Abstract
The liver has enormous regenerative capacity. Following acute liver injury, hepatocyte division regenerates the parenchyma but, if this capacity is overwhelmed during massive or chronic liver injury, the intrinsic hepatic progenitor cells (HPCs) termed oval cells are activated. These HPCs are bipotential and can regenerate both biliary epithelia and hepatocytes. Multiple signalling pathways contribute to the complex mechanism controlling the behaviour of the HPCs. These signals are delivered primarily by the surrounding microenvironment. During liver disease, stem cells extrinsic to the liver are activated and bone-marrow-derived cells play a role in the generation of fibrosis during liver injury and its resolution. Here, we review our current understanding of the role of stem cells during liver disease and their mechanisms of activation.
Similar content being viewed by others
Abbreviations
- αFP:
-
Alpha-fetoprotein
- AAF:
-
2-N-acetylaminofluorene
- BDL:
-
Bile duct ligation
- BM:
-
Bone marrow
- BMSC:
-
Bone marrow stem cell
- CCl4 :
-
Carbon tetrachloride
- CDE:
-
Choline-deficient ethionine-supplemented
- CK:
-
Cytokeratin
- CTGF:
-
Connective tissue growth factor
- DDC:
-
3,5-Diethoxycarbonlyl-1,4-dihydrocollidine-supplemented
- DPPIV:
-
Dipeptidyl peptidase IV
- ECM:
-
Extracellular matrix
- ERK:
-
Extracellular signal-regulated kinase
- EGF:
-
Epidermal growth factor
- FAH −/− :
-
Fumarylacetoacetate hydrolase knockout
- FGF:
-
Fibroblast growth factor
- FGFR:
-
FGF receptor
- G-CSF:
-
Granulocyte colony-stimulating factor
- HGF:
-
Hepatocyte growth factor
- HCC:
-
Hepatocellular carcinoma
- HPC:
-
Hepatic progenitor cell
- IFN:
-
Interferon
- IL:
-
Interleukin
- JAK:
-
Janus kinase
- LIF:
-
Leukaemia inhibitor factor
- LIFR:
-
LIF receptor
- LT:
-
Lymphotoxin
- MMP:
-
Metalloproteinase
- OC:
-
Oval cell
- OSM:
-
Oncostatin M
- OSMR:
-
OSM receptor
- PH:
-
Partial hepatectomy
- PPAR:
-
Peroxisome-proliferator-activated receptor
- SCF:
-
Stem cell factor
- SDF-1:
-
Stromal-cell-derived factor 1
- SgIGSF:
-
Spermatogenic immunoglobulin superfamily
- STAT:
-
Signal transductor and activator of transcription
- TGF:
-
Transforming growth factor
- TNF:
-
Tumour necrosis factor
- TWEAK:
-
TNF-like weak induction of apoptosis
- uPA:
-
Urokinase-type plasminogen activator
References
Abe S, Lauby G, Boyer C, Rennard SI, Sharp JG (2003) Transplanted BM and BM side population cells contribute progeny to the lung and liver in irradiated mice. Cytotherapy 5:523–533
Akhurst B, Matthews V, Husk K, Smyth MJ, Abraham LJ, Yeoh GC (2005) Differential lymphotoxin-beta and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury. Hepatology 41:327–335
Alison M (1998) Liver stem cells: a two compartment system. Curr Opin Cell Biol 10:710–715
Alison MR (2005) Liver stem cells: implications for hepatocarcinogenesis. Stem Cell Rev 1:253–260
Alison MR, Poulsom R, Jeffery R, Dhillon AP, Quaglia A, Jacob J, Novelli M, Prentice G, Williamson J, Wright NA (2000) Hepatocytes from non-hepatic adult stem cells. Nature 406:257
Alpini G, Aragona E, Dabeva M, Salvi R, Shafritz DA, Tavoloni N (1992) Distribution of albumin and alpha-fetoprotein mRNAs in normal, hyperplastic, and preneoplastic rat liver. Am J Pathol 141:623–632
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, Lois C, Morrison SJ, Alvarez-Buylla A (2003) Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425:968–973
Baba S, Fujii H, Hirose T, Yasuchika K, Azuma H, Hoppo T, Naito M, Machimoto T, Ikai I (2004) Commitment of bone marrow cells to hepatic stellate cells in mouse. J Hepatol 40:255–260
Bisgaard HC, Parmelee DC, Dunsford HA, Sechi S, Thorgeirsson SS (1993) Keratin 14 protein in cultured nonparenchymal rat hepatic epithelial cells: characterization of keratin 14 and keratin 19 as antigens for the commonly used mouse monoclonal antibody OV-6. Mol Carcinog 7:60–66
Bisgaard HC, Muller S, Nagy P, Rasmussen LJ, Thorgeirsson SS (1999) Modulation of the gene network connected to interferon-gamma in liver regeneration from oval cells. Am J Pathol 155:1075–1085
Bisgaard HC, Holmskov U, Santoni-Rugiu E, Nagy P, Nielsen O, Ott P, Hage E, Dalhoff K, Rasmussen LJ, Tygstrup N (2002) Heterogeneity of ductular reactions in adult rat and human liver revealed by novel expression of deleted in malignant brain tumor 1. Am J Pathol 161:1187–1198
Brooling JT, Campbell JS, Mitchell C, Yeoh GC, Fausto N (2005) Differential regulation of rodent hepatocyte and oval cell proliferation by interferon gamma. Hepatology 41:906–915
Camargo FD, Finegold M, Goodell MA (2004) Hematopoietic myelomonocytic cells are the major source of hepatocyte fusion partners. J Clin Invest 113:1266–1270
Cameron R, Kellen J, Kolin A, Malkin A, Farber E (1978) Gamma-glutamyltransferase in putative premalignant liver cell populations during hepatocarcinogenesis. Cancer Res 38:823–829
Cassiman D, Libbrecht L, Sinelli N, Desmet V, Denef C, Roskams T (2002) The vagal nerve stimulates activation of the hepatic progenitor cell compartment via muscarinic acetylcholine receptor type 3. Am J Pathol 161:521–530
Chiba T, Kita K, Zheng YW, Yokosuka O, Saisho H, Iwama A, Nakauchi H, Taniguchi H (2006) Side population purified from hepatocellular carcinoma cells harbors cancer stem cell-like properties. Hepatology 44:240–251
Chinzei R, Tanaka Y, Shimizu-Saito K, Hara Y, Kakinuma S, Watanabe M, Teramoto K, Arii S, Takase K, Sato C, Terada N, Teraoka H (2002) Embryoid-body cells derived from a mouse embryonic stem cell line show differentiation into functional hepatocytes. Hepatology 36:22–29
Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, Robb L, Greenhalgh CJ, Forster I, Clausen BE, Nicola NA, Metcalf D, Hilton DJ, Roberts AW, Alexander WS (2003) SOCS3 negatively regulates IL-6 signaling in vivo. Nat Immunol 4:540–545
Davies RA, Knight B, Tian YW, Yeoh GC, Olynyk JK (2006) Hepatic oval cell response to the choline-deficient, ethionine supplemented model of murine liver injury is attenuated by the administration of a cyclo-oxygenase 2 inhibitor. Carcinogenesis 27:1607–1616
De Silvestro G, Vicarioto M, Donadel C, Menegazzo M, Marson P, Corsini A (2004) Mobilization of peripheral blood hematopoietic stem cells following liver resection surgery. Hepatogastroenterology 51:805–810
De Vos R, Desmet V (1992) Ultrastructural characteristics of novel epithelial cell types identified in human pathologic liver specimens with chronic ductular reaction. Am J Pathol 140:1441–1450
Demetris AJ, Seaberg EC, Wennerberg A, Ionellie J, Michalopoulos G (1996) Ductular reaction after submassive necrosis in humans. Special emphasis on analysis of ductular hepatocytes. Am J Pathol 149:439–448
Dudas J, Elmaouhoub A, Mansuroglu T, Batusic D, Tron K, Saile B, Papoutsi M, Pieler T, Wilting J, Ramadori G (2006) Prospero-related homeobox 1 (Prox1) is a stable hepatocyte marker during liver development, injury and regeneration, and is absent from “oval cells”. Histochem Cell Biol 126:549–562
Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115:56–65
Engelhardt NV, Factor VM, Medvinsky AL, Baranov VN, Lazareva MN, Poltoranina VS (1993) Common antigen of oval and biliary epithelial cells (A6) is a differentiation marker of epithelial and erythroid cell lineages in early development of the mouse. Differentiation 55:19–26
Evarts RP, Nagy P, Marsden E, Thorgeirsson SS (1987) A precursor-product relationship exists between oval cells and hepatocytes in rat liver. Carcinogenesis 8:1737–1740
Evarts RP, Nagy P, Nakatsukasa H, Marsden E, Thorgeirsson SS (1989) In vivo differentiation of rat liver oval cells into hepatocytes. Cancer Res 49:1541–1547
Evarts RP, Nakatsukasa H, Marsden ER, Hu Z, Thorgeirsson SS (1992) Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation. Mol Carcinog 5:25–31
Evarts RP, Hu Z, Fujio K, Marsden ER, Thorgeirsson SS (1993) Activation of hepatic stem cell compartment in the rat: role of transforming growth factor alpha, hepatocyte growth factor, and acidic fibroblast growth factor in early proliferation. Cell Growth Differ 4:555–561
Falkowski O, An HJ, Ianus IA, Chiriboga L, Yee H, West AB, Theise ND (2003) Regeneration of hepatocyte “buds” in cirrhosis from intrabiliary stem cells. J Hepatol 39:357–364
Farber E (1956) Similarities in the sequence of early histological changes induced in the liver of the rat by ethionine, 2-acetylamino-fluorene, and 3′-methyl-4-dimethylaminoazobenzene. Cancer Res 16:142–148
Faris RA, Hixson DC (1989) Selective proliferation of chemically altered rat liver epithelial cells following hepatic transplantation. Transplantation 48:87–92
Faris RA, Monfils BA, Dunsford HA, Hixson DC (1991) Antigenic relationship between oval cells and a subpopulation of hepatic foci, nodules, and carcinomas induced by the “resistant hepatocyte” model system. Cancer Res 51:1308–1317
Fausto N, Campbell JS, Riehle KJ (2006) Liver regeneration. Hepatology 43:S45–53
Fischer M, Goldschmitt J, Peschel C, Brakenhoff JP, Kallen KJ, Wollmer A, Grotzinger J, Rose-John S (1997) A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol 15:142–145
Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR (2004) A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126:955–963
Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83:803–812
Fujii H, Hirose T, Oe S, Yasuchika K, Azuma H, Fujikawa T, Nagao M, Yamaoka Y (2002) Contribution of bone marrow cells to liver regeneration after partial hepatectomy in mice. J Hepatol 36:653–659
Fujio K, Evarts RP, Hu Z, Marsden ER, Thorgeirsson SS (1994) 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
Furst G, Schulte am Esch J, Poll LW, Hosch SB, Fritz LB, Klein M, Godehardt E, Krieg A, Wecker B, Stoldt V, Stockschlader M, Eisenberger CF, Modder U, Knoefel WT (2007) Portal vein embolization and autologous CD133+ bone marrow stem cells for liver regeneration: initial experience. Radiology 243:171–179
Gaia S, Smedile A, Omede P, Olivero A, Sanavio F, Balzola F, Ottobrelli A, Abate ML, Marzano A, Rizzetto M, Tarella C (2006) Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. J Hepatol 45:13–19
Gao Z, McAlister VC, Williams GM (2001) Repopulation of liver endothelium by bone-marrow-derived cells. Lancet 357:932–933
Gasbarrini A, Rapaccini GL, Rutella S, Zocco MA, Zocco P, Leone G, Pola P, Gasbarrini G, Di Campli C (2006) Rescue therapy by portal infusion of autologous stem cells in a case of drug-induced hepatitis. Dig Liver Dis 39:878–882
Gauldie J, Lamontagne L, Horsewood P, Jenkins E (1980) Immunohistochemical localization of alpha 1-antitrypsin in normal mouse liver and pancreas. Am J Pathol 101:723–735
Gehling UM, Willems M, Dandri M, Petersen J, Berna M, Thill M, Wulf T, Muller L, Pollok JM, Schlagner K, Faltz C, Hossfeld DK, Rogiers X (2005) Partial hepatectomy induces mobilization of a unique population of haematopoietic progenitor cells in human healthy liver donors. J Hepatol 43:845–853
Girgenrath M, Weng S, Kostek CA, Browning B, Wang M, Brown SA, Winkles JA, Michaelson JS, Allaire N, Schneider P, Scott ML, Hsu YM, Yagita H, Flavell RA, Miller JB, Burkly LC, Zheng TS (2006) TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J 25:5826–5839
Gordon GJ, Coleman WB, Grisham JW (2000) Temporal analysis of hepatocyte differentiation by small hepatocyte-like progenitor cells during liver regeneration in retrorsine-exposed rats. Am J Pathol 157:771–786
Gordon MY, Levicar N, Pai M, Bachellier P, Dimarakis I, Al-Allaf F, M’Hamdi H, Thalji T, Welsh JP, Marley SB, Davies J, Dazzi F, Marelli-Berg F, Tait P, Playford R, Jiao L, Jensen S, Nicholls JP, Ayav A, Nohandani M, Farzaneh F, Gaken J, Dodge R, Alison M, Apperley JF, Lechler R, Habib NA (2006) Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem Cells 24:1822–1830
Gouw AS, Heuvel MC van den, Boot M, Slooff MJ, Poppema S, Jong KP de (2006) Dynamics of the vascular profile of the finer branches of the biliary tree in normal and diseased human livers. J Hepatol 45:393–400
Gressner AM, Yagmur E, Lahme B, Gressner O, Stanzel S (2006) Connective tissue growth factor in serum as a new candidate test for assessment of hepatic fibrosis. Clin Chem 52:1815–1817
Hansson GK (2007) Medicine. LIGHT hits the liver. Science 316:206–207
Hasuike S, Ido A, Uto H, Moriuchi A, Tahara Y, Numata M, Nagata K, Hori T, Hayashi K, Tsubouchi H (2005) Hepatocyte growth factor accelerates the proliferation of hepatic oval cells and possibly promotes the differentiation in a 2-acetylaminofluorene/partial hepatectomy model in rats. J Gastroenterol Hepatol 20:1753–1761
Hatch HM, Zheng D, Jorgensen ML, Petersen BE (2002) SDF-1alpha/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 4:339–351
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374:1–20
Henderson NC, Iredale JP (2007) Liver fibrosis: cellular mechanisms of progression and resolution. Clin Sci (Lond) 112:265–280
Herrera MB, Bruno S, Buttiglieri S, Tetta C, Gatti S, Deregibus MC, Bussolati B, Camussi G (2006) Isolation and characterization of a stem cell population from adult human liver. Stem Cells 24:2840–2850
Higashiyama R, Inagaki Y, Hong YY, Kushida M, Nakao S, Niioka M, Watanabe T, Okano H, Matsuzaki Y, Shiota G, Okazaki I (2007) Bone marrow-derived cells express matrix metalloproteinases and contribute to regression of liver fibrosis in mice. Hepatology 45:213–222
Hixson DC, Allison JP (1985) Monoclonal antibodies recognizing oval cells induced in the liver of rats by N-2-fluorenylacetamide or ethionine in a choline-deficient diet. Cancer Res 45:3750–3760
Holic N, Suzuki T, Corlu A, Couchie D, Chobert MN, Guguen-Guillouzo C, Laperche Y (2000) Differential expression of the rat gamma-glutamyl transpeptidase gene promoters along with differentiation of hepatoblasts into biliary or hepatocytic lineage. Am J Pathol 157:537–548
Hsia CC, Thorgeirsson SS, Tabor E (1994) Expression of hepatitis B surface and core antigens and transforming growth factor-alpha in “oval cells” of the liver in patients with hepatocellular carcinoma. J Med Virol 43:216–221
Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1993) Expression of hepatocyte growth factor and c-met genes during hepatic differentiation and liver development in the rat. Am J Pathol 142:1823–1830
Hu Z, Evarts RP, Fujio K, Marsden ER, Thorgeirsson SS (1995) Expression of fibroblast growth factor receptors flg and bek during hepatic ontogenesis and regeneration in the rat. Cell Growth Differ 6:1019–1025
Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J (2005) Effects of gadolinium chloride (GdCl3) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions. J Comp Pathol 133:92–102
Isfort RJ, Cody DB, Stuard SB, Randall CJ, Miller C, Ridder GM, Doersen CJ, Richards WG, Yoder BK, Wilkinson JE, Woychik RPJ (1997)The combination of epidermal growth factor and transforming growth factor-beta induces novel phenotypic changes in mouse liver stem cell lines. J Cell Sci 110:3117–3129
Ito A, Nishikawa Y, Ohnuma K, Ohnuma I, Koma Y, Sato A, Enomoto K, Tsujimura T, Yokozaki H (2007) SgIGSF is a novel biliary-epithelial cell adhesion molecule mediating duct/ductule development. Hepatology 45:684–694
Jakubowski A, Browning B, Lukashev M, Sizing I, Thompson JS, Benjamin CD, Hsu YM, Ambrose C, Zheng TS, Burkly LC (2002) Dual role for TWEAK in angiogenic regulation. J Cell Sci 115:267–274
Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng S, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC (2005) TWEAK induces liver progenitor cell proliferation. J Clin Invest 115:2330–2340
Jelnes P, Santoni-Rugiu E, Rasmussen M, Friis SL, Nielsen JH, Tygstrup N, Bisgaard HC (2007) Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration. Hepatology 45:1462–1470
Jensen CH, Jauho EI, Santoni-Rugiu E, Holmskov U, Teisner B, Tygstrup N, Bisgaard HC (2004) Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1. Am J Pathol 164:1347–1359
Jin-no K, Tanimizu M, Hyodo I, Kurimoto F, Yamashita T (1997) Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease. J Gastroenterol 32:119–121
Jung J, Zheng M, Goldfarb M, Zaret KS (1999) Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284:1998–2003
Kawakita T, Shiraki K, Yamanaka Y, Yamaguchi Y, Saitou Y, Enokimura N, Yamamoto N, Okano H, Sugimoto K, Murata K, Nakano T (2005) Functional expression of TWEAK in human colonic adenocarcinoma cells. Int J Oncol 26:87–93
Kinoshita T, Sekiguchi T, Xu MJ, Ito Y, Kamiya A, Tsuji K, Nakahata T, Miyajima A (1999) Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. Proc Natl Acad Sci USA 96:7265–7270
Kinosita R (1937) Studies on the cancerogenic chemical substances. Trans Soc Pathol Jpn 27:329–334
Kirillova I, Chaisson M, Fausto N (1999) Tumor necrosis factor induces DNA replication in hepatic cells through nuclear factor kappaB activation. Cell Growth Differ 10:819–828
Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA (2006) Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol 45:429–438
Knight B, Yeoh GC (2005) TNF/LTalpha double knockout mice display abnormal inflammatory and regenerative responses to acute and chronic liver injury. Cell Tissue Res 319:61–70
Knight B, Yeoh GC, Husk KL, Ly T, Abraham LJ, Yu C, Rhim JA, Fausto N (2000) Impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice. J Exp Med 192:1809–1818
Knight B, Matthews VB, Akhurst B, Croager EJ, Klinken E, Abraham LJ, Olynyk JK, Yeoh G (2005a) Liver inflammation and cytokine production, but not acute phase protein synthesis, accompany the adult liver progenitor (oval) cell response to chronic liver injury.Immunol Cell Biol 83:364–374
Knight B, Yeap BB, Yeoh GC, Olynyk JK (2005b) Inhibition of adult liver progenitor (oval) cell growth and viability by an agonist of the peroxisome proliferator activated receptor (PPAR) family member gamma, but not alpha or delta. Carcinogenesis 26:1782–1792
Knight B, Akhurst B, Matthews VB, Ruddell RG, Ramm GA, Abraham LJ, Olynyk JK, Yeoh GC (2007) Attenuated liver progenitor (oval) cell and fibrogenic responses to the choline deficient, ethionine supplemented diet in the BALB/c inbred strain of mice. J Hepatol 46:134–141
Koivisto UM, Hubbard AL, Mellman I (2001) A novel cellular phenotype for familial hypercholesterolemia due to a defect in polarized targeting of LDL receptor. Cell 105:575–585
Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD, Kahn J, Spiegel A, Dar A, Samira S, Goichberg P, Kalinkovich A, Arenzana-Seisdedos F, Nagler A, Hardan I, Revel M, Shafritz DA, Lapidot T (2003) HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 112:160–169
Komuves LG, Feren A, Jones AL, Fodor E (2000) Expression of epidermal growth factor and its receptor in cirrhotic liver disease. J Histochem Cytochem 48:821–830
Kon J, Ooe H, Oshima H, Kikkawa Y, Mitaka T (2006) Expression of CD44 in rat hepatic progenitor cells. J Hepatol 45:90–98
Lagasse E, Connors H, Al-Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M (2000) Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 6:1229–1234
Lamas E, Kahn A, Guillouzo A (1987) Detection of mRNAs present at low concentrations in rat liver by in situ hybridization: application to the study of metabolic regulation and azo dye hepatocarcinogenesis. J Histochem Cytochem 35:559–563
Laconi S, Curreli F, Diana S, Pasciu D, De Filippo G, Sarma DS, Pani P, Laconi E (1999) Liver regeneration in response to partial hepatectomy in rats treated with retrorsine: a kinetic study.J Hepatol 31:1069–1074
Lazaro CA, Rhim JA, Yamada Y, Fausto N (1998) Generation of hepatocytes from oval cell precursors in culture. Cancer Res 58:5514–5522
Leahy DJ (2004) Structure and function of the epidermal growth factor (EGF/ErbB) family of receptors. Adv Protein Chem 68:1–27
Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, Roberts LR, Demetris AJ, Sun Z, Nevens F, Roskams T, Thorgeirsson SS (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410–416
Lemoli RM, Catani L, Talarico S, Loggi E, Gramenzi A, Baccarani U, Fogli M, Grazi GL, Aluigi M, Marzocchi G, Bernardi M, Pinna A, Bresadola F, Baccarani M, Andreone P (2006) Mobilization of bone marrow-derived hematopoietic and endothelial stem cells after orthotopic liver transplantation and liver resection. Stem Cells 24:2817–2825
Libbrecht L, Desmet V, Van Damme B, Roskams T (2000a) Deep intralobular extension of human hepatic “progenitor cells” correlates with parenchymal inflammation in chronic viral hepatitis: can “progenitor cells” migrate? J Pathol 192:373–378
Libbrecht L, Desmet V, Van Damme B, Roskams T (2000b) The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells. J Hepatol 33:76–84
Lim R, Knight B, Patel K, McHutchison JG, Yeoh GC, Olynyk JK (2006) Antiproliferative effects of interferon alpha on hepatic progenitor cells in vitro and in vivo. Hepatology 43:1074–1083
Lo JC, Wang Y, Tumanov AV, Bamji M, Yao Z, Reardon CA, Getz GS, Fu YX (2007) Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science 316:285–288
Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487–501
Lowes KN, Brennan BA, Yeoh GC, Olynyk JK (1999) Oval cell numbers in human chronic liver diseases are directly related to disease severity. Am J Pathol 154:537–541
Mandache E, Vidulescu C, Gherghiceanu M, Dragomir P, Popescu LM (2002) Neoductular progenitor cells regenerate hepatocytes in severely damaged liver: a comparative ultrastructural study. J Cell Mol Med 6:59–73
Marsden ER, Hu Z, Fujio K, Nakatsukasa H, Thorgeirsson SS, Evarts RP (1992) Expression of acidic fibroblast growth factor in regenerating liver and during hepatic differentiation. Lab Invest 67:427–433
Marshall A, Rushbrook S, Davies SE, Morris LS, Scott IS, Vowler SL, Coleman N, Alexander G (2005) Relation between hepatocyte G1 arrest, impaired hepatic regeneration, and fibrosis in chronic hepatitis C virus infection. Gastroenterology 128:33–42
Matsusaka S, Tsujimura T, Toyosaka A, Nakasho K, Sugihara A, Okamoto E, Uematsu K, Terada N (1999) Role of c-kit receptor tyrosine kinase in development of oval cells in the rat 2-acetylaminofluorene/partial hepatectomy model. Hepatology 29:670–676
Matthews VB, Klinken E, Yeoh GC (2004) Direct effects of interleukin-6 on liver progenitor oval cells in culture. Wound Repair Regen 12:650–656
Matthews VB, Knight B, Tirnitz-Parker JE, Boon J, Olynyk JK, Yeoh GC (2005) Oncostatin M induces an acute phase response but does not modulate the growth or maturation-status of liver progenitor (oval) cells in culture. Exp Cell Res 306:252–263
Mavier P, Martin N, Couchie D, Preaux AM, Laperche Y, Zafrani ES (2004) Expression of stromal cell-derived factor-1 and of its receptor CXCR4 in liver regeneration from oval cells in rat. Am J Pathol 165:1969–1977
Menthena A, Deb N, Oertel M, Grozdanov PN, Sandhu J, Shah S, Guha C, Shafritz DA, Dabeva MD (2004) Bone marrow progenitors are not the source of expanding oval cells in injured liver. Stem Cells 22:1049–1061
Metcalf D, Gearing DP (1989) A myelosclerotic syndrome in mice engrafted with cells producing high levels of leukemia inhibitory factor (LIF). Leukemia 3:847–852
Michalopoulos GK, Bowen WC, Mule K, Stolz DB (2001) Histological organization in hepatocyte organoid cultures. Am J Pathol 159:1877–1887
Michalopoulos GK, Barua L, Bowen WC (2005) Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41:535–544
Muller M, Morotti A, Ponzetto C (2002) Activation of NF-kappaB is essential for hepatocyte growth factor-mediated proliferation and tubulogenesis. Mol Cell Biol 22:1060–1072
Nagy P, Bisgaard HC, Thorgeirsson SS (1994) Expression of hepatic transcription factors during liver development and oval cell differentiation. J Cell Biol 126:223–233
Nagy P, Bisgaard HC, Santoni-Rugiu E, Thorgeirsson SS (1996) In vivo infusion of growth factors enhances the mitogenic response of rat hepatic ductal (oval) cells after administration of 2-acetylaminofluorene. Hepatology 23:71–79
Nagy P, Kiss A, Schnur J, Thorgeirsson SS (1998) Dexamethasone inhibits the proliferation of hepatocytes and oval cells but not bile duct cells in rat liver. Hepatology 28:423–429
Nakayama M, Kayagaki N, Yamaguchi N, Okumura K, Yagita H (2000) Involvement of TWEAK in interferon gamma-stimulated monocyte cytotoxicity. J Exp Med 192:1373–1380
Nguyen LN, Furuya MH, Wolfraim LA, Nguyen AP, Holdren MS, Campbell JS, Knight B, Yeoh GC, Fausto N, Parks WT (2007) Transforming growth factor-beta differentially regulates oval cell and hepatocyte proliferation. Hepatology 45:31–41
Neirhoff D, Ogawa A, Oertel M, Chen YQ, Shafritz DA (2005) Purification and characterization of mouse fetal liver epithelial cells with high in vivo repopulation capacity. Hepatology 42:130–139
Oben JA, Roskams T, Yang S, Lin H, Sinelli N, Li Z, Torbenson M, Huang J, Guarino P, Kafrouni M, Diehl AM (2003) Sympathetic nervous system inhibition increases hepatic progenitors and reduces liver injury. Hepatology 38:664–673
Oe H, Kaido T, Mori A, Onodera H, Imamura M (2005) Hepatocyte growth factor as well as vascular endothelial growth factor gene induction effectively promotes liver regeneration after hepatectomy in Solt-Farber rats.Hepatogastroenterology 52:1393–1397
Oh SH, Witek RP, Bae SH, Zheng D, Jung Y, Piscaglia AC, Petersen BE (2007) Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Gastroenterology 132:1077–1087
Olynyk JK, Yeoh GC, Ramm GA, Clarke SL, Hall PM, Britton RS, Bacon BR, Tracy TF (1998) Gadolinium chloride suppresses hepatic oval cell proliferation in rats with biliary obstruction. Am J Pathol 152:347–352
Omori N, Evarts RP, Omori M, Hu Z, Marsden ER, Thorgeirsson SS (1996) Expression of leukemia inhibitory factor and its receptor during liver regeneration in the adult rat. Lab Invest 75:15–24
Omori N, Omori M, Evarts RP, Teramoto T, Miller MJ, Hoang TN, Thorgeirsson SS (1997) Partial cloning of rat CD34 cDNA and expression during stem cell-dependent liver regeneration in the adult rat. Hepatology 26:720–727
Overturf K, Al-Dhalimy M, Ou CN, Finegold M, Grompe M (1997) Serial transplantation reveals the stem-cell-like regenerative potential of adult mouse hepatocytes. Am J Pathol 151:1273–1280
Overturf K, Al-Dhalimy M, Finegold M, Grompe M (1999) The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am J Pathol 155:2135–2143
Paku S, Schnur J, Nagy P, Thorgeirsson SS (2001) Origin and structural evolution of the early proliferating oval cells in rat liver. Am J Pathol 158:1313–1323
Paku S, Dezso K, Kopper L, Nagy P (2005) Immunohistochemical analysis of cytokeratin 7 expression in resting and proliferating biliary structures of rat liver. Hepatology 42:863–870
Paradis V, Perlemuter G, Bonvoust F, Dargere D, Parfait B, Vidaud M, Conti M, Huet S, Ba N, Buffet C, Bedossa P (2001) High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34:738–744
Park DY, Suh KS (1999) Transforming growth factor-beta1 protein, proliferation and apoptosis of oval cells in acetylaminofluorene-induced rat liver regeneration. J Korean Med Sci 14:531–538
Pellegrini L (2001) Role of heparan sulfate in fibroblast growth factor signalling: a structural view. Curr Opin Struct Biol 11:629–634
Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170
Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW (2003) Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology 37:632–640
Pi L, Oh SH, Shupe T, Petersen BE (2005) Role of connective tissue growth factor in oval cell response during liver regeneration after 2-AAF/PHx in rats. Gastroenterology 128:2077–2088
Preisegger KH, Factor VM, Fuchsbichler A, Stumptner C, Denk H, Thorgeirsson SS (1999) Atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model for chronic alcoholic liver disease. Lab Invest 79:103–109
Rhim JA, Sandgren EP, Degen JL, Palmiter RD, Brinster RL (1994) Replacement of diseased mouse liver by hepatic cell transplantation. Science 263:1149–1152
Rosenberg D, Ilic Z, Yin L, Sell S (2000) Proliferation of hepatic lineage cells of normal C57BL and interleukin-6 knockout mice after cocaine-induced periportal injury. Hepatology 31:948–955
Roskams T (2003) Progenitor cell involvement in cirrhotic human liver diseases: from controversy to consensus. J Hepatol 39:431–434
Roskams T (2006) Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene 25:3818–3822
Roskams T, De Vos R, Oord JJ van den, Desmet V (1991) Cells with neuroendocrine features in regenerating human liver. APMIS Suppl 23:32–39
Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, Achten R, Verslype C, Diehl AM (2003a) Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 163:1301–1311
Roskams TA, Libbrecht L, Desmet VJ (2003b) Progenitor cells in diseased human liver. Semin Liver Dis 23:385–396
Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ (2006) The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130:1807–1821
Sanchez A, Factor VM, Schroeder IS, Nagy P, Thorgeirsson SS (2004) Activation of NF-kappaB and STAT3 in rat oval cells during 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration. Hepatology 39:376–385
Santoni-Rugiu E, Jelnes P, Thorgeirsson SS, Bisgaard HC (2005) Progenitor cells in liver regeneration: molecular responses controlling their activation and expansion. APMIS 113:876–902
Saxena R, Theise ND, Crawford JM (1999) Microanatomy of the human liver-exploring the hidden interfaces. Hepatology 30:1339–1346
Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T, Lenvik T, Johnson S, Hu WS, Verfaillie CM (2002) Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 109:1291–1302
Shafritz DA, Oertel M, Menthena A, Nierhoff D, Dabeva MD (2006) Liver stem cells and prospects for liver reconstitution by transplanted cells. Hepatology 43:S89–S98
Shiojiri N, Lemire JM, Fausto N (1991) Cell lineages and oval cell progenitors in rat liver development. Cancer Res 51:2611–2620
Shiota G, Okano J, Kawasaki H, Kawamoto T, Nakamura T (1995) Serum hepatocyte growth factor levels in liver diseases: clinical implications. Hepatology 21:106–112
Solt D, Farber E (1976) New principle for the analysis of chemical carcinogenesis. Nature 263:701–703
Streetz KL, Tacke F, Leifeld L, Wustefeld T, Graw A, Klein C, Kamino K, Spengler U, Kreipe H, Kubicka S, Muller W, Manns MP, Trautwein C (2003) Interleukin 6/gp130-dependent pathways are protective during chronic liver diseases. Hepatology 38:218–229
Subrata LS, Lowes KN, Olynyk JK, Yeoh GC, Quail EA, Abraham LJ (2005) Hepatic expression of the tumor necrosis factor family member lymphotoxin-beta is regulated by interleukin (IL)-6 and IL-1beta: transcriptional control mechanisms in oval cells and hepatoma cell lines. Liver Int 25:633–646
Suzuki A, Iwama A, Miyashita H, Nakauchi H, Taniguchi H (2003) Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 130:2513–2524
Taniguchi E, Kin M, Torimura T, Nakamura T, Kumemura H, Hanada S, Hisamoto T, Yoshida T, Kawaguchi T, Baba S, Maeyama M, Koga H, Harada M, Kumashiro R, Ueno T, Mizuno S, Ikeda H, Imaizumi T, Murohara T, Sata M (2006) Endothelial progenitor cell transplantation improves the survival following liver injury in mice. Gastroenterology 130:521–531
Tee LB, Smith PG, Yeoh GC (1992) Expression of alpha, mu and pi class glutathione S-transferases in oval and ductal cells in liver of rats placed on a choline-deficient, ethionine-supplemented diet. Carcinogenesis 13:1879–1885
Terada R, Yamamoto K, Hakoda T, Shimada N, Okano N, Baba N, Ninomiya Y, Gershwin ME, Shiratori Y (2003) Stromal cell-derived factor-1 from biliary epithelial cells recruits CXCR4-positive cells: implications for inflammatory liver diseases. Lab Invest 83:665–672
Terai S, Ishikawa T, Omori K, Aoyama K, Marumoto Y, Urata Y, Yokoyama Y, Uchida K, Yamasaki T, Fujii Y, Okita K, Sakaida I (2006) Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem Cells 24:2292–2298
Theise ND, Saxena R, Portmann BC, Thung SN, Yee H, Chiriboga L, Kumar A, Crawford JM (1999) The canals of Hering and hepatic stem cells in humans. Hepatology 30:1425–1433
Theise ND, Nimmakayalu M, Gardner R, Illei PB, Morgan G, Teperman L, Henegariu O, Krause DS (2000) Liver from bone marrow in humans. Hepatology 32:11–16
Theocharis SE, Margeli AP, Skaltsas SD, Skopelitou AS, Mykoniatis MG, Kittas CN (1997) Effect of interferon-alpha2b administration on rat liver regeneration after partial hepatectomy. Dig Dis Sci 42:1981–1986
Thorgeirsson SS, Grisham JW (2006) Hematopoietic cells as hepatocyte stem cells: a critical review of the evidence. Hepatology 43:2–8
Tian YW, Smith PG, Yeoh GC (1997) The oval-shaped cell as a candidate for a liver stem cell in embryonic, neonatal and precancerous liver: identification based on morphology and immunohistochemical staining for albumin and pyruvate kinase isoenzyme expression. Histochem Cell Biol 107:243–250
Tilg H, Wilmer A, Vogel W, Herold M, Nolchen B, Judmaier G, Huber C (1992) Serum levels of cytokines in chronic liver diseases. Gastroenterology 103:264–274
Toyonaga T, Hino O, Sugai S, Wakasugi S, Abe K, Shichiri M, Yamamura K (1994) Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. Proc Natl Acad Sci USA 91:614–618
Tsamandas AC, Syrokosta I, Thomopoulos K, Zolota V, Dimitropoulou D, Liava A, Coupoulou AA, Siagris D, Petsas T, Karatza C, Gogos CA (2006) Potential role of hepatic progenitor cells expression in cases of chronic hepatitis C and their relation to response to therapy: a clinicopathologic study. Liver Int 26:817–826
Tsuchiya A, Heike T, Fujino H, Shiota M, Umeda K, Yoshimoto M, Matsuda Y, Ichida T, Aoyagi Y, Nakahata T (2005) Long-term extensive expansion of mouse hepatic stem/progenitor cells in a novel serum-free culture system. Gastroenterology 128:2089–2104
Vassilopoulos G, Wang PR, Russell DW (2003) Transplanted bone marrow regenerates liver by cell fusion. Nature 422:901–904
Vig P, Russo FP, Edwards RJ, Tadrous PJ, Wright NA, Thomas HC, Alison MR, Forbes SJ (2006) The sources of parenchymal regeneration after chronic hepatocellular liver injury in mice. Hepatology 43:316–324
Vivier I, Marguet D, Naquet P, Bonicel J, Black D, Li CX, Bernard AM, Gorvel JP, Pierres M (1991) Evidence that thymocyte-activating molecule is mouse CD26 (dipeptidyl peptidase IV). J Immunol 147:447–454
Wang X, Montini E, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M (2002) Kinetics of liver repopulation after bone marrow transplantation. Am J Pathol 161:565–574
Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M (2003a) The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci USA 100 Suppl 1:11881–11888
Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Olson S, Grompe M (2003b) Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 422:897–901
Wege H, Muller A, Muller L, Petri S, Petersen J, Hillert C (2007) Regeneration in pig livers by compensatory hyperplasia induces high levels of telomerase activity. Comp Hepatol 6:6
Wiemann SU, Satyanarayana A, Tsahuridu M, Tillmann HL, Zender L, Klempnauer J, Flemming P, Franco S, Blasco MA, Manns MP, Rudolph KL (2002) Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J 16:935–942
Willenbring H, Bailey AS, Foster M, Akkari Y, Dorrell C, Olson S, Finegold M, Fleming WH, Grompe M (2004) Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 10:744–748
Wong S, Gauthier T, Kaita KD, Minuk GY (1995) The differential effects of three forms of interferon alfa on hepatic regeneration after partial hepatectomy in the rat. Hepatology 22:883–886
Yamada Y, Nishimoto E, Mitsuya H, Yonemura Y (2006) In vitro transdifferentiation of adult bone marrow Sca-1+ cKit- cells cocultured with fetal liver cells into hepatic-like cells without fusion. Exp Hematol 34:97–106
Yamazaki S, Miki K, Hasegawa K, Sata M, Takayama T, Makuuchi M (2003) Sera from liver failure patients and a demethylating agent stimulate transdifferentiation of murine bone marrow cells into hepatocytes in coculture with nonparenchymal liver cells. J Hepatol 39:17–23
Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, Proya E, Anagnostopoulos A, Fassas A (2005) G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol 33:108–119
Yasui O, Miura N, Terada K, Kawarada Y, Koyama K, Sugiyama T (1997) Isolation of oval cells from Long-Evans Cinnamon rats and their transformation into hepatocytes in vivo in the rat liver. Hepatology 25:329–334
Yeoh GC, Ernst M, Rose-John S, Akhurst B, Payne C, Long S, Alexander W, Croker B, Grail D, Matthews VB (2007) Opposing roles of gp130-mediated STAT-3 and ERK-1/ 2 signaling in liver progenitor cell migration and proliferation. Hepatology 45:486–494
Yin L, Lynch D, Sell S (1999) Participation of different cell types in the restitutive response of the rat liver to periportal injury induced by allyl alcohol. J Hepatol 31:497–507
Yin L, Sun M, Ilic Z, Leffert HL, Sell S (2002) Derivation, characterization, and phenotypic variation of hepatic progenitor cell lines isolated from adult rats. Hepatology 35:315–324
Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD (2007) Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 45:139–149
Zhang M, Thorgeirsson SS (1994) Modulation of connexins during differentiation of oval cells into hepatocytes. Exp Cell Res 213:37–42
Zheng D, Oh SH, Jung Y, Petersen BE (2006) Oval cell response in 2-acetylaminofluorene/partial hepatectomy rat is attenuated by short interfering RNA targeted to stromal cell-derived factor-1. Am J Pathol 169:2066–2074
Znoyko I, Sohara N, Spicer SS, Trojanowska M, Reuben A (2005) Expression of oncostatin M and its receptors in normal and cirrhotic human liver. J Hepatol 43:893–900
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was supported by a Wellcome Trust Clinical Training Fellowship to T.G.B.; S.L. is supported by an EASL Sheila Sherlock Fellowship Post-Doctoral Fellowship.
Rights and permissions
About this article
Cite this article
Bird, T.G., Lorenzini, S. & Forbes, S.J. Activation of stem cells in hepatic diseases. Cell Tissue Res 331, 283–300 (2008). https://doi.org/10.1007/s00441-007-0542-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00441-007-0542-z