Comprehensive Physiology Wiley Online Library

Hepatic Stellate Cells and Liver Fibrosis

Full Article on Wiley Online Library


Hepatic stellate cells are resident perisinusoidal cells distributed throughout the liver, with a remarkable range of functions in normal and injured liver. Derived embryologically from septum transversum mesenchyme, their precursors include submesothelial cells that invade the liver parenchyma from the hepatic capsule. In normal adult liver, their most characteristic feature is the presence of cytoplasmic perinuclear droplets that are laden with retinyl (vitamin A) esters. Normal stellate cells display several patterns of intermediate filaments expression (e.g., desmin, vimentin, and/or glial fibrillary acidic protein) suggesting that there are subpopulations within this parental cell type. In the normal liver, stellate cells participate in retinoid storage, vasoregulation through endothelial cell interactions, extracellular matrix homeostasis, drug detoxification, immunotolerance, and possibly the preservation of hepatocyte mass through secretion of mitogens including hepatocyte growth factor. During liver injury, stellate cells activate into alpha smooth muscle actin‐expressing contractile myofibroblasts, which contribute to vascular distortion and increased vascular resistance, thereby promoting portal hypertension. Other features of stellate cell activation include mitogen‐mediated proliferation, increased fibrogenesis driven by connective tissue growth factor, and transforming growth factor beta 1, amplified inflammation and immunoregulation, and altered matrix degradation. Evolving areas of interest in stellate cell biology seek to understand mechanisms of their clearance during fibrosis resolution by either apoptosis, senescence, or reversion, and their contribution to hepatic stem cell amplification, regeneration, and hepatocellular cancer. © 2013 American Physiological Society. Compr Physiol 3:1473‐1492, 2013.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images

Figure 1. Figure 1. Appearance of hepatic stellate cells and the sinusoidal microenvironment in normal and injured liver. In normal liver, stellate cells (shown in blue) are laden with perinuclear retinoid droplets and preserve the differentiated function of surrounding cells, including hepatocytes and sinusoidal endothelial cells. In liver injury, the cells multiply, lose vitamin A and become embedded within dense extracellular matrix. This leads to deterioration of hepatocyte function manifested as loss of microvilli, and decreased size and number of endothelial fenestrations. Reprinted, with permission, from (2002).
Figure 2. Figure 2. Roles of hepatic stellate cells in normal liver.
Figure 3. Figure 3. Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). (A) Sinusoids are separated from hepatocytes by a low‐density basement membrane‐like matrix confined to the space of Disse, which ensures metabolic exchange. Upon injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM), resulting in progressive thickening of the septa. (B) Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow and hepatocytes and the development of portal hypertension.
Figure 4. Figure 4. Pathways of hepatic stellate cell activation and loss during liver injury and resolution. Features of stellate cell activation can be distinguished between those that stimulate initiation and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. During resolution of hepatic fibrosis, there is both programmed cell death (apoptosis) to clear fibrogenic cells, as well as reversion to a more quiescient phenotype. FGF, fibroblast growth factor; ET‐1, endothelin‐1; NK, natural killer; NO, nitric oxide; MT, membrane type. Reprinted, with permission, from (2008).

Figure 1. Appearance of hepatic stellate cells and the sinusoidal microenvironment in normal and injured liver. In normal liver, stellate cells (shown in blue) are laden with perinuclear retinoid droplets and preserve the differentiated function of surrounding cells, including hepatocytes and sinusoidal endothelial cells. In liver injury, the cells multiply, lose vitamin A and become embedded within dense extracellular matrix. This leads to deterioration of hepatocyte function manifested as loss of microvilli, and decreased size and number of endothelial fenestrations. Reprinted, with permission, from (2002).

Figure 2. Roles of hepatic stellate cells in normal liver.

Figure 3. Matrix and cellular alteration in hepatic fibrosis. Normal liver parenchyma contains epithelial cells (hepatocytes) and nonparenchymal cells: fenestrated sinusoidal endothelium, hepatic stellate cells (HSCs), and Kupffer cells (KCs). (A) Sinusoids are separated from hepatocytes by a low‐density basement membrane‐like matrix confined to the space of Disse, which ensures metabolic exchange. Upon injury, the stellate cells become activated and secrete large amounts of extracellular matrix (ECM), resulting in progressive thickening of the septa. (B) Deposition of ECM in the space of Disse leads to the loss of both endothelial fenestrations and hepatocyte microvilli, which results in both the impairment of normal bidirectional metabolic exchange between portal venous flow and hepatocytes and the development of portal hypertension.

Figure 4. Pathways of hepatic stellate cell activation and loss during liver injury and resolution. Features of stellate cell activation can be distinguished between those that stimulate initiation and those that contribute to perpetuation. Initiation is provoked by soluble stimuli that include oxidant stress signals (reactive oxygen intermediates), apoptotic bodies, lipopolysaccharide (LPS), and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. Perpetuation follows, characterized by a number of specific phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. During resolution of hepatic fibrosis, there is both programmed cell death (apoptosis) to clear fibrogenic cells, as well as reversion to a more quiescient phenotype. FGF, fibroblast growth factor; ET‐1, endothelin‐1; NK, natural killer; NO, nitric oxide; MT, membrane type. Reprinted, with permission, from (2008).
 1.Abramovitch S, Dahan‐Bachar L, Sharvit E, Weisman Y, Ben Tov A, Brazowski E, Reif S. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide‐induced liver fibrosis in rats. Gut 60: 1728‐1737, 2011.
 2.Anania FA, Womack L, Jiang M, Saxena NK. Aldehydes potentiate alpha(2)(I) collagen gene activity by JNK in hepatic stellate cells. Free Radic Biol Med 30: 846‐857, 2001.
 3.Anthony PP, Ishak KG, Nayak NC, Poulsen HE, Scheuer PJ, Sobin LH. The morphology of cirrhosis. Recommendations on definition, nomenclature, and classification by a working group sponsored by the World Health Organization. J Clin Pathol 31: 395‐414, 1978.
 4.Apte MV, Pirola RC, Wilson JS. Pancreatic stellate cells: A starring role in normal and diseased pancreas. Front Physiol 3: 344, 2012.
 5.Apte MV, Wilson JS. Dangerous liaisons: Pancreatic stellate cells and pancreatic cancer cells. J Gastroenterol Hepatol 27(Suppl 2): 69‐74, 2012.
 6.Arthur MJ, Friedman SL, Roll FJ, Bissell DM. Lipocytes from normal rat liver release a neutral metalloproteinase that degrades basement membrane (type IV) collagen. J Clin Invest 84: 1076‐1085, 1989.
 7.Arthur MJ, Stanley A, Iredale JP, Rafferty JA, Hembry RM, Friedman SL. Secretion of 72 kDa type IV collagenase/gelatinase by cultured human lipocytes. Analysis of gene expression, protein synthesis and proteinase activity. Biochem J 287: 701‐707, 1992.
 8.Asahina K. Hepatic stellate cell progenitor cells. J Gastroenterol Hepatol 27(Suppl 2): 80‐84, 2012.
 9.Asahina K, Sato H, Yamasaki C, Kataoka M, Shiokawa M, Katayama S, Tateno C, Yoshizato K. Pleiotrophin/heparin‐binding growth‐associated molecule as a mitogen of rat hepatocytes and its role in regeneration and development of liver. Am J Pathol 160: 2191‐2205, 2002.
 10.Asahina K, Tsai SY, Li P, Ishii M, Maxson RE, Jr., Sucov HM, Tsukamoto H. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology 49: 998‐1011, 2009.
 11.Asahina K, Zhou B, Pu WT, Tsukamoto H. Septum transversum‐derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 53: 983‐995, 2011.
 12.Baba S, Fujii H, Hirose T, Yasuchika K, Azuma H, Hoppo T, Naito M, Machimoto T, Ikai I. Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol 40: 255‐260, 2004.
 13.Bach Kristensen D, Kawada N, Imamura K, Miyamoto Y, Tateno C, Seki S, Kuroki T, Yoshizato K. Proteome analysis of rat hepatic stellate cells. Hepatology 32: 268‐277, 2000.
 14.Bachem MG, Melchior R, Gressner AM. The role of thrombocytes in liver fibrogenesis: Effects of platelet lysate and thrombocyte‐derived growth factors on the mitogenic activity and glycosaminoglycan synthesis of cultured rat liver fat storing cells. J Clin Chem Clin Biochem 27: 555‐565, 1989.
 15.Baghy K, Iozzo RV, Kovalszky I. Decorin‐TGFbeta axis in hepatic fibrosis and cirrhosis. J Histochem Cytochem 60: 262‐268, 2012.
 16.Ballardini G, Groff P, Badiali dGL, Schuppan D, Bianchi FB. Ito cell heterogeneity: Desmin‐negative Ito cells in normal rat liver. Hepatology 19: 440‐446, 1994.
 17.Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 115: 209‐218, 2005.
 18.Bian EB, Huang C, Ma TT, Tao H, Zhang H, Cheng C, Lv XW, Li J. DNMT1‐mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol 264: 13‐22, 2012.
 19.Bioulac‐Sage P, Lafon ME, Saric J, Balabaud C. Nerves and perisinusoidal cells in human liver. J Hepatol 10: 105‐112, 1990.
 20.Bissell DM, Arenson DM, Maher JJ, Roll FJ. Support of cultured hepatocytes by a laminin‐rich gel. Evidence for a functionally significant subendothelial matrix in normal rat liver. J Clin Invest 79: 801‐812, 1987.
 21.Bissell DM, Wang SS, Jarnagin WR, Roll FJ. Cell‐specific expression of transforming growth factor‐beta in rat liver. Evidence for autocrine regulation of hepatocyte proliferation. J Clin Invest 96: 447‐455, 1995.
 22.Bonacchi A, Petrai I, Defranco RM, Lazzeri E, Annunziato F, Efsen E, Cosmi L, Romagnani P, Milani S, Failli P, Batignani G, Liotta F, Laffi G, Pinzani M, Gentilini P, Marra F. The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 125: 1060‐1076, 2003.
 23.Bonacchi A, Romagnani P, Romanelli RG, Efsen E, Annunziato F, Lasagni L, Francalanci M, Serio M, Laffi G, Pinzani M, Gentilini P, Marra F. Signal transduction by the chemokine receptor CXCR3: Activation of Ras/ERK, Src, and phosphatidylinositol 3‐kinase/Akt controls cell migration and proliferation in human vascular pericytes. J Biol Chem 276: 9945‐9954, 2001.
 24.Borkham‐Kamphorst E, van Roeyen CR, Ostendorf T, Floege J, Gressner AM, Weiskirchen R. Pro‐fibrogenic potential of PDGF‐D in liver fibrosis. J Hepatol 46: 1064‐1074, 2007.
 25.Botella LM, Sanchez‐Elsner T, Sanz‐Rodriguez F, Kojima S, Shimada J, Guerrero‐Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C. Transcriptional activation of endoglin and transforming growth factor‐beta signaling components by cooperative interaction between Sp1 and KLF6: Their potential role in the response to vascular injury. Blood 100: 4001‐4010, 2002.
 26.Bourd‐Boittin K, Bonnier D, Leyme A, Mari B, Tuffery P, Samson M, Ezan F, Baffet G, Theret N. Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta. Hepatology 54: 2173‐2184, 2011.
 27.Brasaemle DL, Wolins NE. Packaging of fat: An evolving model of lipid droplet assembly and expansion. J Biol Chem 287: 2273‐2279, 2012.
 28.Buers I, Hofnagel O, Ruebel A, Severs NJ, Robenek H. Lipid droplet associated proteins: An emerging role in atherogenesis. Histol Histopathol 26: 631‐642, 2011.
 29.Burt AD, Griffiths MR, Schuppan D, Voss B, MacSween RN. Ultrastructural localization of extracellular matrix proteins in liver biopsies using ultracryomicrotomy and immuno‐gold labelling. Histopathology 16: 53‐58, 1990.
 30.Byun JS, Suh YG, Yi HS, Lee YS, Jeong WI. 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.
 31.Canbay A, Feldstein AE, Higuchi H, Werneburg N, Grambihler A, Bronk SF, Gores GJ. Kupffer cell engulfment of apoptotic bodies stimulates death ligand and cytokine expression. Hepatology 38: 1188‐1198, 2003.
 32.Canbay A, Higuchi H, Bronk SF, Taniai M, Sebo TJ, Gores GJ. Fas enhances fibrogenesis in the bile duct ligated mouse: A link between apoptosis and fibrosis. Gastroenterology 123: 1323‐1330, 2002.
 33.Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest 83: 655‐663, 2003.
 34.Casini A, Pellegrini G, Ceni E, Salzano R, Parola M, Robino G, Milani S, Dianzani MU, Surrenti C. Human hepatic stellate cells express class I alcohol dehydrogenase and aldehyde dehydrogenase but not cytochrome P4502E1. J Hepatol 28: 40‐45, 1998.
 35.Cassiman D, Barlow A, Vander Borght S, Libbrecht L, Pachnis V. Hepatic stellate cells do not derive from the neural crest. J Hepatol 44: 1098‐1104, 2006.
 36.Cassiman D, Denef C, Desmet VJ, Roskams T. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 33: 148‐158, 2001.
 37.Challa AA, Vukmirovic M, Blackmon J, Stefanovic B. Withaferin‐A reduces type I collagen expression in vitro and inhibits development of myocardial fibrosis in vivo. PLoS One 7: e42989, 2012.
 38.Chan ES, Montesinos MC, Fernandez P, Desai A, Delano DL, Yee H, Reiss AB, Pillinger MH, Chen JF, Schwarzschild MA, Friedman SL, Cronstein BN. Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 148: 1144‐1155, 2006.
 39.Chan KM, Fu YH, Wu TJ, Hsu PY, Lee WC. Hepatic stellate cells promote the differentiation of embryonic stem cell‐derived definitive endodermal cells into hepatic progenitor cells. Hepatol Res 43: 648‐657, 2012.
 40.Chen L, Zhang W, Zhou QD, Yang HQ, Liang HF, Zhang BX, Long X, Chen XP. HSCs play a distinct role in different phases of oval cell‐mediated liver regeneration. Cell Biochem Funct 30: 588‐596, 2012.
 41.Chen SL, Zheng MH, Yang T, Song M, Chen YP. Disparate profiles of dys‐regulated miRNAs in activated hepatic stellate cells. Hepatology 57: 1285‐1286, 2013.
 42.Connolly MK, Bedrosian AS, Mallen‐St Clair J, Mitchell AP, Ibrahim J, Stroud A, Pachter HL, Bar‐Sagi D, Frey AB, Miller G. In liver fibrosis, dendritic cells govern hepatic inflammation in mice via TNF‐alpha. J Clin Invest 119: 3213‐3225, 2009.
 43.Costentin CE, Roudot‐Thoraval F, Zafrani ES, Medkour F, Pawlotsky JM, Mallat A, Hezode C. Association of caffeine intake and histological features of chronic hepatitis C. J Hepatol 54: 1123‐1129, 2011.
 44.Coulouarn C, Corlu A, Glaise D, Guenon I, Thorgeirsson SS, Clement B. Hepatocyte‐stellate cell cross‐talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 72: 2533‐2542, 2012.
 45.D'Ambrosio DN, Walewski JL, Clugston RD, Berk PD, Rippe RA, Blaner WS. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage. PLoS One 6: e24993, 2011.
 46.Dangi A, Sumpter TL, Kimura S, Stolz DB, Murase N, Raimondi G, Vodovotz Y, Huang C, Thomson AW, Gandhi CR. Selective expansion of allogeneic regulatory T cells by hepatic stellate cells: Role of endotoxin and implications for allograft tolerance. J Immunol 188: 3667‐3677, 2012.
 47.Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, Caviglia JM, Khiabanian H, Adeyemi A, Bataller R, Lefkowitch JH, Bower M, Friedman R, Sartor RB, Rabadan R, Schwabe RF. Promotion of Hepatocellular Carcinoma by the Intestinal Microbiota and TLR4. Cancer Cell 21: 504‐516, 2012.
 48.De Bleser PJ, Niki T, Rogiers V, Geerts A. Transforming growth factor‐beta gene expression in normal and fibrotic rat liver. J Hepatol 26: 886‐893, 1997. Leeuw AM, McCarthy SP, Geerts A, Knook DL. Purified rat liver fat‐storing cells in culture divide and contain collagen. Hepatology 4: 392‐403, 1984.
 50.De Minicis S, Brenner DA. NOX in liver fibrosis. Arch Biochem Biophys 462: 266‐272, 2007.
 51.Dooley S, Delvoux B, Lahme B, Mangasser‐Stephan K, Gressner AM. Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 31: 1094‐1106, 2000.
 52.Dranoff JA, Ogawa M, Kruglov EA, Gaca MD, Sevigny J, Robson SC, Wells RG. Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287: G417‐G424, 2004.
 53.Dranoff JA, Wells RG. Portal fibroblasts: Underappreciated mediators of biliary fibrosis. Hepatology 51: 1438‐1444, 2010.
 54.Ebrahimkhani MR, Oakley F, Murphy LB, Mann J, Moles A, Perugorria MJ, Ellis E, Lakey AF, Burt AD, Douglass A, Wright MC, White SA, Jaffre F, Maroteaux L, Mann DA. Stimulating healthy tissue regeneration by targeting the 5‐HT(2B) receptor in chronic liver disease. Nat Med 17: 1668‐1673, 2011.
 55.Elsharkawy AM, Oakley F, Mann DA. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10: 927‐939, 2005.
 56.Enzan H, Hayashi Y, Miyazaki E, Naruse K, Tao R, Kuroda N, Nakayama H, Kiyoku H, Hiroi M, Saibara T. Morphological aspects of hepatic fibrosis and Ito cells (hepatic stellate cells), with special reference to their myofibroblastic transformation. In: Tanikawa K and Ueno T, editors. Liver Diseases and Hepatic Sinusoidal Cells. Tokyo: Springer‐Verlag, 1999, p. 219‐231.
 57.Erkan M, Adler G, Apte MV, Bachem MG, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress TM, Habisch HJ, Hwang RF, Jaster R, Kleeff J, Kloppel G, Kordes C, Logsdon CD, Masamune A, Michalski CW, Oh J, Phillips PA, Pinzani M, Reiser‐Erkan C, Tsukamoto H, Wilson J. StellaTUM: Current consensus and discussion on pancreatic stellate cell research. Gut 61: 172‐178, 2012.
 58.Fallowfield JA, Iredale JP. Reversal of liver fibrosis and cirrhosis–an emerging reality. Scott Med J 49: 3‐6, 2004.
 59.Fibbi G, Pucci M, D'Alessio S, Grappone C, Pellegrini G, Salzano R, Casini A, Milani S, Del Rosso M. Transforming growth factor beta‐1 stimulates invasivity of hepatic stellate cells by engagement of the cell‐associated fibrinolytic system. Growth Factors 19: 87‐100, 2001.
 60.Fischer R, Cariers A, Reinehr R, Haussinger D. Caspase 9‐dependent killing of hepatic stellate cells by activated Kupffer cells. Gastroenterology 123: 845‐861, 2002.
 61.Fowell AJ, Collins JE, Duncombe DR, Pickering JA, Rosenberg WM, Benyon RC. Silencing tissue inhibitors of metalloproteinases (TIMPs) with short interfering RNA reveals a role for TIMP‐1 in hepatic stellate cell proliferation. Biochem Biophys Res Commun 407: 277‐282, 2011.
 62.Friedman SL. Seminars in medicine of the Beth Israel Hospital, Boston. The cellular basis of hepatic fibrosis. Mechanisms and treatment strategies. N Engl J Med 328: 1828‐1835, 1993.
 63.Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275: 2247‐2250, 2000.
 64.Friedman SL. Hepatic fibrosis‐Overview. Toxicology 254: 120‐129, 2008.
 65.Friedman SL. Hepatic stellate cells – protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88: 125‐172, 2008.
 66.Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 134: 1655‐1669, 2008.
 67.Friedman SL. Fibrogenic cell reversion underlies fibrosis regression in liver. Proc Natl Acad Sci U S A 109: 9230‐9231, 2012.
 68.Friedman SL, Arthur MJ. Reversing hepatic fibrosis. Sci Med 8: 194‐205, 2002.
 69.Friedman SL, Bansal MB. Reversal of hepatic fibrosis – fact or fantasy? Hepatology 43: S82‐S88, 2006.
 70.Friedman SL, Roll FJ, Boyles J, Arenson DM, Bissell DM. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 264: 10756‐10762, 1989.
 71.Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: The principal collagen‐producing cells of normal rat liver. Proc Natl Acad Sci U S A 82: 8681‐8685, 1985.
 72.Friedman SL, Wei S, Blaner WS. Retinol release by activated rat hepatic lipocytes: Regulation by Kupffer cell‐conditioned medium and PDGF. Am J Physiol 264: G947‐G952, 1993.
 73.Fritz D, Stefanovic B. RNA‐binding protein RBMS3 is expressed in activated hepatic stellate cells and liver fibrosis and increases expression of transcription factor Prx1. J Mol Biol 371: 585‐595, 2007.
 74.Frizell E, Liu SL, Abraham A, Ozaki I, Eghbali M, Sage EH, Zern MA. Expression of SPARC in normal and fibrotic livers. Hepatology 21: 847‐854, 1995.
 75.Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS. Expression of stem cell factor and its receptor, c kit, during liver regeneration from putative stem cells in adult rat. Lab Invest 70: 511‐516, 1994.
 76.Gao B, Radaeva S. Natural killer and natural killer T cells in liver fibrosis. Biochim Biophys Acta 1832: 1061‐1069, 2012.
 77.Gao B, Radaeva S, Park O. Liver natural killer and natural killer T cells: Immunobiology and emerging roles in liver diseases. J Leukoc Biol 86: 513‐528, 2009.
 78.Gao R, Brigstock DR. Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C‐terminal domain to integrin alpha(v)beta(3) and heparan sulfate proteoglycan. J Biol Chem 279: 8848‐8855, 2004.
 79.Gascon‐Barre M, Demers C, Mirshahi A, Neron S, Zalzal S, Nanci A. The normal liver harbors the vitamin D nuclear receptor in nonparenchymal and biliary epithelial cells. Hepatology 37: 1034‐1042, 2003.
 80.Geerts A. History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. Semin Liver Dis 21: 311‐335, 2001.
 81.Geerts A, Bouwens L, Wisse E. Ultrastructure and function of hepatic fat‐storing and pit cells. J Electr Micr Tech 14: 247‐256, 1990.
 82.Geerts A, Lazou JM, De Bleser P, Wisse E. Tissue distribution, quantitation and proliferation kinetics of fat‐storing cells in carbon tetrachloride‐injured rat liver. Hepatology 13: 1193‐1202, 1991.
 83.Geerts A, Vrijsen R, Rauterberg J, Burt A, Schellinck P, Wisse E. In vitro differentiation of fat‐storing cells parallels marked increase of collagen synthesis and secretion. J Hepatol 9: 59‐68, 1989.
 84.Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, Mick R, Janmey PA, Furth EE, Wells RG. Increased stiffness of the rat liver precedes matrix deposition: Implications for fibrosis. Am J Physiol Gastrointest Liver Physiol 293: G1147‐G1154, 2007.
 85.Ghiassi‐Nejad Z, Hernandez‐Gea V, Woodrell C, Lang UE, Dumic K, Kwong A, Friedman SL. Reduced hepatic stellate cell expression of Kruppel‐like factor 6 tumor suppressor isoforms amplifies fibrosis during acute and chronic rodent liver injury. Hepatology 57: 786‐796, 2013.
 86.Giampieri MP, Jezequel AM, Orlandi F. The lipocytes in normal human liver. Digestion 22: 165‐169, 1981.
 87.Gong Y, Hart E, Shchurin A, Hoover‐Plow J. Inflammatory macrophage migration requires MMP‐9 activation by plasminogen in mice. J Clin Invest 118: 3012‐3024, 2008.
 88.Gorbig MN, Gines P, Bataller R, Nicolas JM, Garcia‐Ramallo E, Cejudo P, Sancho‐Bru P, Jimenez W, Arroyo V, Rodes J. Human hepatic stellate cells secrete adrenomedullin: Potential autocrine factor in the regulation of cell contractility. J Hepatol 34: 222‐229, 2001.
 89.Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol 43: 222‐229, 2011.
 90.Gressner AM. The cell biology of liver fibrogenesis ‐ an imbalance of proliferation, growth arrest and apoptosis of myofibroblasts. Cell Tissue Res 292: 447‐452, 1998.
 91.Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of tgf‐Beta in hepatic fibrosis. Front Biosci 7: D793‐D807, 2002.
 92.Gressner OA, Gressner AM. Connective tissue growth factor: A fibrogenic master switch in fibrotic liver diseases. Liver Int 28: 1065‐1079, 2008.
 93.Guo CJ, Pan Q, Li DG, Sun H, Liu BW. 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.
 94.Guo J, Loke J, Zheng F, Hong F, Yea S, Fukata M, Tarocchi M, Abar OT, Huang H, Sninsky JJ, Friedman SL. Functional linkage of cirrhosis‐predictive single nucleotide polymorphisms of Toll‐like receptor 4 to hepatic stellate cell responses. Hepatology 49: 960‐968, 2009.
 95.Hammel P, Couvelard A, O'Toole D, Ratouis A, Sauvanet A, Flejou JF, Degott C, Belghiti J, Bernades P, Valla D, Ruszniewski P, Levy P. Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct. N Engl J Med 344: 418‐423, 2001.
 96.Han YP, Yan C, Zhou L, Qin L, Tsukamoto H. A matrix metalloproteinase‐9 activation cascade by hepatic stellate cells in trans‐differentiation in the three‐dimensional extracellular matrix. J Biol Chem 282: 12928‐12939, 2007.
 97.Hartland SN, Murphy F, Aucott RL, Abergel A, Zhou X, Waung J, Patel N, Bradshaw C, Collins J, Mann D, Benyon RC, Iredale JP. Active matrix metalloproteinase‐2 promotes apoptosis of hepatic stellate cells via the cleavage of cellular N‐cadherin. Liver Int 29: 966‐978, 2009.
 98.He H, Mennone A, Boyer JL, Cai SY. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct‐ligated rats and human hepatic cells. Hepatology 53: 548‐557, 2011.
 99.He Y, Huang C, Zhang SP, Sun X, Long XR, Li J. The potential of microRNAs in liver fibrosis. Cell Signal 24: 2268‐2272, 2012.
 100.Hellemans K, Verbuyst P, Quartier E, Schuit F, Rombouts K, Chandraratna RA, Schuppan D, Geerts A. Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. Hepatology 39: 97‐108, 2004.
 101.Hendriks HF, Verhoofstad WA, Brouwer A, de Leeuw AM, Knook DL. Perisinusoidal fat‐storing cells are the main vitamin A storage sites in rat liver. Exp Cell Res 160: 138‐149, 1985.
 102.Hernandez‐Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 6: 425‐456, 2011.
 103.Hernandez‐Gea V, Friedman SL. Autophagy fuels tissue fibrogenesis. Autophagy 8: 849‐850, 2012.
 104.Hernandez‐Gea V, Ghiassi‐Nejad Z, Rozenfeld R, Gordon R, Fiel MI, Yue Z, Czaja MJ, Friedman SL. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 142: 938‐946, 2012.
 105.Hernandez‐Gea V, Hilscher M, Rozenfeld R, Lim MP, Nieto N, Werner S, Devi LA, Friedman SL. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol 59: 98‐104, 2013.
 106.Heymann F, Trautwein C, Tacke F. Monocytes and macrophages as cellular targets in liver fibrosis. Inflamm Allergy Drug Targets 8: 307‐318, 2009.
 107.Holt AP, Haughton EL, Lalor PF, Filer A, Buckley CD, Adams DH. Liver myofibroblasts regulate infiltration and positioning of lymphocytes in human liver. Gastroenterology 136: 705‐714, 2009.
 108.Hong F, Tuyama A, Lee TF, Loke J, Agarwal R, Cheng X, Garg A, Fiel MI, Schwartz M, Walewski J, Branch A, Schecter AD, Bansal MB. Hepatic stellate cells express functional CXCR4: Role in stromal cell‐derived factor‐1alpha‐mediated stellate cell activation. Hepatology 49: 2055‐2067, 2009.
 109.Hsieh CC, Chou HS, Fung JJ, Qian S, Lu L. The role of liver stromal cells in dendritic cells development in mice. Transplant Proc 42: 4279‐4281, 2010.
 110.Huang G, Brigstock DR. Integrin expression and function in the response of primary culture hepatic stellate cells to connective tissue growth factor (CCN2). J Cell Mol Med 15: 1087‐1095, 2011.
 111.Huang G, Brigstock DR. Regulation of hepatic stellate cells by connective tissue growth factor. Front Biosci 17: 2495‐2507, 2012.
 112.Iizuka M, Ogawa T, Enomoto M, Motoyama H, Yoshizato K, Ikeda K, Kawada N. Induction of microRNA‐214‐5p in human and rodent liver fibrosis. Fibrogenesis Tissue Repair 5: 12, 2012.
 113.Ikeda K, Wakahara T, Wang YQ, Kadoya H, Kawada N, Kaneda K. In vitro migratory potential of rat quiescent hepatic stellate cells and its augmentation by cell activation. Hepatology 29: 1760‐1767, 1999.
 114.Ikeda N, Murata S, Maruyama T, Tamura T, Nozaki R, Kawasaki T, Fukunaga K, Oda T, Sasaki R, Homma M, Ohkohchi N. Platelet‐derived adenosine 5′‐triphosphate suppresses activation of human hepatic stellate cell: In vitro study. Hepatol Res 42: 91‐102, 2012.
 115.Imai K, Senoo H. Morphology of sites of adhesion between hepatic stellate cells (vitamin A‐storing cells) and a three‐dimensional extracellular matrix. Anat Rec 250: 430‐437, 1998.
 116.Inagaki Y, Kushida M, Higashi K, Itoh J, Higashiyama R, Hong YY, Kawada N, Namikawa K, Kiyama H, Bou‐Gharios G, Watanabe T, Okazaki I, Ikeda K. Cell type‐specific intervention of transforming growth factor beta/Smad signaling suppresses collagen gene expression and hepatic fibrosis in mice. Gastroenterology 129: 259‐268, 2005.
 117.Inagaki Y, Mamura M, Kanamaru Y, Greenwel P, Nemoto T, Takehara K, Ten Dijke P, Nakao A. Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol 187: 117‐123, 2001.
 118.Inagaki Y, Nemoto T, Kushida M, Sheng Y, Higashi K, Ikeda K, Kawada N, Shirasaki F, Takehara K, Sugiyama K, Fujii M, Yamauchi H, Nakao A, De Crombrugghe B, Watanabe T, Okazaki I. Interferon alfa down‐regulates collagen gene transcription and suppresses experimental hepatic fibrosis in mice. Hepatology 38: 890‐899, 2003.
 119.Inagaki Y, Truter S, Greenwel P, Rojkind M, Unoura M, Kobayashi K, Ramirez F. Regulation of the alpha 2(I) collagen gene transcription in fat‐storing cells derived from a cirrhotic liver. Hepatology 22: 573‐579, 1995.
 120.Iredale JP. Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 21: 427‐436, 2001.
 121.Iredale JP. Models of liver fibrosis: Exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Invest 117: 539‐548, 2007.
 122.Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ. 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.
 123.Issa R, Williams E, Trim N, Kendall T, Arthur MJ, Reichen J, Benyon RC, Iredale JP. Apoptosis of hepatic stellate cells: Involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut 48: 548‐557, 2001.
 124.Issa R, Zhou X, Constandinou CM, Fallowfield J, Millward‐Sadler H, Gaca MD, Sands E, Suliman I, Trim N, Knorr A, Arthur MJ, Benyon RC, Iredale JP. Spontaneous recovery from micronodular cirrhosis: Evidence for incomplete resolution associated with matrix cross‐linking. Gastroenterology 126: 1795‐1808, 2004.
 125.Jarnagin WR, Rockey DC, Koteliansky VE, Wang SS, Bissell DM. Expression of variant fibronectins in wound healing: Cellular source and biological activity of the EIIIA segment in rat hepatic fibrogenesis. J Cell Biol 127: 2037‐2048, 1994.
 126.Jezequel AM, Novelli G, Venturini C, Orlandi F. Quantitative analysis of the perisinusoidal cells in human liver; the lipocytes. Front Gastrointestinal Res 8: 85‐90, 1984.
 127.Ji J, Yu F, Ji Q, Li Z, Wang K, Zhang J, Lu J, Chen L, Qun E, Zeng Y, Ji Y. Comparative proteomic analysis of rat hepatic stellate cell activation: A comprehensive view and suppressed immune response. Hepatology 56: 332‐349, 2012.
 128.Ji J, Zhang J, Huang G, Qian J, Wang X, Mei S. Over‐expressed microRNA‐27a and 27b influence fat accumulation and cell proliferation during rat hepatic stellate cell activation. FEBS Lett 583: 759‐766, 2009.
 129.Jiang JX, Chen X, Hsu DK, Baghy K, Serizawa N, Scott F, Takada Y, Fukada H, Chen J, Devaraj S, Adamson R, Liu FT, Torok NJ. Galectin‐3 modulates phagocytosis‐induced stellate cell activation and liver fibrosis in vivo. Am J Physiol Gastrointest Liver Physiol 302: G439‐G446, 2012.
 130.Jiang Z, Chen Y, Feng X, Jiang J, Chen T, Xie H, Zhou L, Zheng S. Hepatic stellate cells promote immunotolerance following orthotopic liver transplantation in rats via induction of T cell apoptosis and regulation of Th2/Th3‐like cell cytokine production. Exp Ther Med 5: 165‐169, 2013.
 131.Jiao J, Sastre D, Fiel MI, Lee UE, Ghiassi‐Nejad Z, Ginhoux F, Vivier E, Friedman SL, Merad M, Aloman C. Dendritic cell regulation of carbon tetrachloride‐induced murine liver fibrosis regression. Hepatology 55: 244‐255, 2012.
 132.Kageyama Y, Ikeda H, Watanabe N, Nagamine M, Kusumoto Y, Yashiro M, Satoh Y, Shimosawa T, Shinozaki K, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Yokota H, Koyama T, Ishimaru K, Okamoto Y, Takuwa Y, Koike K, Yatomi Y. Antagonism of sphingosine 1‐phosphate receptor 2 causes a selective reduction of portal vein pressure in bile duct‐ligated rodents. Hepatology 56: 1427‐1438, 2012.
 133.Kalinichenko VV, Bhattacharyya D, Zhou Y, Gusarova GA, Kim W, Shin B, Costa RH. Foxf1+/− mice exhibit defective stellate cell activation and abnormal liver regeneration following CCl4 injury. Hepatology 37: 107‐117, 2003.
 134.Kang N, Gores GJ, Shah VH. Hepatic stellate cells: Partners in crime for liver metastases? Hepatology 54: 707‐713, 2011.
 135.Kaur S, Tripathi D, Dongre K, Garg V, Rooge S, Mukopadhyay A, Sakhuja P, Sarin SK. Increased number and function of endothelial progenitor cells stimulate angiogenesis by resident liver sinusoidal endothelial cells (SECs) in cirrhosis through paracrine factors. J Hepatol 57: 1193‐1198, 2012.
 136.Kawashima R, Mochida S, Matsui A, YouLuTu ZY, Ishikawa K, Toshima K, Yamanobe F, Inao M, Ikeda H, Ohno A, Nagoshi S, Uede T, Fujiwara K. Expression of osteopontin in Kupffer cells and hepatic macrophages and Stellate cells in rat liver after carbon tetrachloride intoxication: A possible factor for macrophage migration into hepatic necrotic areas. Biochem Biophys Res Commun 256: 527‐531, 1999.
 137.Kendall TJ, Hennedige S, Aucott RL, Hartland SN, Vernon MA, Benyon RC, Iredale JP. p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology 49: 901‐910, 2009.
 138.Khimji AK, Rockey DC. Endothelin and hepatic wound healing. Pharmacol Res 63: 512‐518, 2011.
 139.Kida Y, Xia Z, Zheng S, Mordwinkin NM, Louie SG, Zheng SG, Feng M, Shi H, Duan Z, Han YP. Interleukin‐1 as an injury signal mobilizes retinyl esters in hepatic stellate cells through down regulation of lecithin retinol acyltransferase. PLoS One 6: e26644, 2011.
 140.Kikuchi S, Griffin CT, Wang SS, Bissell DM. Role of CD44 in epithelial wound repair: Migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6. J Biol Chem 280: 15398‐15404, 2005.
 141.Kinnman N, Francoz C, Barbu V, Wendum D, Rey C, Hultcrantz R, Poupon R, Housset C. The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet‐derived growth factor during liver fibrogenesis. Lab Invest 83: 163‐173, 2003.
 142.Kinnman N, Hultcrantz R, Barbu V, Rey C, Wendum D, Poupon R, Housset C. PDGF‐mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury. Lab Invest 80: 697‐707, 2000.
 143.Kisseleva T, Cong M, Paik Y, Scholten D, Jiang C, Benner C, Iwaisako K, Moore‐Morris T, Scott B, Tsukamoto H, Evans SM, Dillmann W, Glass CK, Brenner DA. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci U S A 109: 9448‐9453, 2012.
 144.Kluwe J, Wongsiriroj N, Troeger JS, Gwak GY, Dapito DH, Pradere JP, Jiang H, Siddiqi M, Piantedosi R, O'Byrne SM, Blaner WS, Schwabe RF. Absence of hepatic stellate cell retinoid lipid droplets does not enhance hepatic fibrosis but decreases hepatic carcinogenesis. Gut 60: 1260‐1268, 2011.
 145.Knittel T, Mehde M, Kobold D, Saile B, Dinter C, Ramadori G. Expression patterns of matrix metalloproteinases and their inhibitors in parenchymal and non‐parenchymal cells of rat liver: Regulation by TNF‐alpha and TGF‐beta1. J Hepatol 30: 48‐60, 1999.
 146.Knolle PA, Gerken G. Local control of the immune response in the liver. Immunol Rev 174: 21‐34, 2000.
 147.Kodama T, Takehara T, Hikita H, Shimizu S, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Tadokoro S, Ido A, Tsubouchi H, Hayashi N. Thrombocytopenia exacerbates cholestasis‐induced liver fibrosis in mice. Gastroenterology 138: 2487‐2498, 2498 e2481‐2487, 2010.
 148.Kojima N, Sato M, Imai K, Miura M, Matano Y, Senoo H. Hepatic stellate cells (vitamin A‐storing cells) change their cytoskeleton structure by extracellular matrix components through a signal transduction system. Histochem Cell Biol 110: 121‐128, 1998.
 149.Kojima S, Hayashi S, Shimokado K, Suzuki Y, Shimada J, Crippa MP, Friedman SL. Transcriptional activation of urokinase by the Kruppel‐like factor Zf9/COPEB activates latent TGF‐beta1 in vascular endothelial cells. Blood 95: 1309‐1316, 2000.
 150.Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880‐884, 2006.
 151.Komatsu M, Wang QJ, Holstein GR, Friedrich VL, Jr., Iwata J, Kominami E, Chait BT, Tanaka K, Yue Z. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci U S A 104: 14489‐14494, 2007.
 152.Kong X, Horiguchi N, Mori M, Gao B. Cytokines and STATs in liver fibrosis. Front Physiol 3: 69, 2012.
 153.Kordes C, Sawitza I, Gotze S, Haussinger D. Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 7: e51878, 2012.
 154.Kordes C, Sawitza I, Muller‐Marbach A, Ale‐Agha N, Keitel V, Klonowski‐Stumpe H, Haussinger D. CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352: 410‐417, 2007.
 155.Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW. Senescence of activated stellate cells limits liver fibrosis. Cell 134: 657‐667, 2008.
 156.Kruglov EA, Nathanson RA, Nguyen T, Dranoff JA. Secretion of MCP‐1/CCL2 by bile duct epithelia induces myofibroblastic transdifferentiation of portal fibroblasts. Am J Physiol Gastrointest Liver Physiol 290: G765‐G771, 2006.
 157.Kubota H, Yao HL, Reid LM. Identification and characterization of vitamin A‐storing cells in fetal liver: Implications for functional importance of hepatic stellate cells in liver development and hematopoiesis. Stem Cells 25: 2339‐2349, 2007.
 158.Laleman W, Van Landeghem L, Severi T, Vander Elst I, Zeegers M, Bisschops R, Van Pelt J, Roskams T, Cassiman D, Fevery J, Nevens F. Both Ca2+ ‐dependent and ‐independent pathways are involved in rat hepatic stellate cell contraction and intrahepatic hyperresponsiveness to methoxamine. Am J Physiol Gastrointest Liver Physiol 292: G556‐G564, 2007.
 159.Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and angiogenesis: A new function for the liver‐specific pericyte? Hepatology 45: 817‐825, 2007.
 160.Lee SJ, Friedman SL, Whalen R, Boyer TD. Cellular sources of glutathione S‐transferase P in primary cultured rat hepatocytes: Localization by in situ hybridization. Biochem J 299: 79‐83, 1994.
 161.Lee TF, Mak KM, Rackovsky O, Lin YL, Kwong AJ, Loke JC, Friedman SL. Downregulation of hepatic stellate cell activation by retinol and palmitate mediated by adipose differentiation‐related protein (ADRP). J Cell Physiol 223: 648‐657, 2010.
 162.Lemoinne S, Cadoret A, Mourabit HE, Thabut D, Housset C. Origins and functions of liver myofibroblasts. Biochim Biophys Acta 1832: 948‐954, 2013.
 163.Li J, Ghazwani M, Zhang Y, Lu J, Fan J, Gandhi CR, Li S. miR‐122 regulates collagen production via targeting hepatic stellate cells and suppressing P4HA1 expression. J Hepatol 58: 522‐528, 2013.
 164.Li T, Shi Z, Rockey DC. Preproendothelin‐1 expression is negatively regulated by IFNgamma during hepatic stellate cell activation. Am J Physiol Gastrointest Liver Physiol 302: G948‐G957, 2012.
 165.Li Y, Wang J, Asahina K. Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial‐mesenchymal transition in liver injury. Proc Natl Acad Sci U S A 110: 2324‐2329, 2013.
 166.Libbrecht L, Cassiman D, Desmet V, Roskams T. The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver. Liver 22: 252‐258, 2002.
 167.Lindquist J, Stefanovic B, Brenner D. Regulation of collagen alpha1(I) expression in hepatic stellate cells. J Gastroenterol 35(Suppl 12): 80‐83, 2000.
 168.Liu Z, Rossen EV, Timmermans JP, Geerts A, van Grunsven LA, Reynaert H. Distinct roles for non‐muscle myosin II isoforms in mouse hepatic stellate cells. J Hepatol 54: 132‐141, 2011.
 169.Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, Zhao Z, Thapar V, Joyce JA, Krizhanovsky V, Lowe SW. Non‐Cell‐Autonomous Tumor Suppression by p53. Cell 153: 449‐460, 2013.
 170.Magness ST, Bataller R, Yang L, Brenner DA. A dual reporter gene transgenic mouse demonstrates heterogeneity in hepatic fibrogenic cell populations. Hepatology 40: 1151‐1159, 2004.
 171.Maher JJ, McGuire RF. Extracellular matrix gene expression increases preferentially in rat lipocytes and sinusoidal endothelial cells during hepatic fibrosis in vivo. J Clin Invest 86: 1641‐1648, 1990.
 172.Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, Mann DA. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 138: 705‐714, 714 e701‐704, 2010.
 173.Mann J, Mann DA. Transcriptional regulation of hepatic stellate cells. Adv Drug Deliv Rev 61: 497‐512, 2009.
 174.Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: Implications for wound healing and fibrogenesis. Cell Death Differ 14: 275‐285, 2007.
 175.Manojlovic Z, Stefanovic B. A novel role of RNA helicase A in regulation of translation of type I collagen mRNAs. RNA 18: 321‐334, 2012.
 176.Marra F, Romanelli RG, Giannini C, Failli P, Pastacaldi S, Arrighi MC, Pinzani M, Laffi G, Montalto P, Gentilini P. Monocyte chemotactic protein‐1 as a chemoattractant for human hepatic stellate cells. Hepatology 29: 140‐148, 1999.
 177.Marsden ER, Hu Z, Fujio K, Nakatsukasa H, Thorgeirsson SS, Evarts RP. Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation. Lab Invest 67: 427‐433, 1992.
 178.Matsumoto K, Miki R, Nakayama M, Tatsumi N, Yokouchi Y. Wnt9a secreted from the walls of hepatic sinusoids is essential for morphogenesis, proliferation, and glycogen accumulation of chick hepatic epithelium. Dev Biol 319: 234‐247, 2008.
 179.Mehal WZ, Friedman SL. The role of inflammation and immunity in the pathogenesis of liver fibrosis. In: Gershwin ME, Veirling JM, Manns MP, editors. Liver Immunology. Totowa, New Jersey: Humana Press, 2007, p. 99‐109.
 180.Melton AC, Yee HF. Hepatic stellate cell protrusions couple platelet‐derived growth factor‐BB to chemotaxis. Hepatology 45: 1446‐1453, 2007.
 181.Meng F, Wang K, Aoyama T, Grivennikov SI, Paik Y, Scholten D, Cong M, Iwaisako K, Liu X, Zhang M, Osterreicher CH, Stickel F, Ley K, Brenner DA, Kisseleva T. Interleukin‐17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 143: 765‐776 e761‐763, 2012.
 182.Meyer DH, Bachem MG, Gressner AM. Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell‐derived transforming growth factors type beta 1 and type alpha. Biochem Biophys Res Commun 171: 1122‐1129, 1990.
 183.Milani S, Herbst H, Schuppan D, Grappone C, Pellegrini G, Pinzani M, Casini A, Calabró A, Ciancio G, Stefanini F, Ciancio AK, Surrenti C. Differential expression of matrix‐metalloproteinase‐1 and ‐2 genes in normal and fibrotic human liver. Am J Pathol 144: 528‐537, 1994.
 184.Miura K, Nagai H, Ueno Y, Goto T, Mikami K, Nakane K, Yoneyama K, Watanabe D, Terada K, Sugiyama T, Imai K, Senoo H, Watanabe S. Epimorphin is involved in differentiation of rat hepatic stem‐like cells through cell‐cell contact. Biochem Biophys Res Commun 311: 415‐423, 2003.
 185.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.
 186.Miyata E, Masuya M, Yoshida S, Nakamura S, Kato K, Sugimoto Y, Shibasaki T, Yamamura K, Ohishi K, Nishii K, Ishikawa F, Shiku H, Katayama N. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 111: 2427‐2435, 2008.
 187.Modi AA, Feld JJ, Park Y, Kleiner DE, Everhart JE, Liang TJ, Hoofnagle JH. Increased caffeine consumption is associated with reduced hepatic fibrosis. Hepatology 51: 201‐209, 2010.
 188.Moriwaki H, Blaner WS, Piantedosi R, Goodman DS. Effects of dietary retinoid and triglyceride on the lipid composition of rat liver stellate cells and stellate cell lipid droplets. J Lipid Res 29: 1523‐1534, 1988.
 189.Muhanna N, Abu Tair L, Doron S, Amer J, Azzeh M, Mahamid M, Friedman S, Safadi R. Amelioration of hepatic fibrosis by NK cell activation. Gut 60: 90‐98, 2011.
 190.Muhanna N, Doron S, Wald O, Horani A, Eid A, Pappo O, Friedman SL, Safadi R. Activation of hepatic stellate cells after phagocytosis of lymphocytes: A novel pathway of fibrogenesis. Hepatology 48: 963‐977, 2008.
 191.Mullhaupt B, Feren A, Fodor E, Jones A. Liver expression of epidermal growth factor RNA. Rapid increases in immediate‐early phase of liver regeneration. J Biol Chem 269: 19667‐19670, 1994.
 192.Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ, Benyon C, Iredale JP. 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.
 193.Nieto N, Friedman SL, Cederbaum AI. Cytochrome P450 2E1‐derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells. J Biol Chem 277: 9853‐9864, 2002.
 194.Niiya M, Uemura M, Zheng XW, Pollak ES, Dockal M, Scheiflinger F, Wells RG, Zheng XL. Increased ADAMTS‐13 proteolytic activity in rat hepatic stellate cells upon activation in vitro and in vivo. J Thromb Haemost 4: 1063‐1070, 2006.
 195.Niki T, De Bleser PJ, Xu G, Van Den Berg K, Wisse E, Geerts A. Comparison of glial fibrillary acidic protein and desmin staining in normal and CCl4‐induced fibrotic rat livers. Hepatology 23: 1538‐1545, 1996.
 196.Noetel A, Elfimova N, Altmuller J, Becker C, Becker D, Lahr W, Nurnberg P, Wasmuth H, Teufel A, Buttner R, Dienes HP, Odenthal M. Next generation sequencing of the Ago2 interacting transcriptome identified chemokine family members as novel targets of neuronal microRNAs in hepatic stellate cells. J Hepatol 58: 335‐341, 2013.
 197.Noetel A, Kwiecinski M, Elfimova N, Huang J, Odenthal M. microRNA are central players in anti‐ and profibrotic gene regulation during liver fibrosis. Front Physiol 3: 49, 2012.
 198.Novo E, Busletta C, Bonzo LV, Povero D, Paternostro C, Mareschi K, Ferrero I, David E, Bertolani C, Caligiuri A, Cannito S, Tamagno E, Compagnone A, Colombatto S, Marra F, Fagioli F, Pinzani M, Parola M. 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.
 199.Novo E, Cannito S, Zamara E, Valfre di Bonzo L, Caligiuri A, Cravanzola C, Compagnone A, Colombatto S, Marra F, Pinzani M, Parola M. Proangiogenic cytokines as hypoxia‐dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol 170: 1942‐1953, 2007.
 200.Novo E, Povero D, Busletta C, Paternostro C, di Bonzo LV, Cannito S, Compagnone A, Bandino A, Marra F, Colombatto S, David E, Pinzani M, Parola M. The biphasic nature of hypoxia‐induced directional migration of activated human hepatic stellate cells. J Pathol 226: 588‐597, 2012.
 201.Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S, Shlomchik MJ, Koteliansky V, Hochman PS, Ibraghimov A. Attenuated liver fibrosis in the absence of B cells. J Clin Invest 115: 3072‐3082, 2005.
 202.Oakley F, Meso M, Iredale JP, Green K, Marek CJ, Zhou X, May MJ, Millward‐Sadler H, Wright MC, Mann DA. Inhibition of inhibitor of kappaB kinases stimulates hepatic stellate cell apoptosis and accelerated recovery from rat liver fibrosis. Gastroenterology 128: 108‐120, 2005.
 203.Oakley F, Trim N, Constandinou CM, Ye W, Gray AM, Frantz G, Hillan K, Kendall T, Benyon RC, Mann DA, Iredale JP. Hepatocytes express nerve growth factor during liver injury: Evidence for paracrine regulation of hepatic stellate cell apoptosis. Am J Pathol 163: 1849‐1858, 2003.
 204.Odena G, Bataller R. Actin‐binding proteins as molecular targets to modulate hepatic stellate cell proliferation. Focus on “MARCKS actin‐binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells”. Am J Physiol Cell Physiol 303: C355‐C356, 2012.
 205.Ogawa T, Enomoto M, Fujii H, Sekiya Y, Yoshizato K, Ikeda K, Kawada N. MicroRNA‐221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut 61: 1600‐1609, 2012.
 206.Ohata M, Lin M, Satre M, Tsukamoto H. Diminished retinoic acid signaling in hepatic stellate cells in cholestatic liver fibrosis. Am J Physiol 272: G589‐G596, 1997.
 207.Okuno M, Moriwaki H, Imai S, Muto Y, Kawada N, Suzuki Y, Kojima S. Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF‐beta in liver stellate cells. Hepatology 26: 913‐921, 1997.
 208.Olaso E, Arteta B, Benedicto A, Crende O, Friedman SL. Loss of discoidin domain receptor 2 promotes hepatic fibrosis after chronic carbon tetrachloride through altered paracrine interactions between hepatic stellate cells and liver‐associated macrophages. Am J Pathol 179: 2894‐2904, 2011.
 209.Olaso E, Salado C, Egilegor E, Gutierrez V, Santisteban A, Sancho‐Bru P, Friedman SL, Vidal‐Vanaclocha F. Proangiogenic role of tumor‐activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 37: 674‐685, 2003.
 210.Olsen AL, Sackey BK, Marcinkiewicz C, Boettiger D, Wells RG. Fibronectin extra domain‐A promotes hepatic stellate cell motility but not differentiation into myofibroblasts. Gastroenterology 142: 928‐937 e923, 2012.
 211.Ong A, Wong VW, Wong GL, Chan HL. The effect of caffeine and alcohol consumption on liver fibrosis ‐ a study of 1045 Asian hepatitis B patients using transient elastography. Liver Int 31: 1047‐1053, 2011.
 212.Paik YH, Iwaisako K, Seki E, Inokuchi S, Schnabl B, Osterreicher CH, Kisseleva T, Brenner DA. The nicotinamide adenine dinucleotide phosphate oxidase (NOX) homologues NOX1 and NOX2/gp91(phox) mediate hepatic fibrosis in mice. Hepatology 53: 1730‐1741, 2011.
 213.Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA. Toll‐like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37: 1043‐1055, 2003.
 214.Parsons CJ, Stefanovic B, Seki E, Aoyama T, Latour AM, Marzluff WF, Rippe RA, Brenner DA. Mutation of the 5′‐untranslated region stem‐loop structure inhibits alpha1(I) collagen expression in vivo. J Biol Chem 286: 8609‐8619, 2011.
 215.Passino MA, Adams RA, Sikorski SL, Akassoglou K. Regulation of hepatic stellate cell differentiation by the neurotrophin receptor p75NTR. Science 315: 1853‐1856, 2007.
 216.Patsenker E, Stickel F. Role of integrins in fibrosing liver diseases. Am J Physiol Gastrointest Liver Physiol 301: G425‐G434, 2011.
 217.Perez‐Tamayo R. Cirrhosis of the liver: A reversible disease? Pathol Annu 14(Pt 2): 183‐213, 1979.
 218.Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, White SA, Burt AD, Oakley F, Tsukamoto H, Mann DA, Mann J. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 56: 1129‐1139, 2012.
 219.Pintilie DG, Shupe TD, Oh SH, Salganik SV, Darwiche H, Petersen BE. Hepatic stellate cells' involvement in progenitor‐mediated liver regeneration. Lab Invest 90: 1199‐1208, 2010.
 220.Pinzani M. PDGF and signal transduction in hepatic stellate cells. Front Biosci 7: d1720‐d1726, 2002.
 221.Pinzani M, Milani S, De FR, Grappone C, Caligiuri A, Gentilini A, Tosti GC, Maggi M, Failli P, Ruocco C, Gentilini P. Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110: 534‐548, 1996.
 222.Popov Y, Patsenker E, Stickel F, Zaks J, Bhaskar KR, Niedobitek G, Kolb A, Friess H, Schuppan D. Integrin alphavbeta6 is a marker of the progression of biliary and portal liver fibrosis and a novel target for antifibrotic therapies. J Hepatol 48: 453‐464, 2008.
 223.Popper H, Schaffner F. Hepatic cirrhosis. A problem in communication. Isr J Med Sci 4: 1‐7, 1968.
 224.Popper H, Udenfriend S. Hepatic fibrosis. Correlation of biologic and morphologic investigations. Am J Med 49: 707‐721, 1970.
 225.Putz‐Bankuti C, Pilz S, Stojakovic T, Scharnagl H, Pieber TR, Trauner M, Obermayer‐Pietsch B, Stauber RE. Association of 25‐hydroxyvitamin D levels with liver dysfunction and mortality in chronic liver disease. Liver Int 32: 845‐851, 2012.
 226.Qin L, Han YP. Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: Implication in tissue fibrosis. Am J Pathol 177: 1915‐1928, 2010.
 227.Racine‐Samson L, Rockey DC, Bissell DM. Expression of the collagen‐binding integrins alpha1 beta1 and alpha 2 beta1 during activation of rat hepatic stellate cells in vivo. J Biol Chem 272(49): 30911‐30917, 1997.
 228.Radaeva S, Sun R, Jaruga B, Nguyen VT, Tian Z, Gao B. Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D‐dependent and tumor necrosis factor‐related apoptosis‐inducing ligand‐dependent manners. Gastroenterology 130: 435‐452, 2006.
 229.Radbill BD, Gupta R, Ramirez MC, DiFeo A, Martignetti JA, Alvarez CE, Friedman SL, Narla G, Vrabie R, Bowles R, Saiman Y, Bansal MB. Loss of matrix metalloproteinase‐2 amplifies murine toxin‐induced liver fibrosis by upregulating collagen I expression. Dig Dis Sci 56: 406‐416, 2011.
 230.Ramachandran P, Iredale JP. Macrophages: Central regulators of hepatic fibrogenesis and fibrosis resolution. J Hepatol 56: 1417‐1419, 2012.
 231.Ramachandran P, Pellicoro A, Vernon MA, Boulter L, Aucott RL, Ali A, Hartland SN, Snowdon VK, Cappon A, Gordon‐Walker TT, Williams MJ, Dunbar DR, Manning JR, van Rooijen N, Fallowfield JA, Forbes SJ, Iredale JP. Differential Ly‐6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci U S A 109: E3186‐E3195, 2012.
 232.Ramadori G, Neubauer K, Odenthal M, Nakamura T, Knittel T, Schwogler S, Meyer zum Buschenfelde KH. The gene of hepatocyte growth factor is expressed in fat‐storing cells of rat liver and is downregulated during cell growth and by transforming growth factor‐beta. BBRC 183: 739‐742, 1992.
 233.Ramadori G, Rieder H, Theiss F, Meyer zum Buschenfelde KH. Fat‐storing (Ito) cells of rat liver synthesize and secrete apolipoproteins: Comparison with hepatocytes. Gastroenterology 97: 163‐172, 1989.
 234.Ramadori G, Veit T, Schwogler S, Dienes HP, Knittel T, Rieder H, Meyer zum Buschenfelde KH. Expression of the gene of the alpha smooth muscle alpha actin isoform in rat liver and in rat fat‐storing (ITO) cells. Virchows Arch B Cell Pathol Incl Mol Pathol 59: 349‐357, 1990.
 235.Ramm GA, Britton RS, O'Neill R, Blaner WS, Bacon BR. Vitamin A‐poor lipocytes: A novel desmin‐negative lipocyte subpopulation, which can be activated to myofibroblasts. Am J Physiol 269: G532‐G541, 1995.
 236.Rashid ST, Humphries JD, Byron A, Dhar A, Askari JA, Selley JN, Knight D, Goldin RD, Thursz M, Humphries MJ. Proteomic analysis of extracellular matrix from the hepatic stellate cell line LX‐2 identifies CYR61 and Wnt‐5a as novel constituents of fibrotic liver. J Proteome Res 11: 4052‐4064, 2012.
 237.Reynaert H, Thompson MG, Thomas T, Geerts A. Hepatic stellate cells: Role in microcirculation and pathophysiology of portal hypertension. Gut 50: 571‐581, 2002.
 238.Rippe RA. Role of transcriptional factors in stellate cell activation. Alcohol Clin Exp Res 23: 926‐929, 1999.
 239.Rockey DC. Hepatic blood flow regulation by stellate cells in normal and injured liver. Semin Liver Dis 21: 337‐350, 2001.
 240.Rockey DC. Vascular mediators in the injured liver. Hepatology 37: 4‐12, 2003.
 241.Rockey DC, Boyles JK, Gabbiani G, Friedman SL. Rat hepatic lipocytes express smooth muscle actin upon activation in vivo and in culture. J Submicrosc Cytol Pathol 24: 193‐203, 1992.
 242.Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, Housset C. Cellular localization of endothelin‐1 and increased production in liver injury in the rat: Potential for autocrine and paracrine effects on stellate cells. Hepatology 27: 472‐480, 1998.
 243.Roderburg C, Luedde M, Cardenas DV, Vucur M, Mollnow T, Zimmermann HW, Koch A, Hellerbrand C, Weiskirchen R, Frey N, Tacke F, Trautwein C, Luedde T. miR‐133a mediates TGF‐beta‐dependent de‐repression of collagen‐synthesis in hepatic stellate cells during liver fibrosis. J Hepatol 58: 736‐742, 2012.
 244.Roderburg C, Urban GW, Bettermann K, Vucur M, Zimmermann H, Schmidt S, Janssen J, Koppe C, Knolle P, Castoldi M, Tacke F, Trautwein C, Luedde T. Micro‐RNA profiling reveals a role for miR‐29 in human and murine liver fibrosis. Hepatology 53: 209‐218, 2011.
 245.Rojkind M, Giambrone MA, Biempica L. Collagen types in normal and cirrhotic liver. Gastroenterology 76: 710‐719, 1979.
 246.Rombouts K, Mello T, Liotta F, Galli A, Caligiuri A, Annunziato F, Pinzani M. MARCKS actin‐binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells. Am J Physiol Cell Physiol 303: C357‐C367, 2012.
 247.Rosenbaum J, Blazejewski S, Preaux AM, Mallat A, Dhumeaux D, Mavier P. Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts. Gastroenterology 109: 1986‐1996, 1995.
 248.Roskams T. Different types of liver progenitor cells and their niches. J Hepatol 45: 1‐4, 2006.
 249.Roskams T, Cassiman D, De Vos R, Libbrecht L. Neuroregulation of the neuroendocrine compartment of the liver. Anat Rec A Discov Mol Cell Evol Biol 280: 910‐923, 2004.
 250.Sahin H, Trautwein C, Wasmuth HE. Functional role of chemokines in liver disease models. Nat Rev Gastroenterol Hepatol 7: 682‐690, 2010.
 251.Saile B, Matthes N, Knittel T, Ramadori G. Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology 30: 196‐202, 1999.
 252.Sato M, Kojima N, Miura M, Imai K, Senoo H. Induction of cellular processes containing collagenase and retinoid by integrin‐binding to interstitial collagen in hepatic stellate cell culture. Cell Biol Int 22: 115‐125, 1998.
 253.Sauvant P, Cansell M, Atgie C. Vitamin A and lipid metabolism: Relationship between hepatic stellate cells (HSCs) and adipocytes. J Physiol Biochem 67: 487‐496, 2011.
 254.Sawitza I, Kordes C, Reister S, Haussinger D. The niche of stellate cells within rat liver. Hepatology 50: 1617‐1624, 2009.
 255.Schildberg FA, Wojtalla A, Siegmund SV, Endl E, Diehl L, Abdullah Z, Kurts C, Knolle PA. Murine hepatic stellate cells veto CD8 T cell activation by a CD54‐dependent mechanism. Hepatology 54: 262‐272, 2011.
 256.Schirmacher P, Geerts A, Pietrangelo A, Dienes HP, Rogler CE. Hepatocyte growth factor/hepatopoietin A is expressed in fat‐storing cells from rat liver but not myofibroblast‐like cells derived from fat‐storing cells. Hepatology 15: 5‐11, 1992.
 257.Schmitt‐Graff A, Desmouliere A, Gabbiani G. Heterogeneity of myofibroblast phenotypic features: An example of fibroblastic cell plasticity. Virchows Archiv 425: 3‐24, 1994.
 258.Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology 37: 653‐664, 2003.
 259.Schuppan D. Structure of the extracellular matrix in normal and fibrotic liver: Collagens and glycoproteins. Semin Liver Dis 10: 1‐10, 1990.
 260.Schwabe RF, Bataller R, Brenner DA. Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 285: G949‐G958, 2003.
 261.Schwettmann L, Wehmeier M, Jokovic D, Aleksandrova K, Brand K, Manns MP, Lichtinghagen R, Bahr MJ. Hepatic expression of A disintegrin and metalloproteinase (ADAM) and ADAMs with thrombospondin motives (ADAM‐TS) enzymes in patients with chronic liver diseases. J Hepatol 49: 243‐250, 2008.
 262.Seki E, De Minicis S, Gwak GY, Kluwe J, Inokuchi S, Bursill CA, Llovet JM, Brenner DA, Schwabe RF. CCR1 and CCR5 promote hepatic fibrosis in mice. J Clin Invest 119: 1858‐1870, 2009.
 263.Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, Schwabe RF, Brenner DA. CCR2 promotes hepatic fibrosis in mice. Hepatology 50: 185‐197, 2009.
 264.Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, Schwabe RF. TLR4 enhances TGF‐beta signaling and hepatic fibrosis. Nat Med 13: 1324‐1332, 2007.
 265.Sekiya Y, Ogawa T, Iizuka M, Yoshizato K, Ikeda K, Kawada N. 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.
 266.Sekiya Y, Ogawa T, Yoshizato K, Ikeda K, Kawada N. Suppression of hepatic stellate cell activation by microRNA‐29b. Biochem Biophys Res Commun 412: 74‐79, 2011.
 267.Senoo H, Yoshikawa K, Morii M, Miura M, Imai K, Mezaki Y. Hepatic stellate cell (vitamin A‐storing cell) and its relative – past, present and future. Cell Biol Int 34: 1247‐1272, 2010.
 268.Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, Richards DR, McDonald‐Smith GP, Gao H, Hennessy L, Finnerty CC, Lopez CM, Honari S, Moore EE, Minei JP, Cuschieri J, Bankey PE, Johnson JL, Sperry J, Nathens AB, Billiar TR, West MA, Jeschke MG, Klein MB, Gamelli RL, Gibran NS, Brownstein BH, Miller‐Graziano C, Calvano SE, Mason PH, Cobb JP, Rahme LG, Lowry SF, Maier RV, Moldawer LL, Herndon DN, Davis RW, Xiao W, Tompkins RG. Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110: 3507‐3512, 2013.
 269.Shafiei MS, Rockey DC. The function of integrin‐linked kinase in normal and activated stellate cells: Implications for fibrogenesis in wound healing. Lab Invest 92: 305‐316, 2012.
 270.Shao R, Yan W, Rockey DC. Regulation of endothelin‐1 synthesis by endothelin‐converting enzyme‐1 during wound healing. J Biol Chem 274: 3228‐3234, 1999.
 271.Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA. Latent TGF‐beta structure and activation. Nature 474: 343‐349, 2011.
 272.Shirakami Y, Gottesman ME, Blaner WS. Diethylnitrosamine‐induced hepatocarcinogenesis is suppressed in lecithin:retinol acyltransferase‐deficient mice primarily through retinoid actions immediately after carcinogen administration. Carcinogenesis 33: 268‐274, 2012.
 273.Shomron N, Hamasaki‐Katagiri N, Hunt R, Hershko K, Pommier E, Geetha S, Blaisdell A, Dobkin A, Marple A, Roma I, Newell J, Allen C, Friedman S, Kimchi‐Sarfaty C. A splice variant of ADAMTS13 is expressed in human hepatic stellate cells and cancerous tissues. Thromb Haemost 104: 531‐535, 2010.
 274.Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature 458: 1131‐1135, 2009.
 275.Smedsrod B, Le Couteur D, Ikejima K, Jaeschke H, Kawada N, Naito M, Knolle P, Nagy L, Senoo H, Vidal‐Vanaclocha F, Yamaguchi N. Hepatic sinusoidal cells in health and disease: Update from the 14th International Symposium. Liver Int 29: 490‐501, 2009.
 276.Sohail MA, Hashmi AZ, Hakim W, Watanabe A, Zipprich A, Groszmann RJ, Dranoff JA, Torok NJ, Mehal WZ. Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition. Hepatology 49: 185‐194, 2009.
 277.Sprenger H, Kaufmann A, Garn H, Lahme B, Gemsa D, Gressner AM. Differential expression of monocyte chemotactic protein‐1 (MCP‐1) in transforming rat hepatic stellate cells. J Hepatol 30: 88‐94, 1999.
 278.Starkel P, Sempoux C, Leclercq I, Herin M, Deby C, Desager JP, Horsmans Y. Oxidative stress, KLF6 and transforming growth factor‐beta up‐regulation differentiate non‐alcoholic steatohepatitis progressing to fibrosis from uncomplicated steatosis in rats. J Hepatol 39: 538‐546, 2003.
 279.Stefanovic B, Hellerbrand C, Brenner DA. Regulatory role of the conserved stem‐loop structure at the 5′ end of collagen alpha1(I) mRNA. Mol Cell Biol 19: 4334‐4342, 1999.
 280.Stefanovic B, Hellerbrand C, Holcik M, Briendl M, Aliebhaber S, Brenner DA. Posttranscriptional regulation of collagen alpha1(I) mRNA in hepatic stellate cells. Mol Cell Biol 17: 5201‐5209, 1997.
 281.Stefanovic L, Brenner DA, Stefanovic B. Direct hepatotoxic effect of KC chemokine in the liver without infiltration of neutrophils. Exp Biol Med (Maywood) 230: 573‐586, 2005.
 282.Steiling H, Muhlbauer M, Bataille F, Scholmerich J, Werner S, Hellerbrand C. Activated hepatic stellate cells express keratinocyte growth factor in chronic liver disease. Am J Pathol 165: 1233‐1241, 2004.
 283.Su YH, Shu KH, Hu C, Cheng CH, Wu MJ, Yu TM, Chuang YW, Huang ST, Chen CH. Hepatic stellate cells attenuate the immune response in renal transplant recipients with chronic hepatitis. Transplant Proc 44: 725‐729, 2012.
 284.Suzuki K, Tanaka M, Watanabe N, Saito S, Nonaka H, Miyajima A. p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology 135: 270‐281 e273, 2008.
 285.Syal G, Fausther M, Dranoff JA. Advances in cholangiocyte immunobiology. Am J Physiol Gastrointest Liver Physiol 303: G1077‐G1086, 2012.
 286.Szabo G, Mandrekar P, Dolganiuc A. Innate immune response and hepatic inflammation. Semin Liver Dis 27: 339‐350, 2007.
 287.Tacke F. Monocytes and Macrophages as Cellular Targets in Liver Fibrosis. Inflamm Allergy Drug Targets 8: 307‐318, 2009.
 288.Tacke F, Weiskirchen R. Update on hepatic stellate cells: Pathogenic role in liver fibrosis and novel isolation techniques. Expert Rev Gastroenterol Hepatol 6: 67‐80, 2012.
 289.Takahara T, Kojima T, Miyabayashi C, Inoue K, Sasaki H, Muragaki Y, Ooshima A. Collagen production in fat‐storing cells after carbon tetrachloride intoxication in the rat. Immunoelectron microscopic observation of type I, type III collagens, and prolyl hydroxylase. Lab Invest 59: 509‐521, 1988.
 290.Tanaka H, Leung PS, Kenny TP, Gershwin ME, Bowlus CL. Immunological orchestration of liver fibrosis. Clin Rev Allergy Immunol 43: 220‐229, 2012.
 291.Tarrats N, Moles A, Morales A, Garcia‐Ruiz C, Fernandez‐Checa JC, Mari M. Critical role of tumor necrosis factor receptor 1, but not 2, in hepatic stellate cell proliferation, extracellular matrix remodeling, and liver fibrogenesis. Hepatology 54: 319‐327, 2011.
 292.Taura K, De Minicis S, Seki E, Hatano E, Iwaisako K, Osterreicher CH, Kodama Y, Miura K, Ikai I, Uemoto S, Brenner DA. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135: 1729‐1738, 2008.
 293.Thabut D, Routray C, Lomberk G, Shergill U, Glaser K, Huebert R, Patel L, Masyuk T, Blechacz B, Vercnocke A, Ritman E, Ehman R, Urrutia R, Shah V. Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 54: 573‐585, 2011.
 294.Troeger JS, Mederacke I, Gwak GY, Dapito DH, Mu X, Hsu CC, Pradere JP, Friedman RA, Schwabe RF. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology 143: 1073‐1083 e1022, 2012.
 295.Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis. Clin Chim Acta 364: 33‐60, 2006.
 296.Tsukada S, Westwick JK, Ikejima K, Sato N, Rippe RA. SMAD and p38 MAPK signaling pathways independently regulate alpha1(I) collagen gene expression in unstimulated and transforming growth factor‐beta‐stimulated hepatic stellate cells. J Biol Chem 280: 10055‐10064, 2005.
 297.Tsukamoto H. Epigenetic mechanism of stellate cell trans‐differentiation. J Hepatol 46: 352‐353, 2007.
 298.Tsukamoto H, Zhu NL, Wang J, Asahina K, Machida K. Morphogens and hepatic stellate cell fate regulation in chronic liver disease. J Gastroenterol Hepatol 27 Suppl 2: 94‐98, 2012.
 299.Ueno T, Sata M, Sakata R, Torimura T, Sakamoto M, Sugawara H, Tanikawa K. Hepatic stellate cells and intralobular innervation in human liver cirrhosis. Hum Pathol 28: 953‐959, 1997.
 300.Urtasun R, Lopategi A, George J, Leung TM, Lu Y, Wang X, Ge X, Fiel MI, Nieto N. 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.
 301.Vinas O, Bataller R, Sancho‐Bru P, Gines P, Berenguer C, Enrich C, Nicolas JM, Ercilla G, Gallart T, Vives J, Arroyo V, Rodes J. Human hepatic stellate cells show features of antigen‐presenting cells and stimulate lymphocyte proliferation. Hepatology 38: 919‐929, 2003.
 302.Vyas SK, Leyland H, Gentry J, Arthur MJ. Rat hepatic lipocytes synthesize and secrete transin (stromelysin) in early primary culture. Gastroenterology 109: 889‐898, 1995.
 303.Wake K. “Sternzellen” in the liver: Perisinuosoidal cells with special reference to storage of vitamin A. Am J Anat 132: 429‐462, 1971.
 304.Wake K. Perisinusoidal stellate cells (Fat‐storing cells, interstitial cells, lipocytes) their related structure in and around liver sinusoids, and vitamin A storing cells in extrahepatic organs. Int Rev Cytology 66: 303‐353, 1980.
 305.Wake K, Sato T. Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver. Cell Tissue Res 273: 227‐237, 1993.
 306.Wandzioch E, Kolterud A, Jacobsson M, Friedman SL, Carlsson L. Lhx2‐/‐ mice develop liver fibrosis. Proc Natl Acad Sci U S A 101: 16549‐16554, 2004.
 307.Wang B, Li W, Guo K, Xiao Y, Wang Y, Fan J. miR‐181b Promotes hepatic stellate cells proliferation by targeting p27 and is elevated in the serum of cirrhosis patients. Biochem Biophys Res Commun 421: 4‐8, 2012.
 308.Wang J, Leclercq I, Brymora JM, Xu N, Ramezani‐Moghadam M, London RM, Brigstock D, George J. Kupffer cells mediate leptin‐induced liver fibrosis. Gastroenterology 137: 713‐723, 2009.
 309.Wang L, Wang X, Chiu JD, van de Ven G, Gaarde WA, Deleve LD. Hepatic vascular endothelial growth factor regulates recruitment of rat liver sinusoidal endothelial cell progenitor cells. Gastroenterology 143: 1555‐1563 e1552, 2012.
 310.Wang L, Wang X, Xie G, Hill CK, DeLeve LD. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J Clin Invest 122: 1567‐1573, 2012.
 311.Wang Y, Yao HL, Cui CB, Wauthier E, Barbier C, Costello MJ, Moss N, Yamauchi M, Sricholpech M, Gerber D, Loboa EG, Reid LM. Paracrine signals from mesenchymal cell populations govern the expansion and differentiation of human hepatic stem cells to adult liver fates. Hepatology 52: 1443‐1454, 2010.
 312.Wang Y, Zhang JS, Qian J, Huang GC, Chen Q. Adrenomedullin regulates expressions of transforming growth factor‐beta1 and beta1‐induced matrix metalloproteinase‐2 in hepatic stellate cells. Int J Exp Pathol 87: 177‐184, 2006.
 313.Watanabe A, Sohail MA, Gomes DA, Hashmi A, Nagata J, Sutterwala FS, Mahmood S, Jhandier MN, Shi Y, Flavell RA, Mehal WZ. Inflammasome‐mediated regulation of hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 296: G1248‐G1257, 2009.
 314.Watanabe N, Ikeda H, Kume Y, Satoh Y, Kaneko M, Takai D, Tejima K, Nagamine M, Mashima H, Tomiya T, Noiri E, Omata M, Matsumoto M, Fujimura Y, Yatomi Y. Increased production of ADAMTS13 in hepatic stellate cells contributes to enhanced plasma ADAMTS13 activity in rat models of cholestasis and steatohepatitis. Thromb Haemost 102: 389‐396, 2009.
 315.Wells RG. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol 39: S158‐S161, 2005.
 316.wIshikawa K, Mochida S, Mashiba S, Inao M, Matsui A, Ikeda H, Ohno A, Shibuya M, Fujiwara K. Expressions of vascular endothelial growth factor in nonparenchymal as well as parenchymal cells in rat liver after necrosis. Biochem Biophys Res Commun 254: 587‐593, 1999.
 317.Wong L, Yamasaki G, Johnson RJ, Friedman SL. 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.
 318.Wu TJ, Wang YC, Wu TH, Lee CF, Chan KM, Lee WC. Inhibition of allogenic T‐cell cytotoxicity by hepatic stellate cell via CD4(+) CD25(+) Foxp3(+) regulatory T cells in vitro. Transplant Proc 44: 1055‐1059, 2012.
 319.Xie G, Wang X, Wang L, Atkinson RD, Kanel GC, Gaarde WA, Deleve LD. Role of differentiation of liver sinusoidal endothelial cells in progression and regression of hepatic fibrosis in rats. Gastroenterology 142: 918‐927 e916, 2012.
 320.Yamada M, Blaner WS, Soprano DR, Dixon JL, Kjeldbye HM, Goodman DS. Biochemical characteristics of isolated rat liver stellate cells. Hepatology 7: 1224‐1229, 1987.
 321.Yamada T, Imaoka S, Kawada N, Seki S, Kuroki T, Kobayashi K, Monna T, Funae Y. Expression of cytochrome P450 isoforms in rat hepatic stellate cells. Life Sci 61: 171‐179, 1997.
 322.Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411‐415, 1988.
 323.Yang C, Zeisberg M, Mosterman B, Sudhakar A, Yerramalla U, Holthaus K, Xu L, Eng F, Afdhal N, Kalluri R. Liver fibrosis: Insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology 124: 147‐159, 2003.
 324.Yang L, Jung Y, Omenetti A, Witek RP, Choi S, Vandongen HM, Huang J, Alpini GD, Diehl AM. Fate‐mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 26: 2104‐2113, 2008.
 325.Yin C, Evason KJ, Maher JJ, Stainier DY. 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.
 326.Yin L, Lynch D, Ilic Z, Sell S. Proliferation and differentiation of ductular progenitor cells and littoral cells during the regeneration of the rat liver to CCl4/2‐AAF injury. Histol Histopathol 17: 65‐81, 2002.
 327.Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Wu Y, Yanase K, Namisaki T, Yamazaki M, Tsujinoue H, Imazu H, Masaki T, Fukui H. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut 52: 1347‐1354, 2003.
 328.Yu C, Wang F, Jin C, Huang X, Miller DL, Basilico C, McKeehan WL. Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride‐induced hepatic injury and fibrogenesis. Am J Pathol 163: 1653‐1662, 2003.
 329.Zhao Y, Wang Y, Wang Q, Liu Z, Liu Q, Deng X. Hepatic stellate cells produce vascular endothelial growth factor via phospho‐p44/42 mitogen‐activated protein kinase/cyclooxygenase‐2 pathway. Mol Cell Biochem 359: 217‐223, 2012.
 330.Zhu NL, Asahina K, Wang J, Ueno A, Lazaro R, Miyaoka Y, Miyajima A, Tsukamoto H. Hepatic stellate cell‐derived delta‐like homolog 1 (DLK1) protein in liver regeneration. J Biol Chem 287: 10355‐10367, 2012.
 331.Zhu Q, Zou L, Jagavelu K, Simonetto DA, Huebert RC, Jiang ZD, DuPont HL, Shah VH. Intestinal decontamination inhibits TLR4 dependent fibronectin‐mediated cross‐talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol 56: 893‐899, 2012.
 332.Zindy F, Lamas E, Schmidt S, Kirn A, Brechot C. Expression of insulin‐like growth factor II (IGF‐II) and IGF‐II, IGF‐I and insulin receptors mRNAs in isolated non‐parenchymal rat liver cells. J Hepatol 14: 30‐34, 1992.
 333.Zvibel I, Atias D, Phillips A, Halpern Z, Oren R. Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho. Lab Invest 90: 674‐684, 2010.
Further Reading
 1. Friedman SL, Sheppard D, Duffield J and Violette S. Therapy for fibrotic diseases: Nearing the starting line. Sci Transl Med, 5:167sr1, 2013.
 2.Friedman SL, guest editor. Special issue on fibrosis. Biochim Biophys Acta. 2013 Mar 16. pii: S0925‐4439(13)00077‐X. doi: 10.1016/j.bbadis.

Further Reading

Friedman SL, Sheppard D, Duffield J and Violette S.  Therapy for fibrotic diseases: nearing the starting line.  Science Translational Medicine, 5:167sr1, 2013.

Friedman SL, guest editor.   Special issue on fibrosis.  Biochimica Biophysica Acta, in press, 2013.

Related Articles:

Cellular and Molecular Basis of Liver Development
Hepatic circulation
Principles of Liver Regeneration and Growth Homeostasis
Top cited articles of 2017

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Juan E. Puche, Yedidya Saiman, Scott L. Friedman. Hepatic Stellate Cells and Liver Fibrosis. Compr Physiol 2013, 3: 1473-1492. doi: 10.1002/cphy.c120035