Mechanisms of hepatic stellate cell activation (original) (raw)

• Trautwein, C., Friedman, S. L., Schuppan, D. & Pinzani, M. Hepatic fibrosis: concept to treatment. J. Hepatol. 62, S15–S24 (2015).
  CAS PubMed Google Scholar
• Lee, Y. A., Wallace, M. C. & Friedman, S. L. Pathobiology of liver fibrosis: a translational success story. Gut 64, 830–841 (2015).
  CAS PubMed Google Scholar
• Puche, J. E., Saiman, Y. & Friedman, S. L. Hepatic stellate cells and liver fibrosis. Compr. Physiol. 3, 1473–1492 (2013).
  PubMed Google Scholar
• Ellis, E. L. & Mann, D. A. Clinical evidence for the regression of liver fibrosis. J. Hepatol. 56, 1171–1180 (2012).
  PubMed Google Scholar
• Marcellin, P. et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet 381, 468–475 (2013).
  CAS PubMed Google Scholar
• Chang, T. T. et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 52, 886–893 (2010).
  CAS PubMed Google Scholar
• D'Ambrosio, R. et al. A morphometric and immunohistochemical study to assess the benefit of a sustained virological response in hepatitis C virus patients with cirrhosis. Hepatology 56, 532–543 (2012).
  PubMed Google Scholar
• Wake, K. “Sternzellen” in the liver: perisinuosoidal cells with special reference to storage of vitamin A. Am. J. Anat. 132, 429–462 (1971).
  CAS PubMed Google Scholar
• Friedman, S. L. & Roll, F. J. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal. Biochem. 161, 207–218 (1987).
  CAS PubMed Google Scholar
• Mederacke, I., Dapito, D. H., Affo, S., Uchinami, H. & Schwabe, R. F. High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat. Protoc. 10, 305–315 (2015).
  CAS PubMed PubMed Central Google Scholar
• Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).
  PubMed Google Scholar
• Iwaisako, K. et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc. Natl Acad. Sci. USA 111, E3297–E3305 (2014).
  CAS PubMed PubMed Central Google Scholar
• Lemoinne, S., Cadoret, A., Mourabit, H. E., Thabut, D. & Housset, C. Origins and functions of liver myofibroblasts. Biochim. Biophys. Acta 1832, 948–954 (2013).
  CAS PubMed Google Scholar
• Kluwe, J. et al. Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. Gut 60, 1260–1268 (2011).
  CAS PubMed Google Scholar
• Henderson, N. C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19, 1617–1624 (2013).
  CAS PubMed Google Scholar
• Yin, C., Evason, K. J., Maher, J. J. & Stainier, D. Y. The basic helix-loop-helix transcription factor, heart and neural crest derivatives expressed transcript 2, marks hepatic stellate cells in zebrafish: analysis of stellate cell entry into the developing liver. Hepatology 56, 1958–1970 (2012).
  CAS PubMed Google Scholar
• Geerts, A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin. Liver Dis. 21, 311–335 (2001).
  CAS PubMed Google Scholar
• Miyata, E. et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 111, 2427–2435 (2008).
  CAS PubMed Google Scholar
• Zhang, D. Y. et al. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut 65, 1754–1764 (2016).
  CAS PubMed Google Scholar
• Friedman, S. L. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J. Biol. Chem. 275, 2247–2250 (2000).
  CAS PubMed Google Scholar
• Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657–667 (2008).
  CAS PubMed PubMed Central Google Scholar
• Schnabl, B., Choi, Y. H., Olsen, J. C., Hagedorn, C. H. & Brenner, D. A. Immortal activated human hepatic stellate cells generated by ectopic telomerase expression. Lab. Invest. 82, 323–333 (2002).
  CAS PubMed Google Scholar
• Iredale, J. P. et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J. Clin. Invest. 102, 538–549 (1998).
  CAS PubMed PubMed Central Google Scholar
• Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).
  CAS PubMed PubMed Central Google Scholar
• Troeger, J. S. et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143, 1073–1083.e22 (2012).
  CAS PubMed Google Scholar
• Mehal, W. Z., Iredale, J. & Friedman, S. L. Scraping fibrosis: expressway to the core of fibrosis. Nat. Med. 17, 552–553 (2011).
  CAS PubMed PubMed Central Google Scholar
• Hellerbrand, C., Stefanovic, B., Giordano, F., Burchardt, E. R. & Brenner, D. A. The role of TGFbeta1 in initiating hepatic stellate cell activation in vivo . J. Hepatol. 30, 77–87 (1999).
  CAS PubMed Google Scholar
• Breitkopf, K., Godoy, P., Ciuclan, L., Singer, M. V. & Dooley, S. TGF-beta/Smad signaling in the injured liver. Z. Gastroenterol. 44, 57–66 (2006).
  CAS PubMed Google Scholar
• Friedman, S. L. Hepatic stellate cells — protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125–172 (2008).
  CAS PubMed Google Scholar
• Hanafusa, H. et al. Involvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expression. J. Biol. Chem. 274, 27161–27167 (1999).
  CAS PubMed Google Scholar
• Engel, M. E., McDonnell, M. A., Law, B. K. & Moses, H. L. Interdependent SMAD and JNK signaling in transforming growth factor-beta-mediated transcription. J. Biol. Chem. 274, 37413–37420 (1999).
  CAS PubMed Google Scholar
• Wong, L., Yamasaki, G., Johnson, R. J. & Friedman, S. L. Induction of beta-platelet-derived growth factor receptor in rat hepatic lipocytes during cellular activation in vivo and in culture. J. Clin. Invest. 94, 1563–1569 (1994).
  CAS PubMed PubMed Central Google Scholar
• Pinzani, M. PDGF and signal transduction in hepatic stellate cells. Front. Biosci. 7, d1720–d1726 (2002).
  CAS PubMed Google Scholar
• Kocabayoglu, P. et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J. Hepatol. 63, 141–147 (2015).
  CAS PubMed PubMed Central Google Scholar
• Yang, L. et al. Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 146, 1339–1350.e1 (2014).
  CAS PubMed Google Scholar
• Kantari-Mimoun, C. et al. Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis. Hepatology 61, 2042–2055 (2015).
  CAS PubMed Google Scholar
• Huang, G. & Brigstock, D. R. Regulation of hepatic stellate cells by connective tissue growth factor. Front. Biosci. 17, 2495–2507 (2015).
  Google Scholar
• Chen, L. et al. Epigenetic regulation of connective tissue growth factor by MicroRNA-214 delivery in exosomes from mouse or human hepatic stellate cells. Hepatology 59, 1118–1129 (2014).
  CAS PubMed Google Scholar
• Chen, L., Chen, R., Kemper, S., Charrier, A. & Brigstock, D. R. Suppression of fibrogenic signaling in hepatic stellate cells by Twist1-dependent microRNA-214 expression: role of exosomes in horizontal transfer of Twist1. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G491–G499 (2015).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT01217632 (2016).
• Olaso, E. et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J. Clin. Invest. 108, 1369–1378 (2001).
  CAS PubMed PubMed Central Google Scholar
• Schuppan, D., Ruehl, M., Somasundaram, R. & Hahn, E. G. Matrix as a modulator of hepatic fibrogenesis. Semin. Liver Dis. 21, 351–372 (2001).
  CAS PubMed Google Scholar
• Martin, K. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat. Commun. 7, 12502 (2016).
  CAS PubMed PubMed Central Google Scholar
• Ikeda, K. et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J. Biol. Chem. 277, 19206–19212 (2002).
  CAS PubMed Google Scholar
• Omenetti, A., Choi, S., Michelotti, G. & Diehl, A. M. Hedgehog signaling in the liver. J. Hepatol. 54, 366–373 (2011).
  CAS PubMed Google Scholar
• Michelotti, G. A. et al. Smoothened is a master regulator of adult liver repair. J. Clin. Invest. 123, 2380–2394 (2013).
  CAS PubMed PubMed Central Google Scholar
• Syn, W. K. et al. Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Hepatology 53, 106–115 (2012).
  Google Scholar
• Urtasun, R. et al. Osteopontin, an oxidant stress sensitive cytokine, up-regulates collagen-I via integrin alpha(V)beta(3) engagement and PI3K/pAkt/NFkappaB signaling. Hepatology 55, 594–608 (2012).
  CAS PubMed Google Scholar
• Machado, M. V. et al. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut 64, 1148–1157 (2015).
  CAS PubMed Google Scholar
• Greenbaum, L. E. & Wells, R. G. The role of stem cells in liver repair and fibrosis. Int. J. Biochem. Cell Biol. 43, 222–229 (2011).
  CAS PubMed Google Scholar
• Swiderska-Syn, M. et al. Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 63, 1333–1344 (2014).
  CAS PubMed Google Scholar
• Xie, G. et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 58, 1801–1813 (2013).
  CAS PubMed Google Scholar
• Hernandez-Gea, V. et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142, 938–946 (2012).
  PubMed Google Scholar
• Thoen, L. F. et al. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55, 1353–1360 (2011).
  CAS PubMed Google Scholar
• Hernandez-Gea, V. et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J. Hepatol. 59, 98–104 (2013).
  CAS PubMed PubMed Central Google Scholar
• Koo, J. H., Lee, H. J., Kim, W. & Kim, S. G. Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology 150, 181–193.e8 (2016).
  CAS PubMed Google Scholar
• Kim, R. S. et al. The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy. Sci. Rep. 6, 39342 (2016).
  CAS PubMed PubMed Central Google Scholar
• Sato, Y. et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat. Biotechnol. 26, 431–442 (2008).
  CAS PubMed Google Scholar
• Kawasaki, K. et al. Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J. Biol. Chem. 290, 3639–3646 (2015).
  CAS PubMed Google Scholar
• Seki, E., Brenner, D. A. & Karin, M. A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 143, 307–320 (2012).
  CAS PubMed Google Scholar
• Kluwe, J. et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology 138, 347–359 (2010).
  CAS PubMed Google Scholar
• Zhao, G. et al. Jnk1 in murine hepatic stellate cells is a crucial mediator of liver fibrogenesis. Gut 63, 1159–1172 (2014).
  CAS PubMed Google Scholar
• Novo, E. et al. Intracellular reactive oxygen species are required for directional migration of resident and bone marrow-derived hepatic pro-fibrogenic cells. J. Hepatol. 54, 964–974 (2011).
  CAS PubMed Google Scholar
• Novo, E. & Parola, M. Redox mechanisms in hepatic chronic wound healing and fibrogenesis. Fibrogenesis Tissue Repair 1, 5 (2008).
  PubMed PubMed Central Google Scholar
• Lan, T., Kisseleva, T. & Brenner, D. A. Deficiency of NOX1 or NOX4 prevents liver inflammation and fibrosis in mice through inhibition of hepatic stellate cell activation. PLoS ONE 10, e0129743 (2015).
  PubMed PubMed Central Google Scholar
• Jiang, J. X. et al. Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo . Gastroenterology 139, 1375–1384 (2010).
  CAS PubMed Google Scholar
• Aoyama, T. et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology 56, 2316–2327 (2012).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02010242 (2015).
• Tomita, K. et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology 59, 154–169 (2014).
  CAS PubMed Google Scholar
• Yi, H. S. et al. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 60, 1044–1053 (2014).
  CAS PubMed Google Scholar
• Valenti, L. et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin I148M polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 51, 1209–1217 (2010).
  CAS PubMed Google Scholar
• Romeo, S. et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40, 1461–1465 (2008).
  CAS PubMed PubMed Central Google Scholar
• Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).
  CAS PubMed PubMed Central Google Scholar
• Teratani, T. et al. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142, 152–164.e10 (2012).
  CAS PubMed Google Scholar
• Tomita, K. et al. Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. J. Hepatol. 61, 98–106 (2014).
  CAS PubMed Google Scholar
• Van Rooyen, D. M. et al. Pharmacological cholesterol lowering reverses fibrotic NASH in obese, diabetic mice with metabolic syndrome. J. Hepatol. 59, 144–152 (2013).
  CAS PubMed Google Scholar
• Saxena, N. K. & Anania, F. A. Adipocytokines and hepatic fibrosis. Trends Endocrinol. Metab. 26, 153–161 (2015).
  CAS PubMed PubMed Central Google Scholar
• Shafiei, M. S., Shetty, S., Scherer, P. E. & Rockey, D. C. Adiponectin regulation of stellate cell activation via PPARgamma-dependent and -independent mechanisms. Am. J. Pathol. 178, 2690–2699 (2011).
  CAS PubMed PubMed Central Google Scholar
• Kamada, Y. et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125, 1796–1807 (2003).
  CAS PubMed Google Scholar
• Coombes, J. D. et al. Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis. Biochim. Biophys. Acta 1862, 135–144 (2016).
  CAS PubMed Google Scholar
• Sahai, A. et al. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G1035–G1043 (2004).
  CAS PubMed Google Scholar
• Coll, M. et al. Integrative miRNA and gene expression profiling analysis of human quiescent hepatic stellate cells. Sci. Rep. 5, 11549 (2015).
  PubMed PubMed Central Google Scholar
• Zhang, Z. et al. The auto-regulatory feedback loop of microRNA-21/programmed cell death protein 4/activation protein-1 (miR-21/PDCD4/AP-1) as a driving force for hepatic fibrosis development. J. Biol. Chem. http://dx.doi.org/10.1074/jbc.M113.517953 (2013).
• Ogawa, T. et al. MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut 61, 1600–1609 (2012).
  CAS PubMed Google Scholar
• Ji, J. et al. Over-expressed microRNA-27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation. FEBS Lett. 583, 759–766 (2009).
  CAS PubMed Google Scholar
• Hyun, J. et al. MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat. Commun. 7, 10993 (2016).
  CAS PubMed PubMed Central Google Scholar
• Liu, X. Y. et al. Induction of autophagy and apoptosis by miR-148a through the sonic hedgehog signaling pathway in hepatic stellate cells. Am. J. Cancer Res. 5, 2569–2589 (2015).
  CAS PubMed PubMed Central Google Scholar
• Jung, K. H. et al. Differentiation therapy for hepatocellular carcinoma: multifaceted effects of miR-148a on tumor growth and phenotype and liver fibrosis. Hepatology 63, 864–879 (2016).
  CAS PubMed Google Scholar
• Huang, Y. H. et al. Activation of Mir-29a in activated hepatic stellate cells modulates its profibrogenic phenotype through inhibition of histone deacetylases 4. PLoS ONE 10, e0136453 (2015).
  PubMed PubMed Central Google Scholar
• Guo, C. J., Pan, Q., Li, D. G., Sun, H. & Liu, B. W. miR-15b and miR-16 are implicated in activation of the rat hepatic stellate cell: an essential role for apoptosis. J. Hepatol. 50, 766–778 (2009).
  CAS PubMed Google Scholar
• Li, J. et al. miR-122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J. Hepatol. 58, 522–528 (2013).
  CAS PubMed Google Scholar
• Roderburg, C. et al. miR-133a mediates TGF-beta-dependent derepression of collagen synthesis in hepatic stellate cells during liver fibrosis. J. Hepatol. 58, 736–742 (2013).
  CAS PubMed Google Scholar
• Sekiya, Y. et al. Down-regulation of cyclin E1 expression by microRNA-195 accounts for interferon-beta-induced inhibition of hepatic stellate cell proliferation. J. Cell. Physiol. 226, 2535–2542 (2011).
  CAS PubMed Google Scholar
• Venugopal, S. K. et al. Liver fibrosis causes down-regulation of miRNA-150 and miRNA-194 in hepatic stellate cells and their over-expression causes decreased stellate cell activation. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G101–G106 (2009).
  PubMed PubMed Central Google Scholar
• Zhou, C. et al. Long noncoding RNAs expressed in human hepatic stellate cells form networks with extracellular matrix proteins. Genome Med. 8, 31 (2016).
  PubMed PubMed Central Google Scholar
• Tian, W. et al. Myocardin-related transcription factor A (MRTF-A) plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-beta signaling. Int. J. Biochem. Cell Biol. 71, 35–43 (2016).
  CAS PubMed Google Scholar
• Hardy, T. & Mann, D. A. Epigenetics in liver disease: from biology to therapeutics. Gut 65, 1895–1905 (2016).
  CAS PubMed Google Scholar
• Bian, E. B. et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol. Appl. Pharmacol. 264, 13–22 (2012).
  CAS PubMed Google Scholar
• Mann, J. et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138, 705–714 (2010).
  CAS PubMed Google Scholar
• Kweon, S. M., Chi, F., Higashiyama, R., Lai, K. & Tsukamoto, H. Wnt pathway stabilizes MeCP2 protein to repress PPAR-gamma in Activation of hepatic stellate cells. PLoS ONE 11, e0156111 (2016).
  PubMed PubMed Central Google Scholar
• Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nat. Med. 13, 1324–1332 (2007).
  CAS PubMed Google Scholar
• Gabele, E. et al. Role of TLR9 in hepatic stellate cells and experimental liver fibrosis. Biochem. Biophys. Res. Commun. 376, 271–276 (2008).
  PubMed Google Scholar
• Miura, K. et al. Toll-like receptor 2 and palmitic acid cooperatively contribute to the development of nonalcoholic steatohepatitis through inflammasome activation in mice. Hepatology 57, 577–589 (2013).
  CAS PubMed Google Scholar
• Byun, J. S., Suh, Y. G., Yi, H. S., Lee, Y. S. & Jeong, W. I. Activation of Toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice. J. Hepatol. 58, 342–349 (2013).
  CAS PubMed Google Scholar
• Chou, M. H. et al. Selective activation of Toll-like receptor 7 in activated hepatic stellate cells may modulate their profibrogenic phenotype. Biochem. J. 447, 25–34 (2012).
  CAS PubMed Google Scholar
• Huang, H. et al. A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 46, 297–306 (2007).
  CAS PubMed Google Scholar
• Guo, J. et al. Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses. Hepatology 49, 960–968 (2009).
  CAS PubMed Google Scholar
• Seo, W. et al. Exosome-mediated activation of Toll-like receptor 3 in stellate cells stimulates interleukin-17 production by gammadelta T cells in liver fibrosis. Hepatology 64, 616–631 (2016).
  CAS PubMed Google Scholar
• Pinzani, M. & Marra, F. Cytokine receptors and signaling in hepatic stellate cells. Semin. Liver Dis. 21, 397–416 (2001).
  CAS PubMed Google Scholar
• Jiao, J. et al. Interleukin-15 receptor alpha on hepatic stellate cells regulates hepatic fibrogenesis in mice. J. Hepatol. 65, 344–353 (2016).
  CAS PubMed PubMed Central Google Scholar
• Meng, F. et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143, 765–776.e3 (2012).
  CAS PubMed Google Scholar
• Chiu, Y. S., Wei, C. C., Lin, Y. J., Hsu, Y. H. & Chang, M. S. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 60, 1003–1014 (2014).
  CAS PubMed Google Scholar
• Kong, X. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150–1159 (2012).
  CAS PubMed Google Scholar
• Beaven, S. W. et al. Liver x receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology 140, 1052–1062 (2011).
  CAS PubMed Google Scholar
• O'Mahony, F. et al. Liver X receptors balance lipid stores in hepatic stellate cells through Rab18, a retinoid responsive lipid droplet protein. Hepatology 62, 615–626 (2015).
  CAS PubMed Google Scholar
• Kong, B., Luyendyk, J. P., Tawfik, O. & Guo, G. L. Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet. J. Pharmacol. Exp. Ther. 328, 116–122 (2009).
  CAS PubMed Google Scholar
• Neuschwander-Tetri, B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet 385, 956–965 (2015).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02548351 (2017).
• Hazra, S. et al. Peroxisome proliferator-activated receptor gamma induces a phenotypic switch from activated to quiescent hepatic stellate cells. J. Biol. Chem. 279, 11392–11401 (2004).
  CAS PubMed Google Scholar
• Moran-Salvador, E. et al. Cell-specific PPARgamma deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J. Hepatol. 59, 1045–1053 (2013).
  CAS PubMed Google Scholar
• Iwaisako, K. et al. Protection from liver fibrosis by a peroxisome proliferator-activated receptor delta agonist. Proc. Natl Acad. Sci. USA 109, E1369–E1376 (2012).
  CAS PubMed PubMed Central Google Scholar
• Staels, B. et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58, 1941–1952 (2013).
  CAS PubMed Google Scholar
• Ratziu, V. et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150, 1147–1159.e5 (2016).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02704403 (2017).
• Ding, N. et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell 153, 601–613 (2013).
  CAS PubMed PubMed Central Google Scholar
• Duran, A. et al. p62/SQSTM1 by binding to vitamin d receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell 30, 595–609 (2016).
  CAS PubMed PubMed Central Google Scholar
• Li, T. et al. Novel role of nuclear receptor Rev-erbα in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology 59, 2383–2396 (2014).
  CAS PubMed Google Scholar
• Palumbo-Zerr, K. et al. Orphan nuclear receptor NR4A1 regulates transforming growth factor-beta signaling and fibrosis. Nat. Med. 21, 150–158 (2015).
  CAS PubMed Google Scholar
• Teixeira-Clerc, F. et al. CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat. Med. 12, 671–676 (2006).
  CAS PubMed Google Scholar
• Julien, B. et al. Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128, 742–755 (2005).
  CAS PubMed Google Scholar
• Munoz-Luque, J. et al. Regression of fibrosis after chronic stimulation of cannabinoid CB2 receptor in cirrhotic rats. J. Pharmacol. Exp. Ther. 324, 475–483 (2008).
  CAS PubMed Google Scholar
• Guillot, A. et al. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology 59, 296–306 (2014).
  CAS PubMed Google Scholar
• Granzow, M. et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 60, 334–348 (2014).
  CAS PubMed Google Scholar
• Knight, V., Tchongue, J., Lourensz, D., Tipping, P. & Sievert, W. Protease-activated receptor 2 promotes experimental liver fibrosis in mice and activates human hepatic stellate cells. Hepatology 55, 879–887 (2012).
  CAS PubMed Google Scholar
• Seki, E. et al. CCR2 promotes hepatic fibrosis in mice. Hepatology 50, 185–197 (2009).
  CAS PubMed Google Scholar
• Lefebvre, E. et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS ONE 11, e0158156 (2016).
  PubMed PubMed Central Google Scholar
• Ruddell, R. G. et al. A role for serotonin (5-HT) in hepatic stellate cell function and liver fibrosis. Am. J. Pathol. 169, 861–876 (2006).
  CAS PubMed PubMed Central Google Scholar
• Kim, D. C. et al. 5-HT2A receptor antagonists inhibit hepatic stellate cell activation and facilitate apoptosis. Liver Int. 33, 535–543 (2013).
  CAS PubMed Google Scholar
• Ebrahimkhani, M. R. et al. Stimulating healthy tissue regeneration by targeting the 5-HT(2B) receptor in chronic liver disease. Nat. Med. 17, 1668–1673 (2011).
  CAS PubMed PubMed Central Google Scholar
• Li, Y. H., Woo, S. H., Choi, D. H. & Cho, E. H. Succinate causes alpha-SMA production through GPR91 activation in hepatic stellate cells. Biochem. Biophys. Res. Commun. 463, 853–858 (2015).
  CAS PubMed Google Scholar
• Li, Y. H. et al. Sirtuin 3 (SIRT3) regulates alpha-smooth muscle actin (alpha-SMA) production through the succinate dehydrogenase-G protein-coupled receptor 91 (GPR91) pathway in hepatic stellate cells. J. Biol. Chem. 291, 10277–10292 (2016).
  CAS PubMed PubMed Central Google Scholar
• Lopez-Sanchez, I. et al. GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. Nat. Commun. 5, 4451 (2014).
  CAS PubMed Google Scholar
• Aylon, Y. et al. The LATS2 tumor suppressor inhibits SREBP and suppresses hepatic cholesterol accumulation. Genes Dev. 30, 786–797 (2016).
  CAS PubMed PubMed Central Google Scholar
• Halder, G. & Johnson, R. L. Hippo signaling: growth control and beyond. Development 138, 9–22 (2011).
  CAS PubMed PubMed Central Google Scholar
• Moroishi, T., Hansen, C. G. & Guan, K. L. The emerging roles of YAP and TAZ in cancer. Nat. Rev. Cancer 15, 73–79 (2015).
  CAS PubMed PubMed Central Google Scholar
• Yu, F. X. & Guan, K. L. The Hippo pathway: regulators and regulations. Genes Dev. 27, 355–371 (2013).
  CAS PubMed PubMed Central Google Scholar
• Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. J. Hepatol. 63, 679–688 (2015).
  CAS PubMed Google Scholar
• Swiderska-Syn, M. et al. Hedgehog regulates yes-associated protein 1 in regenerating mouse liver. Hepatology 64, 232–244 (2016).
  CAS PubMed Google Scholar
• Machado, M. V. et al. Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease. J. Hepatol. 63, 962–970 (2015).
  CAS PubMed PubMed Central Google Scholar
• Wilhelm, A. et al. CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism. Gut 65, 1175–1185 (2016).
  CAS PubMed Google Scholar
• Mogler, C. et al. Hepatic stellate cell-expressed endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol. Med. 7, 332–338 (2015).
  CAS PubMed PubMed Central Google Scholar
• Ding, N. et al. BRD4 is a novel therapeutic target for liver fibrosis. Proc. Natl Acad. Sci. USA 112, 15713–15718 (2015).
  CAS PubMed PubMed Central Google Scholar
• Henderson, N. C. et al. Galectin-3 regulates myofibroblast activation and hepatic fibrosis. Proc. Natl Acad. Sci. USA 103, 5060–5065 (2006).
  CAS PubMed PubMed Central Google Scholar
• Traber, P. G. et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS ONE 8, e75361 (2013).
  CAS PubMed PubMed Central Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02462967 (2017).
• Delgado, I. et al. GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice. Hepatology 59, 2358–2370 (2014).
  CAS PubMed Google Scholar
• Wandzioch, E., Kolterud, A., Jacobsson, M., Friedman, S. L. & Carlsson, L. Lhx2−/− mice develop liver fibrosis. Proc. Natl Acad. Sci. USA 101, 16549–16554 (2004).
  CAS PubMed PubMed Central Google Scholar
• Arndt, S. et al. Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease. Gut 64, 973–981 (2015).
  CAS PubMed Google Scholar
• Barcena, C. et al. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation. J. Hepatol. 63, 670–678 (2015).
  CAS PubMed PubMed Central Google Scholar
• Lafdil, F. et al. Induction of Gas6 protein in CCl4-induced rat liver injury and anti-apoptotic effect on hepatic stellate cells. Hepatology 44, 228–239 (2006).
  CAS PubMed Google Scholar
• Novo, E. et al. Cellular and molecular mechanisms in liver fibrogenesis. Arch. Biochem. Biophys. 548, 20–37 (2014).
  CAS PubMed Google Scholar
• Chung, S. I. et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J. Hepatol. 64, 618–627 (2016).
  CAS PubMed Google Scholar
• Vaughn, B. P., Robson, S. C. & Longhi, M. S. Purinergic signaling in liver disease. Dig. Dis. 32, 516–524 (2014).
  PubMed Google Scholar
• Wree, A. et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology 59, 898–910 (2014).
  CAS PubMed Google Scholar
• McHedlidze, T. et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity 39, 357–371 (2013).
  CAS PubMed PubMed Central Google Scholar
• Canbay, A. et al. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab. Invest. 83, 655–663 (2003).
  CAS PubMed Google Scholar
• Zhan, S. S. et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo . Hepatology 43, 435–443 (2006).
  CAS PubMed Google Scholar
• Wiegard, C. et al. Murine liver antigen presenting cells control suppressor activity of CD4+CD25+ regulatory T cells. Hepatology 42, 193–199 (2005).
  CAS PubMed Google Scholar
• Seki, S. et al. The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses. Immunol. Rev. 174, 34–46 (2000).
  Google Scholar
• Ju, C. & Pohl, L. R. Tolerogenic role of Kupffer cells in immune-mediated adverse drug reactions. Toxicology 209, 109–112 (2005).
  CAS PubMed Google Scholar
• Sunami, Y. et al. Hepatic activation of IKK/NFkappaB signaling induces liver fibrosis via macrophage-mediated chronic inflammation. Hepatology 56, 1117–1128 (2012).
  CAS PubMed Google Scholar
• Duffield, J. S. et al. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56–65 (2005).
  CAS PubMed PubMed Central Google Scholar
• Pradere, J. P. et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58, 1461–1473 (2013).
  CAS PubMed Google Scholar
• Tacke, F. et al. Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques. J. Clin. Invest. 117, 185–194 (2007).
  CAS PubMed PubMed Central Google Scholar
• Tacke, F. & Randolph, G. J. Migratory fate and differentiation of blood monocyte subsets. Immunobiology 211, 609–618 (2006).
  CAS PubMed Google Scholar
• Seki, E. et al. CCR1 and CCR5 promote hepatic fibrosis in mice. J. Clin. Invest. 119, 1858–1870 (2009).
  CAS PubMed PubMed Central Google Scholar
• Karlmark, K. R. et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology 50, 261–274 (2009).
  CAS PubMed Google Scholar
• Miura, K., Yang, L., van Rooijen, N., Ohnishi, H. & Seki, E. Hepatic recruitment of macrophages promotes nonalcoholic steatohepatitis through CCR2. Am. J. Physiol. Gastrointest. Liver Physiol. 302, G1310–G1321 (2012).
  CAS PubMed PubMed Central Google Scholar
• Heinrichs, D. et al. The chemokine CCL3 promotes experimental liver fibrosis in mice. PLoS ONE 8, e66106 (2013).
  CAS PubMed PubMed Central Google Scholar
• Berres, M. L. et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J. Clin. Invest. 120, 4129–4140 (2010).
  CAS PubMed PubMed Central Google Scholar
• Fallowfield, J. A. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288–5295 (2007).
  CAS PubMed Google Scholar
• Pellicoro, A. et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology 55, 1965–1975 (2012).
  CAS PubMed Google Scholar
• Taimr, P. et al. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 37, 87–95 (2003).
  CAS PubMed Google Scholar
• Ramachandran, P. et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc. Natl Acad. Sci. USA 109, E3186–E3195 (2012).
  CAS PubMed PubMed Central Google Scholar
• Aoyama, T., Inokuchi, S., Brenner, D. A. & Seki, E. CX3CL1–CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology 52, 1390–1400 (2010).
  CAS PubMed Google Scholar
• Jeong, W. I., Park, O. & Gao, B. Abrogation of the antifibrotic effects of natural killer cells/interferon-gamma contributes to alcohol acceleration of liver fibrosis. Gastroenterology 134, 248–258 (2008).
  CAS PubMed Google Scholar
• Jeong, W. I. et al. Suppression of innate immunity (natural killer cell/interferon-gamma) in the advanced stages of liver fibrosis in mice. Hepatology 53, 1342–1351 (2011).
  CAS PubMed Google Scholar
• Glassner, A. et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab. Invest. 92, 967–977 (2012).
  PubMed Google Scholar
• Wang, H. & Yin, S. Natural killer T cells in liver injury, inflammation and cancer. Expert Rev. Gastroenterol. Hepatol. 9, 1077–1085 (2015).
  CAS PubMed Google Scholar
• Park, O. et al. Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride. Hepatology 49, 1683–1694 (2009).
  CAS PubMed Google Scholar
• Wehr, A. et al. Chemokine receptor CXCR6-dependent hepatic NK T Cell accumulation promotes inflammation and liver fibrosis. J. Immunol. 190, 5226–5236 (2013).
  CAS PubMed Google Scholar
• Deleve, L. D., Wang, X. & Guo, Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48, 920–930 (2008).
  CAS PubMed Google Scholar
• Xie, G. et al. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142, 918–927.e6 (2012).
  PubMed Google Scholar
• Ding, B. S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505, 97–102 (2014).
  PubMed Google Scholar
• Kurokawa, T., Zheng, Y. W. & Ohkohchi, N. Novel functions of platelets in the liver. J. Gastroenterol. Hepatol. 31, 745–751 (2016).
  CAS PubMed Google Scholar
• Nowatari, T., Murata, S., Fukunaga, K. & Ohkohchi, N. Role of platelets in chronic liver disease and acute liver injury. Hepatol. Res. 44, 165–172 (2014).
  CAS PubMed Google Scholar
• Yoshida, S. et al. Extrahepatic platelet-derived growth factor-beta, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice. Gastroenterology 147, 1378–1392 (2014).
  CAS PubMed Google Scholar
• Novobrantseva, T. I. et al. Attenuated liver fibrosis in the absence of B cells. J. Clin. Invest. 115, 3072–3082 (2005).
  CAS PubMed PubMed Central Google Scholar
• Thapa, M. et al. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology 61, 2067–2079 (2015).
  CAS PubMed Google Scholar
• 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. 14, 181–194 (2014).
  CAS PubMed Google Scholar
• Kendall, T. J. et al. p75 neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49, 901–910 (2009).
  CAS PubMed Google Scholar
• Oh, Y. et al. Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology 64, 209–223 (2016).
  CAS PubMed Google Scholar
• Murphy, F. R. et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J. Biol. Chem. 277, 11069–11076 (2002).
  CAS PubMed Google Scholar
• Lujambio, A. et al. Non-cell-autonomous tumor suppression by p53. Cell 153, 449–460 (2013).
  CAS PubMed PubMed Central Google Scholar
• Yoon, Y. J., Friedman, S. L. & Lee, Y. A. Antifibrotic therapies: where are we now? Semin. Liver Dis. 36, 87–98 (2016).
  CAS PubMed Google Scholar
• Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).
  PubMed Google Scholar
• Lade, A., Noon, L. A. & Friedman, S. L. Contributions of metabolic dysregulation and inflammation to nonalcoholic steatohepatitis, hepatic fibrosis, and cancer. Curr. Opin. Oncol. 26, 100–107 (2014).
  CAS PubMed PubMed Central Google Scholar
• Bian, Z. & Ma, X. Liver fibrogenesis in non-alcoholic steatohepatitis. Front. Physiol. 3, 248 (2012).
  CAS PubMed PubMed Central Google Scholar
• Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362, 1–5 (2010).
  Google Scholar
• Verbeke, L. et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci. Rep. 6, 33453 (2016).
  CAS PubMed PubMed Central Google Scholar
• Friedman, S. et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR phase 2b study design. Contemp. Clin. Trials 47, 356–365 (2016).
  PubMed Google Scholar
• Liu, S. B. et al. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J. 30, 1599–1609 (2016).
  CAS PubMed Google Scholar
• Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 16, 1009–1017 (2010).
  CAS PubMed Google Scholar
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT00063622 (2012).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT00501592 (2012).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT01694849 (2016).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02217475 (2016).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT01672866 (2017).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT01672879 (2017).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02421094 (2017).
• US National Library of Medicine. ClinicalTrials.gov [online] https://clinicaltrials.gov/ct2/show/NCT02227459 (2016).