Hepatic stellate cells are mainly known for their contribution to fibrogenesis in chronic liver diseases, but their identity and function in normal liver remain unclear. They were recently identified as liver-resident mesenchymal stem cells (MSCs), which can differentiate not only into adipocytes and osteocytes, but also into liver epithelial cells such as hepatocytes and bile duct cells as investigated in vitro and in vivo. During hepatic differentiation, stellate cells and other MSCs transiently develop into liver progenitor cells with epithelial characteristics before hepatocytes are established. Transplanted stellate cells from the liver and pancreas are able to contribute to liver regeneration in stem cell-based liver injury models and can also home into the bone marrow, which is in line with their classification as MSCs. There is experimental evidence that bile acids support liver regeneration and are able to activate signaling pathways in hepatic stellate cells. For this reason, it is important to analyze the influence of bile acids on developmental fate decisions of hepatic stellate cells and other MSC populations.

Keywords:
Hepatic stellate cells, Mesenchymal stem cells, Liver regeneration, Bile acids
1.
Friedman SL: Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88:125-172.
2.
Geerts A: On the origin of stellate cells: mesodermal, endodermal or neuro-ectodermal? J Hepatol 2004;40:331-334.
3.
Gard A, White F, Dutton G: Extra-neural glial fibrillary acidic protein (GFAP) immunoreactivity in perisinusoidal stellate cells of rat liver. J Neuroimmunol 1985;8:359-375.
4.
Cassiman D, Denef C, Desmet VJ, Roskams T: Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 2001;33:148-158.
5.
Enzan H, Himeno H, Hiroi M, Kiyoku H, Saibara T, Onishi S: Development of hepatic sinusoidal structure with special reference to the Ito cells. Microsc Res Tech 1997;39:336-349.
6.
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 2009;49:998-1011.
7.
Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, Watanabe S, Usui K: Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 1984;4:709-714.
8.
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 2008;135:270-281.
9.
Schmitt-Gräff A, Krüger S, Bochard F, Gabbiani G, Denk H: Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am J Pathol 1991;138:1233-1242.
10.
Hautekeete ML, Geerts A: The hepatic stellate (Ito) cell: its role in human liver disease. Virchows Arch 1997;430:195-207.
11.
Shiratori Y, Ichida T, Geerts A, Wisse E: Modulation of collagen synthesis by fat-storing cells, isolated from CCl4- or vitamin A-treated rats. Dig Dis Sci 1987;32:1281-1289.
12.
Davis BH, Kramer RT, Davidson NO: Retinoic acid modulates rat Ito cell proliferation, collagen, and transforming growth factor beta production. J Clin Invest 1990;86:2062-2070.
13.
Purton LE, Bernstein ID, Collins SJ: All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1+) while enhancing the terminal maturation of committed granulocyte/monocyte progenitors. Blood 1999;94:483-495.
14.
de Hemptinne I, Vermeiren C, Maloteaux JM, Hermans E: Induction of glial glutamate transporters in adult mesenchymal stem cells. J Neurochem 2004;91:155-166.
15.
Niki T, Pekny M, Hellemans K, Bleser PD, Berg KV, Vaeyens F, Quartier E, Schuit F, Geerts A: Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 1999;29:520-527.
16.
Reister S, Kordes C, Sawitza I, Häussinger D: The epigenetic regulation of stem cell factors in hepatic stellate cells. Stem Cells Dev 2011;20:1687-1699.
17.
Wiese C, Rolletschek A, Kania G, Blyszczuk P, Tarasov KV, Tarasova Y, Wersto RP, Boheler KR, Wobus AM: Nestin expression - a property of multi-lineage progenitor cells? Cell Mol Life Sci 2005;61:2510-2522.
18.
Baba S, Fujii H, Hirose T, Yasuchika K, Azuma H, Hoppo T, Naito M, Machimoto T, Ikai I: Commitment of bone morrow cells to hepatic stellate cells in mouse. J Hepatol 2004;40:255-260.
19.
Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ: The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006;130:1807-1821.
20.
da Silva Meirelles L, Chagastelles PC, Nardi NB: Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006;119:2204-2213.
21.
Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B: A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008;3:301-313.
22.
Kordes C, Sawitza I, Müller-Marbach A, Ale-Agha N, Keitel V, Klonowski-Stumpe H, Häussinger D: CD133+ hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 2007;352:410-417.
23.
Covas DT, Panepucci RA, Fontes AM, Silva WA Jr, Orellana MD, Freitas MC, Neder L, Santos AR, Peres LC, Jamur MC, Zago MA: Multipotent mesenchymal stromal cells obtained from diverse human tissues share functional properties and gene-expression profile with CD146+ perivascular cells and fibroblasts. Exp Hematol 2008;36:642-654.
24.
Genz B, Thomas M, Pützer BM, Siatkowski M, Fuellen G, Vollmar B, Abshagen K: Adenoviral overexpression of Lhx2 attenuates cell viability but does not preserve the stem cell like phenotype of hepatic stellate cells. Exp Cell Res 2014;328:429-443.
25.
Kordes C, Sawitza I, Götze S, Häussinger D: Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cell Physiol Biochem 2013;31:290-304.
26.
Eaves CJ, Cashman JD, Sutherland HJ, Otsuka T, Humphries RK, Hogge DE, Lansdorp PL, Eaves AC: Molecular analysis of primitive hematopoietic cell proliferation control mechanisms. Ann NY Acad Sci 1991;628:298-306.
27.
Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma'ayan A, Enikolopov GN, Frenette PS: Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010;466:829-834.
28.
Sawitza I, Kordes C, Reister S, Häussinger D: The niche of stellate cells within rat liver. Hepatology 2009;50:1617-1624.
29.
Kordes C, Häussinger D: Hepatic stem cell niches. J Clin Invest 2013;123:1874-1880.
30.
Castilho-Fernandes A, de Almeida DC, Fontes AM, Melo FU, Picanço-Castro V, Freitas MC, Orellana MD, Palma PV, Hackett PB, Friedman SL, Covas DT: Human hepatic stellate cell line (LX-2) exhibits characteristics of bone marrow-derived mesenchymal stem cells. Exp Mol Pathol 2011;91:664-672.
31.
Yang L, Jung Y, Omenetti A, Witek RP, Choi SS, Vandongen HM, Huang J, Alpini GD, Diehl AM: Fate-mapping evidence that hepatic stellate cells are epithelial progenitors in adult mouse livers. Stem Cells 2008;26:2104-2113.
32.
Kordes C, Sawitza I, Götze S, Häussinger D: Stellate cells from rat pancreas are stem cells and can contribute to liver regeneration. PLoS One 2012;7:e51878.
33.
Michelotti GA, Xie G, Swiderska M, Choi SS, Karaca G, Krüger L, Premont R, Yang L, Syn WK, Metzger D, Diehl AM: Smoothened is a master regulator of adult liver repair. J Clin Invest 2013;123:2380-2394.
34.
Swiderska-Syn M, Syn WK, Xie G, Krüger L, Machado MV, Karaca G, Michelotti GA, Choi SS, Premont RT, Diehl AM: Myofibroblastic cells function as progenitors to regenerate murine livers after partial hepatectomy. Gut 2014;63:1333-1344.
35.
Kordes C, Sawitza I, Götze S, Herebian D, Häussinger D: Hepatic stellate cells contribute to progenitor cells and liver regeneration. J Clin Invest 2014;124:5503-5515.
36.
Sato Y, Araki H, Kato J, Nakamura K, Kawano Y, Kobune M, Sato T, Miyanishi K, Takayama T, Takahashi M, Takimoto R, Iyama S, Matsunaga T, Ohtani S, Matsuura A, Hamada H, Niitsu Y: Human mesenchymal stem cells xenografted directly to rat liver are differentiated into human hepatocytes without fusion. Blood 2005;106:756-763.
37.
Chamberlain J, Yamagami T, Colletti E, Theise ND, Desai J, Frias A, Pixley J, Zanjani ED, Porada CD, Almeida-Porada G: Efficient generation of human hepatocytes by the intrahepatic delivery of clonal human mesenchymal stem cells in fetal sheep. Hepatology 2007;46:1935-1945.
38.
Aurich I, Mueller LP, Aurich H, Luetzkendorf J, Tisljar K, Dollinger MM, Schormann W, Walldorf J, Hengstler JG, Fleig WE, Christ B: Functional integration of hepatocytes derived from human mesenchymal stem cells into mouse livers. Gut 2007;56:405-415.
39.
Caplan AI, Dennis JE: Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006;98:1076-1084.
40.
Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, Yarmush ML: Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS One 2007;2:e941.
41.
Kaplan JM, Yound ME, Lodie TA: Immunomodulatory activity of mesenchymal stem cells. Curr Stem Cell Res Ther 2010;6:297-316.
42.
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 2011;54:262-272.
43.
Mailloux AW, Zhang L, Moscinski L, Bennett JM, Yang L, Yoder SJ, Bloom G, Wei C, Wei S, Sokol L, Loughran TP Jr, Epling-Burnette PK: Fibrosis and subsequent cytopenias are associated with basic fibroblast growth factor-deficient pluripotent mesenchymal stromal cells in large granular lymphocyte leukemia. J Immunol 2013;191:3578-3593.
44.
Judson RN, Zhang RH, Rossi FM: Tissue-resident mesenchymal stem/progenitor cells in skeletal muscle: collaborators or saboteurs? FEBS J 2013;280:4100-4108.
45.
Huang W, Ma K, Zhang J, Qatanani M, Cuvillier J, Liu J, Dong B, Huang X, Moore DD: Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 2006;312:233-236.
46.
Svegliati-Baroni G, Ridolfi F, Hannivoort R, Saccomanno S, Homan M, De Minicis S, Jansen PL, Candelaresi C, Benedetti A, Moshage H: Bile acids induce hepatic stellate cell proliferation via activation of the epidermal growth factor receptor. Gastroenterology 2005;128:1042-1055.
47.
Sommerfeld A, Reinehr R, Häussinger D: Bile acid-induced epidermal growth factor receptor activation in quiescent rat hepatic stellate cells can trigger both proliferation and apoptosis. J Biol Chem 2009;284:22173-22183.
48.
Fiorucci S, Antonelli E, Rizzo G, Renga B, Mencarelli A, Riccardi L, Orlandi S, Pellicciari R, Morelli A: The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 2004;127:1497-1512.
49.
Id Boufker H, Lagneaux L, Fayyad-Kazan H, Badran B, Najar M, Wiedig M, Ghanem G, Laurent G, Body JJ, Journé F: Role of farnesoid X receptor (FXR) in the process of differentiation of bone marrow stromal cells into osteoblasts. Bone 2011;49:1219-1231.
50.
Keitel V, Donner M, Winandy S, Kubitz R, Häussinger D: Expression and function of the bile acid receptor TGR5 in Kupffer cells. Biochem Biophys Res Commun 2008;372:78-84.
51.
Moustafa T, Fickert P, Magnes C, Guelly C, Thueringer A, Frank S, Kratky D, Sattler W, Reicher H, Sinner F, Gumhold J, Silbert D, Fauler G, Höfler G, Lass A, Zechner R, Trauner M: Alterations in lipid metabolism mediate inflammation, fibrosis, and proliferation in a mouse model of chronic cholestatic liver injury. Gastroenterology 2012;142:140-151.
52.
Brady LM, Beno DW, Davis BH: Bile acid stimulation of early growth response gene and mitogen-activated protein kinase is protein kinase C-dependent. Biochem J 1996;316:765-769.
53.
Min IM, Pietramaggiori G, Kim FS, Passegué E, Stevenson KE, Wagers AJ: The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. Cell Stem Cell 2008;2:380-391.
54.
Pritchard MT, Nagy LE: Hepatic fibrosis is enhanced and accompanied by robust oval cell activation after chronic carbon tetrachloride administration to Egr-1-deficient mice. Am J Pathol 2010;176:2743-2752.
55.
Sullivan BP, Cui W, Copple BL, Luyendyk JP: Early growth response factor-1 limits biliary fibrosis in a model of xenobiotic-induced cholestasis in mice. Toxicol Sci 2012;126:267-274.
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2015
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