google Scholar] [CrossRef] [PubMed]
- Liu, J.; Kong, D.; Qiu, J.; Xie, Y.; Lu, Z.; Zhou, C.; Liu, X.; Zhang, R.; Wang, Y. Praziquantel Ameliorates ccl4 -induced liver fibrosis in mice by inhibiting TGF-β/smad signalling via upregulating smad7 in hepatic stellate cells. Br. J. Pharm. 2019. [Google Scholar] [CrossRef] [PubMed]
- Delire, B.; Stärkel, P.; Leclercq, I. Animal models for fibrotic liver diseases: What we have, what we need, and what is under development. J. Clin. Transl. Hepatol. 2015, 3, 53–66. [Google Scholar] [PubMed]
- Hayashi, H.; Sakai, T. Animal models for the study of liver fibrosis: New insights from knockout mouse models. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 300, G729–G738. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hara, M.; Matsuura, T.; Kojima, S. TGF-β LAP Degradation Products, a Novel Biomarker and Promising Therapeutic Target for Liver Fibrogenesis. In Innovative Medicine: Basic Research and Development; Nakao, K., Minato, N., Uemoto, S., Eds.; Springer: Tokyo, Japan, 2015. [Google Scholar]
- Qiao, X.; Rao, P.; Zhang, Y.; Liu, L.; Pang, M.; Wang, H.; Hu, M.; Tian, X.; Zhang, J.; Zhao, Y.; et al. Redirecting TGF-β signaling through the β-catenin/foxo complex prevents kidney fibrosis. J. Am. Soc. Nephrol. 2018, 29, 557–570. [Google Scholar] [CrossRef] [PubMed]
- Akcora, B.Ö.; Storm, G.; Bansal, R. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12. Biochim. Biophys. Acta Mol. Basis Dis. 2018, 1864, 804–818. [Google Scholar] [CrossRef] [PubMed]
- Kimura, K.; Ikoma, A.; Shibakawa, M.; Shimoda, S.; Harada, K.; Saio, M.; Imamura, J.; Osawa, Y.; Kimura, M.; Nishikawa, K.; et al. Safety, tolerability, and preliminary efficacy of the anti-fibrotic small molecule pri-724, a cbp/β-catenin inhibitor, in patients with hepatitis c virus-related cirrhosis: A single-center, open-label, dose escalation phase 1 trial. EBioMedicine 2017, 23, 79–87. [Google Scholar] [CrossRef] [PubMed]
- El-Wakeel, S.A.; Rahmo, R.M.; El-Abhar, H.S. Anti-fibrotic impact of Carvedilol in a CCl-4 model of liver fibrosis via serum microRNA-200a/SMAD7 enhancement to bridle TGF-β1/EMT track. Sci. Rep. 2018, 8, 14327. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, G.; Park, S.Y.; Le, C.T.; Park, W.S.; Choi, D.H.; Cho, E.-H. Metformin ameliorates activation of hepatic stellate cells and hepatic fibrosis by succinate and GPR91 inhibition. Biochem. Biophys. Res. Commun. 2018, 495, 2649–2656. [Google Scholar] [CrossRef] [PubMed]
- Fan, K.; Wu, K.; Lin, L.; Ge, P.; Dai, J.; He, X.; Hu, K.; Zhang, L. Metformin mitigates carbon tetrachloride-induced TGF-β1/Smad3 signaling and liver fibrosis in mice. Biomed. Pharm. 2017, 90, 421–426. [Google Scholar] [CrossRef] [PubMed]
- Batlle, E.; Massagué, J. Transforming growth factor-β signaling in immunity and cancer. Immunity 2019, 50, 924–940. [Google Scholar] [CrossRef] [PubMed]
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Dewidar, B.; Meyer, C.; Dooley, S.; Meindl-Beinker, a.N. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019. Cells 2019, 8, 1419. https://doi.org/10.3390/cells8111419
Dewidar B, Meyer C, Dooley S, Meindl-Beinker aN. TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019. Cells. 2019; 8(11):1419. https://doi.org/10.3390/cells8111419
Chicago/Turabian StyleDewidar, Bedair, Christoph Meyer, Steven Dooley, and and Nadja Meindl-Beinker. 2019. "TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019" Cells 8, no. 11: 1419. https://doi.org/10.3390/cells8111419