Skip to main content
SpringerLink
Log in

Liver Stem Cells

  • Chapter
  • First Online:
Regenerative Medicine - from Protocol to Patient

  • 927 Accesses

Abstract

The liver is an essential organ for life, serving as the center for metabolism and playing various critical functions in controlling systemic homeostasis. Among multiple types of cells comprising the liver, hepatocytes and cholangiocytes are the two epithelial cell lineages in the organ, and commonly originate from hepatoblasts during organogenesis in developing embryos. Thus, hepatoblasts possess bi-lineage differentiation potential into hepatocytes and cholangiocytes, a phenotypic feature that can best distinguish and define liver stem cells. While the liver is considered not to rely on any resident stem cell population for their homeostatic maintenance, facultative stem/progenitor cells with bi-lineage differentiation potential, referred to as oval cells in rodents, may emerge under severe damage conditions and play critical roles in promoting the regenerative processes. However, the extent to which these putative stem/progenitor cells contribute to regeneration has been debated, as recent studies have shown that most regenerative responses are hepatocyte-derived, particularly in mice. Evidence for both scenarios will be discussed in later sections. Nevertheless, identification of specific markers has enabled researchers to isolate and characterize these fetal and adult stem/progenitor cell populations. In vitro culture systems as well as in vivo studies using animal models have allowed elucidation of detailed molecular mechanisms, including intercellular signaling webs and intracellular transcriptional regulatory networks, which coordinately regulate development, differentiation and behavior of these cells. Understanding the cellular and molecular basis of liver development and regeneration from the perspective of the embryonic and adult stem/progenitor cells should make invaluable contributions to future development of technologies to produce fully functional hepatocytes in vitro that are applicable for cell therapy and pharmaceutical screening.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agarwal S, Holton KL, Lanza R (2008) Efficient differentiation of functional hepatocytes from human embryonic stem cells. Stem Cells 26(5):1117–1127

    Article  CAS  PubMed  Google Scholar 

  • Akhurst B, Croager EJ, Farley-Roche CA, Ong JK, Dumble ML, Knight B, Yeoh GC (2001) A modified choline-deficient, ethionine-supplemented diet protocol effectively induces oval cells in mouse liver. Hepatology 34(3):519–522

    Article  CAS  PubMed  Google Scholar 

  • Antoniou A, Raynaud P, Cordi S, Zong Y, Tronche F, Stanger BZ, Jacquemin P, Pierreux CE, Clotman F, Lemaigre FP (2009) Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136(7):2325–2333

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Apte U, Thompson MD, Cui S, Liu B, Cieply B, Monga SP (2008) Wnt/beta-catenin signaling mediates oval cell response in rodents. Hepatology 47(1):288–295

    Article  CAS  PubMed  Google Scholar 

  • Asahina K, Zhou B, Pu WT, Tsukamoto H (2011) Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 53(3):983–995

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basma H, Soto-Gutierrez A, Yannam GR, Liu L, Ito R, Yamamoto T, Ellis E, Carson SD, Sato S, Chen Y, Muirhead D, Navarro-Alvarez N, Wong RJ, Roy-Chowdhury J, Platt JL, Mercer DF, Miller JD, Strom SC, Kobayashi N, Fox IJ (2009) Differentiation and transplantation of human embryonic stem cell-derived hepatocytes. Gastroenterology 136(3):990–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1):60–66

    Article  CAS  PubMed  Google Scholar 

  • Bort R, Signore M, Tremblay K, Martinez Barbera JP, Zaret KS (2006) Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev Biol 290(1):44–56

    Article  CAS  PubMed  Google Scholar 

  • Boulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SS, Spee B, Van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ (2012) Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med 18(4):572–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cai J, Zhao Y, Liu Y, Ye F, Song Z, Qin H, Meng S, Chen Y, Zhou R, Song X, Guo Y, Ding M, Deng H (2007) Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45(5):1229–1239

    Article  CAS  PubMed  Google Scholar 

  • Carpentier R, Suner RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, Antoniou A, Raynaud P, Lepreux S, Jacquemin P, Leclercq IA, Sander M, Lemaigre FP (2011) Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141(4):1432–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen YR, Sekine K, Nakamura K, Yanai H, Tanaka M, Miyajima A (2009) Y-box binding protein-1 down-regulates expression of carbamoyl phosphate synthetase-I by suppressing CCAAT enhancer-binding protein-alpha function in mice. Gastroenterology 137(1):330–340

    Article  CAS  PubMed  Google Scholar 

  • Choi TY, Ninov N, Stainier DY, Shin D (2014) Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146(3):776–788. doi:10.1053/j.gastro.2013.10.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Clotman F, Lannoy VJ, Reber M, Cereghini S, Cassiman D, Jacquemin P, Roskams T, Rousseau GG, Lemaigre FP (2002) The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129(8):1819–1828

    CAS  PubMed  Google Scholar 

  • Clotman F, Jacquemin P, Plumb-Rudewiez N, Pierreux CE, Van der Smissen P, Dietz HC, Courtoy PJ, Rousseau GG, Lemaigre FP (2005) Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev 19(16):1849–1854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coffinier C, Gresh L, Fiette L, Tronche F, Schutz G, Babinet C, Pontoglio M, Yaniv M, Barra J (2002) Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development 129(8):1829–1838

    CAS  PubMed  Google Scholar 

  • Costa RH, Kalinichenko VV, Holterman AX, Wang X (2003) Transcription factors in liver development, differentiation, and regeneration. Hepatology 38(6):1331–1347

    Article  CAS  PubMed  Google Scholar 

  • DeLaForest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA (2011) HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138(19):4143–4153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Deutsch G, Jung J, Zheng M, Lora J, Zaret KS (2001) A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 128(6):871–881

    CAS  PubMed  Google Scholar 

  • Dorrell C, Erker L, Lanxon-Cookson KM, Abraham SL, Victoroff T, Ro S, Canaday PS, Streeter PR, Grompe M (2008) Surface markers for the murine oval cell response. Hepatology 48(4):1282–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dorrell C, Erker L, Schug J, Kopp JL, Canaday PS, Fox AJ, Smirnova O, Duncan AW, Finegold MJ, Sander M, Kaestner KH, Grompe M (2011) Prospective isolation of a bipotential clonogenic liver progenitor cell in adult mice. Genes Dev 25(11):1193–1203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Du Y, Wang J, Jia J, Song N, Xiang C, Xu J, Hou Z, Su X, Liu B, Jiang T, Zhao D, Sun Y, Shu J, Guo Q, Yin M, Sun D, Lu S, Shi Y, Deng H (2014) Human hepatocytes with drug metabolic function induced from fibroblasts by lineage reprogramming. Cell Stem Cell 14:394–403

    Article  CAS  PubMed  Google Scholar 

  • Duncan AW, Dorrell C, Grompe M (2009) Stem cells and liver regeneration. Gastroenterology 137(2):466–481

    Article  PubMed  PubMed Central  Google Scholar 

  • Dunsford HA, Sell S (1989) Production of monoclonal antibodies to preneoplastic liver cell populations induced by chemical carcinogens in rats and to transplantable Morris hepatomas. Cancer Res 49(17):4887–4893

    CAS  PubMed  Google Scholar 

  • Engelhardt NV, Factor VM, Yasova AK, Poltoranina VS, Baranov VN, Lasareva MN (1990) Common antigens of mouse oval and biliary epithelial cells. Expression on newly formed hepatocytes. Differentiation 45(1):29–37

    Article  CAS  PubMed  Google Scholar 

  • 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(2):142–148

    CAS  PubMed  Google Scholar 

  • Fausto N (2004) Liver regeneration and repair: hepatocytes, progenitor cells, and stem cells. Hepatology 39(6):1477–1487

    Article  PubMed  Google Scholar 

  • Fellous TG, Islam S, Tadrous PJ, Elia G, Kocher HM, Bhattacharya S, Mears L, Turnbull DM, Taylor RW, Greaves LC, Chinnery PF, Taylor G, McDonald SA, Wright NA, Alison MR (2009) Locating the stem cell niche and tracing hepatocyte lineages in human liver. Hepatology 49(5):1655–1663

    Article  CAS  PubMed  Google Scholar 

  • Ferber S, Halkin A, Cohen H, Ber I, Einav Y, Goldberg I, Barshack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A (2000) Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat Med 6(5):568–572

    Article  CAS  PubMed  Google Scholar 

  • Floridon C, Jensen CH, Thorsen P, Nielsen O, Sunde L, Westergaard JG, Thomsen SG, Teisner B (2000) Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation. Differentiation 66(1):49–59

    Article  CAS  PubMed  Google Scholar 

  • Furuyama K, Kawaguchi Y, Akiyama H, Horiguchi M, Kodama S, Kuhara T, Hosokawa S, Elbahrawy A, Soeda T, Koizumi M, Masui T, Kawaguchi M, Takaori K, Doi R, Nishi E, Kakinoki R, Deng JM, Behringer RR, Nakamura T, Uemoto S (2011) Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nat Genet 43(1):34–41

    Article  CAS  PubMed  Google Scholar 

  • Gai H, Nguyen DM, Moon YJ, Aguila JR, Fink LM, Ward DC, Ma Y (2010) Generation of murine hepatic lineage cells from induced pluripotent stem cells. Differentiation 79(3):171–181

    Article  CAS  PubMed  Google Scholar 

  • Geisler F, Nagl F, Mazur PK, Lee M, Zimber-Strobl U, Strobl LJ, Radtke F, Schmid RM, Siveke JT (2008) Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 48(2):607–616

    Article  CAS  PubMed  Google Scholar 

  • Gouon-Evans V, Boussemart L, Gadue P, Nierhoff D, Koehler CI, Kubo A, Shafritz DA, Keller G (2006) BMP-4 is required for hepatic specification of mouse embryonic stem cell-derived definitive endoderm. Nat Biotechnol 24(11):1402–1411

    Article  CAS  PubMed  Google Scholar 

  • Grompe M (2003) Pancreatic-hepatic switches in vivo. Mech Dev 120(1):99–106

    Article  CAS  PubMed  Google Scholar 

  • Grozdanov PN, Yovchev MI, Dabeva MD (2006) The oncofetal protein glypican-3 is a novel marker of hepatic progenitor/oval cells. Lab Invest 86(12):1272–1284

    Article  CAS  PubMed  Google Scholar 

  • He J, Lu H, Zou Q, Luo L (2014) Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146(3):789–800 e788. doi:10.1053/j.gastro.2013.11.045

    Article  CAS  PubMed  Google Scholar 

  • Hirose Y, Itoh T, Miyajima A (2009) Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells. Exp Cell Res 315(15):2648–2657

    Article  CAS  PubMed  Google Scholar 

  • Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML (2010) Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137(23):4061–4072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu M, Kurobe M, Jeong YJ, Fuerer C, Ghole S, Nusse R, Sylvester KG (2007) Wnt/beta-catenin signaling in murine hepatic transit amplifying progenitor cells. Gastroenterology 133(5):1579–1591

    Article  CAS  PubMed  Google Scholar 

  • Huang P, He Z, Ji S, Sun H, Xiang D, Liu C, Hu Y, Wang X, Hui L (2011) Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475(7356):386–389

    Article  CAS  PubMed  Google Scholar 

  • Huang M, Chang A, Choi M, Zhou D, Anania FA, Shin CH (2014a) Antagonistic interaction between Wnt and Notch activity modulates the regenerative capacity of a zebrafish fibrotic liver model. Hepatology 60(5):1753–1766. doi:10.1002/hep.27285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang P, Zhang L, Gao Y, He Z, Yao D, Wu Z, Cen J, Chen X, Liu C, Hu Y, Lai D, Hu Z, Chen L, Zhang Y, Cheng X, Ma X, Pan G, Wang X, Hui L (2014b) Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell 14:370–384

    Article  CAS  PubMed  Google Scholar 

  • Huch M, Dorrell C, Boj SF, van Es JH, Li VS, van de Wetering M, Sato T, Hamer K, Sasaki N, Finegold MJ, Haft A, Vries RG, Grompe M, Clevers H (2013) In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494(7436):247–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huch M, Gehart H, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, Ellis E, van Wenum M, Fuchs SA, de Ligt J, van de Wetering M, Sasaki N, Boers SJ, Kemperman H, de Jonge J, Ijzermans JN, Nieuwenhuis EE, Hoekstra R, Strom S, Vries RR, van der Laan LJ, Cuppen E, Clevers H (2015) Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160(1–2):299–312. doi:10.1016/j.cell.2014.11.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Itoh T, Kamiya Y, Okabe M, Tanaka M, Miyajima A (2009) Inducible expression of Wnt genes during adult hepatic stem/progenitor cell response. FEBS Lett 583(4):777–781

    Article  CAS  PubMed  Google Scholar 

  • Jakubowski A, Ambrose C, Parr M, Lincecum JM, Wang MZ, Zheng TS, Browning B, Michaelson JS, Baetscher M, Wang B, Bissell DM, Burkly LC (2005) TWEAK induces liver progenitor cell proliferation. J Clin Invest 115(9):2330–2340

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(6):1462–1470

    Article  CAS  PubMed  Google Scholar 

  • 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(4):1347–1359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jors S, Jeliazkova P, Ringelhan M, Thalhammer J, Durl S, Ferrer J, Sander M, Heikenwalder M, Schmid RM, Siveke JT, Geisler F (2015) Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 125(6):2445–2457. doi:10.1172/JCI78585

    Article  PubMed  PubMed Central  Google Scholar 

  • Jung J, Zheng M, Goldfarb M, Zaret KS (1999) Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284(5422):1998–2003

    Article  CAS  PubMed  Google Scholar 

  • Kakinuma S, Ohta H, Kamiya A, Yamazaki Y, Oikawa T, Okada K, Nakauchi H (2009) Analyses of cell surface molecules on hepatic stem/progenitor cells in mouse fetal liver. J Hepatol 51(1):127–138

    Article  CAS  PubMed  Google Scholar 

  • Kamiya A, Gonzalez FJ (2004) TNF-alpha regulates mouse fetal hepatic maturation induced by oncostatin M and extracellular matrices. Hepatology 40(3):527–536

    Article  CAS  PubMed  Google Scholar 

  • Kamiya A, Kinoshita T, Ito Y, Matsui T, Morikawa Y, Senba E, Nakashima K, Taga T, Yoshida K, Kishimoto T, Miyajima A (1999) Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J 18(8):2127–2136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamiya A, Kojima N, Kinoshita T, Sakai Y, Miyajima A (2002) Maturation of fetal hepatocytes in vitro by extracellular matrices and oncostatin M: induction of tryptophan oxygenase. Hepatology 35(6):1351–1359

    Article  CAS  PubMed  Google Scholar 

  • Kamiya A, Kakinuma S, Yamazaki Y, Nakauchi H (2009) Enrichment and clonal culture of progenitor cells during mouse postnatal liver development in mice. Gastroenterology 137(3):1114–1126

    Article  CAS  PubMed  Google Scholar 

  • Kaneko K, Kamimoto K, Miyajima A, Itoh T (2015) Adaptive remodeling of the biliary architecture underlies liver homeostasis. Hepatology 61(6):2056–2066. doi:10.1002/hep.27685

    Article  CAS  PubMed  Google Scholar 

  • Kim S, Shin JS, Kim HJ, Fisher RC, Lee MJ, Kim CW (2007) Streptozotocin-induced diabetes can be reversed by hepatic oval cell activation through hepatic transdifferentiation and pancreatic islet regeneration. Lab Invest 87(7):702–712

    Article  CAS  PubMed  Google Scholar 

  • Kimura T, Christoffels VM, Chowdhury S, Iwase K, Matsuzaki H, Mori M, Lamers WH, Darlington GJ, Takiguchi M (1998) Hypoglycemia-associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPalpha knockout mice. J Biol Chem 273(42):27505–27510

    Article  CAS  PubMed  Google Scholar 

  • 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 U S A 96(13):7265–7270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(1):134–141

    Article  CAS  PubMed  Google Scholar 

  • Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T (2004) The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 127(6):1775–1786

    Article  CAS  PubMed  Google Scholar 

  • Kojima N, Kinoshita T, Kamiya A, Nakamura K, Nakashima K, Taga T, Miyajima A (2000) Cell density-dependent regulation of hepatic development by a gp130-independent pathway. Biochem Biophys Res Commun 277(1):152–158

    Article  CAS  PubMed  Google Scholar 

  • Kojima H, Fujimiya M, Matsumura K, Younan P, Imaeda H, Maeda M, Chan L (2003) NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Nat Med 9(5):596–603

    Article  CAS  PubMed  Google Scholar 

  • Kubota H, Reid LM (2000) Clonogenic hepatoblasts, common precursors for hepatocytic and biliary lineages, are lacking classical major histocompatibility complex class I antigen. Proc Natl Acad Sci U S A 97(22):12132–12137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kyrmizi I, Hatzis P, Katrakili N, Tronche F, Gonzalez FJ, Talianidis I (2006) Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 20(16):2293–2305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(4):410–416

    Article  CAS  PubMed  Google Scholar 

  • Lemaigre FP (2009) Mechanisms of liver development: concepts for understanding liver disorders and design of novel therapies. Gastroenterology 137(1):62–79

    Article  CAS  PubMed  Google Scholar 

  • Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB (1997) Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 16(3):243–251

    Article  CAS  PubMed  Google Scholar 

  • Loomes KM, Russo P, Ryan M, Nelson A, Underkoffler L, Glover C, Fu H, Gridley T, Kaestner KH, Oakey RJ (2007) Bile duct proliferation in liver-specific Jag1 conditional knockout mice: effects of gene dosage. Hepatology 45(2):323–330

    Article  CAS  PubMed  Google Scholar 

  • Lozier J, McCright B, Gridley T (2008) Notch signaling regulates bile duct morphogenesis in mice. PLoS One 3(3):e1851

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ludtke TH, Christoffels VM, Petry M, Kispert A (2009) Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology 49(3):969–978

    Article  PubMed  CAS  Google Scholar 

  • Malato Y, Naqvi S, Schurmann N, Ng R, Wang B, Zape J, Kay MA, Grimm D, Willenbring H (2011) Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J Clin Invest 121(12):4850–4860

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margagliotti S, Clotman F, Pierreux CE, Beaudry JB, Jacquemin P, Rousseau GG, Lemaigre FP (2007) The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol 311(2):579–589

    Article  CAS  PubMed  Google Scholar 

  • Matsumoto K, Yoshitomi H, Rossant J, Zaret KS (2001) Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294(5542):559–563

    Article  CAS  PubMed  Google Scholar 

  • Matthews VB, Yeoh GC (2005) Liver stem cells. IUBMB Life 57(8):549–553

    Article  CAS  PubMed  Google Scholar 

  • McCright B, Lozier J, Gridley T (2002) A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 129(4):1075–1082

    CAS  PubMed  Google Scholar 

  • McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB (2006) NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet 79(1):169–173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michalopoulos GK, DeFrances MC (1997) Liver regeneration. Science 276(5309):60–66

    Article  CAS  PubMed  Google Scholar 

  • Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP (2004) Beta-catenin is temporally regulated during normal liver development. Gastroenterology 126(4):1134–1146

    Article  CAS  PubMed  Google Scholar 

  • Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A (2012) Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol 22(13):1166–1175

    Article  CAS  PubMed  Google Scholar 

  • Nagahama Y, Sone M, Chen X, Okada Y, Yamamoto M, Xin B, Matsuo Y, Komatsu M, Suzuki A, Enomoto K, Nishikawa Y (2014) Contributions of hepatocytes and bile ductular cells in ductular reactions and remodeling of the biliary system after chronic liver injury. Am J Pathol 184(11):3001–3012. doi:10.1016/j.ajpath.2014.07.005

    Article  CAS  PubMed  Google Scholar 

  • Newsome PN, Hussain MA, Theise ND (2004) Hepatic oval cells: helping redefine a paradigm in stem cell biology. Curr Top Dev Biol 61:1–28

    Article  CAS  PubMed  Google Scholar 

  • Nitou M, Sugiyama Y, Ishikawa K, Shiojiri N (2002) Purification of fetal mouse hepatoblasts by magnetic beads coated with monoclonal anti-e-cadherin antibodies and their in vitro culture. Exp Cell Res 279(2):330–343

    Article  CAS  PubMed  Google Scholar 

  • Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC (1997) Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 16(3):235–242

    Article  CAS  PubMed  Google Scholar 

  • Oertel M, Menthena A, Chen YQ, Teisner B, Jensen CH, Shafritz DA (2008) Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver. Gastroenterology 134(3):823–832

    Article  CAS  PubMed  Google Scholar 

  • Oikawa T, Kamiya A, Kakinuma S, Zeniya M, Nishinakamura R, Tajiri H, Nakauchi H (2009) Sall4 regulates cell fate decision in fetal hepatic stem/progenitor cells. Gastroenterology 136(3):1000–1011

    Article  CAS  PubMed  Google Scholar 

  • Okabe M, Tsukahara Y, Tanaka M, Suzuki K, Saito S, Kamiya Y, Tsujimura T, Nakamura K, Miyajima A (2009) Potential hepatic stem cells reside in EpCAM+ cells of normal and injured mouse liver. Development 136(11):1951–1960

    Article  CAS  PubMed  Google Scholar 

  • 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(4):1313–1323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(2):103–109

    CAS  PubMed  Google Scholar 

  • Roskams TA, Libbrecht L, Desmet VJ (2003) Progenitor cells in diseased human liver. Semin Liver Dis 23(4):385–396

    Article  CAS  PubMed  Google Scholar 

  • Rossi JM, Dunn NR, Hogan BL, Zaret KS (2001) Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 15(15):1998–2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rountree CB, Barsky L, Ge S, Zhu J, Senadheera S, Crooks GM (2007) A CD133-expressing murine liver oval cell population with bilineage potential. Stem Cells 25(10):2419–2429

    Article  CAS  PubMed  Google Scholar 

  • Sackett SD, Li Z, Hurtt R, Gao Y, Wells RG, Brondell K, Kaestner KH, Greenbaum LE (2009) Foxl1 is a marker of bipotential hepatic progenitor cells in mice. Hepatology 49(3):920–929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL, Moss N, Melhem A, McClelland R, Turner W, Kulik M, Sherwood S, Tallheden T, Cheng N, Furth ME, Reid LM (2007) Human hepatic stem cells from fetal and postnatal donors. J Exp Med 204(8):1973–1987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt C, Bladt F, Goedecke S, Brinkmann V, Zschiesche W, Sharpe M, Gherardi E, Birchmeier C (1995) Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373(6516):699–702

    Article  CAS  PubMed  Google Scholar 

  • Schrem H, Klempnauer J, Borlak J (2002) Liver-enriched transcription factors in liver function and development. Part I: the hepatocyte nuclear factor network and liver-specific gene expression. Pharmacol Rev 54(1):129–158

    Article  CAS  PubMed  Google Scholar 

  • Schrem H, Klempnauer J, Borlak J (2004) Liver-enriched transcription factors in liver function and development. Part II: the C/EBPs and D site-binding protein in cell cycle control, carcinogenesis, circadian gene regulation, liver regeneration, apoptosis, and liver-specific gene regulation. Pharmacol Rev 56(2):291–330

    Article  CAS  PubMed  Google Scholar 

  • Sekine K, Chen YR, Kojima N, Ogata K, Fukamizu A, Miyajima A (2007) Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development. EMBO J 26(15):3607–3615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sekiya S, Suzuki A (2011) Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475(7356):390–393

    Article  CAS  PubMed  Google Scholar 

  • Sekiya S, Suzuki A (2014) Hepatocytes, rather than cholangiocytes, can be the major source of primitive ductules in the chronically injured mouse liver. Am J Pathol 184(5):1468–1478. doi:10.1016/j.ajpath.2014.01.005

    Article  CAS  PubMed  Google Scholar 

  • Shin S, Walton G, Aoki R, Brondell K, Schug J, Fox A, Smirnova O, Dorrell C, Erker L, Chu AS, Wells RG, Grompe M, Greenbaum LE, Kaestner KH (2011) Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential. Genes Dev 25(11):1185–1192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin S, Upadhyay N, Greenbaum LE, Kaestner KH (2015) Ablation of Foxl1-Cre-labeled hepatic progenitor cells and their descendants impairs recovery of mice from liver injury. Gastroenterology 148(1):192–202 e193. doi:10.1053/j.gastro.2014.09.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Si-Tayeb K, Noto FK, Nagaoka M, Li J, Battle MA, Duris C, North PE, Dalton S, Duncan SA (2010) Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51(1):297–305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snykers S, De Kock J, Rogiers V, Vanhaecke T (2009) In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27(3):577–605

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Song YD, Lee EJ, Yashar P, Pfaff LE, Kim SY, Jameson JL (2007) Islet cell differentiation in liver by combinatorial expression of transcription factors neurogenin-3, BETA2, and RIPE3b1. Biochem Biophys Res Commun 354(2):334–339

    Article  CAS  PubMed  Google Scholar 

  • Song Z, Cai J, Liu Y, Zhao D, Yong J, Duo S, Song X, Guo Y, Zhao Y, Qin H, Yin X, Wu C, Che J, Lu S, Ding M, Deng H (2009) Efficient generation of hepatocyte-like cells from human induced pluripotent stem cells. Cell Res 19(11):1233–1242

    Article  PubMed  Google Scholar 

  • Sosa-Pineda B, Wigle JT, Oliver G (2000) Hepatocyte migration during liver development requires Prox1. Nat Genet 25(3):254–255

    Article  CAS  PubMed  Google Scholar 

  • Strick-Marchand H, Masse GX, Weiss MC, Di Santo JP (2008) Lymphocytes support oval cell-dependent liver regeneration. J Immunol 181(4):2764–2771

    Article  CAS  PubMed  Google Scholar 

  • Sullivan GJ, Hay DC, Park IH, Fletcher J, Hannoun Z, Payne CM, Dalgetty D, Black JR, Ross JA, Samuel K, Wang G, Daley GQ, Lee JH, Church GM, Forbes SJ, Iredale JP, Wilmut I (2010) Generation of functional human hepatic endoderm from human induced pluripotent stem cells. Hepatology 51(1):329–335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki A, Zheng Y, Kondo R, Kusakabe M, Takada Y, Fukao K, Nakauchi H, Taniguchi H (2000) Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology 32(6):1230–1239

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Zheng YW, Kaneko S, Onodera M, Fukao K, Nakauchi H, Taniguchi H (2002) Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol 156(1):173–184

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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(11):2513–2524

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Kanai Y, Hara T, Sasaki J, Sasaki T, Kohara M, Maehama T, Taya C, Shitara H, Yonekawa H, Frohman MA, Yokozeki T, Kanaho Y (2006) Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development. Mol Cell Biol 26(16):6149–6156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki A, Sekiya S, Buscher D, Izpisua Belmonte JC, Taniguchi H (2008a) Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development 135(9):1589–1595

    Article  CAS  PubMed  Google Scholar 

  • Suzuki A, Sekiya S, Onishi M, Oshima N, Kiyonari H, Nakauchi H, Taniguchi H (2008b) Flow cytometric isolation and clonal identification of self-renewing bipotent hepatic progenitor cells in adult mouse liver. Hepatology 48(6):1964–1978

    Article  CAS  PubMed  Google Scholar 

  • Suzuki K, Tanaka M, Watanabe N, Saito S, Nonaka H, Miyajima A (2008c) p75 Neurotrophin receptor is a marker for precursors of stellate cells and portal fibroblasts in mouse fetal liver. Gastroenterology 135(1):270–281, e273

    Article  CAS  PubMed  Google Scholar 

  • Takase HM, Itoh T, Ino S, Wang T, Koji T, Akira S, Takikawa Y, Miyajima A (2013) FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. Genes Dev 27(2):169–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka M, Hirabayashi Y, Sekiguchi T, Inoue T, Katsuki M, Miyajima A (2003) Targeted disruption of oncostatin M receptor results in altered hematopoiesis. Blood 102(9):3154–3162

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Okabe M, Suzuki K, Kamiya Y, Tsukahara Y, Saito S, Miyajima A (2009) Mouse hepatoblasts at distinct developmental stages are characterized by expression of EpCAM and DLK1: drastic change of EpCAM expression during liver development. Mech Dev 126(8–9):665–676

    Article  CAS  PubMed  Google Scholar 

  • Tanaka M, Itoh T, Tanimizu N, Miyajima A (2011) Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J Biochem 149(3):231–239

    Article  CAS  PubMed  Google Scholar 

  • Tang DQ, Lu S, Sun YP, Rodrigues E, Chou W, Yang C, Cao LZ, Chang LJ, Yang LJ (2006) Reprogramming liver-stem WB cells into functional insulin-producing cells by persistent expression of Pdx1- and Pdx1-VP16 mediated by lentiviral vectors. Lab Invest 86(1):83–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanimizu N, Miyajima A (2004) Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci 117(Pt 15):3165–3174

    Article  CAS  PubMed  Google Scholar 

  • Tanimizu N, Miyajima A (2007) Molecular mechanism of liver development and regeneration. Int Rev Cytol 259:1–48

    Article  CAS  PubMed  Google Scholar 

  • Tanimizu N, Tsujimura T, Takahide K, Kodama T, Nakamura K, Miyajima A (2004) Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver. Gene Expr Patterns 5(2):209–218

    Article  CAS  PubMed  Google Scholar 

  • Tarlow BD, Finegold MJ, Grompe M (2014a) Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60(1):278–289. doi:10.1002/hep.27084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM, Finegold MJ, Grompe M (2014b) Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15(5):605–618. doi:10.1016/j.stem.2014.09.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, Darlington GJ (1995) Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269(5227):1108–1112

    Article  CAS  PubMed  Google Scholar 

  • Wang AY, Ehrhardt A, Xu H, Kay MA (2007) Adenovirus transduction is required for the correction of diabetes using Pdx-1 or Neurogenin-3 in the liver. Mol Ther 15(2):255–263

    Article  CAS  PubMed  Google Scholar 

  • Watanabe T, Nakagawa K, Ohata S, Kitagawa D, Nishitai G, Seo J, Tanemura S, Shimizu N, Kishimoto H, Wada T, Aoki J, Arai H, Iwatsubo T, Mochita M, Watanabe T, Satake M, Ito Y, Matsuyama T, Mak TW, Penninger JM, Nishina H, Katada T (2002) SEK1/MKK4-mediated SAPK/JNK signaling participates in embryonic hepatoblast proliferation via a pathway different from NF-kappaB-induced anti-apoptosis. Dev Biol 250(2):332–347

    Article  CAS  PubMed  Google Scholar 

  • Weinstein M, Monga SP, Liu Y, Brodie SG, Tang Y, Li C, Mishra L, Deng CX (2001) Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to promote normal liver development. Mol Cell Biol 21(15):5122–5131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yanagida A, Ito K, Chikada H, Nakauchi H, Kamiya A (2013) An in vitro expansion system for generation of human iPS cell-derived hepatic progenitor-like cells exhibiting a bipotent differentiation potential. PLoS One 8(7):e67541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang L, Li S, Hatch H, Ahrens K, Cornelius JG, Petersen BE, Peck AB (2002) In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci U S A 99(12):8078–8083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W, Yan HX, Chen L, Liu Q, He YQ, Yu LX, Zhang SH, Huang DD, Tang L, Kong XN, Chen C, Liu SQ, Wu MC, Wang HY (2008) Wnt/beta-catenin signaling contributes to activation of normal and tumorigenic liver progenitor cells. Cancer Res 68(11):4287–4295

    Article  CAS  PubMed  Google Scholar 

  • Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R, Aiello NM, Thung SN, Wells RG, Greenbaum LE, Stanger BZ (2013) Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 27(7):719–724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yechoor V, Liu V, Espiritu C, Paul A, Oka K, Kojima H, Chan L (2009) Neurogenin3 is sufficient for transdetermination of hepatic progenitor cells into neo-islets in vivo but not transdifferentiation of hepatocytes. Dev Cell 16(3):358–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yovchev MI, Grozdanov PN, Joseph B, Gupta S, Dabeva MD (2007) Novel hepatic progenitor cell surface markers in the adult rat liver. Hepatology 45(1):139–149

    Article  CAS  PubMed  Google Scholar 

  • Yovchev MI, Zhang J, Neufeld DS, Grozdanov PN, Dabeva MD (2009) Thymus cell antigen-1-expressing cells in the oval cell compartment. Hepatology 50(2):601–611

    Article  CAS  PubMed  Google Scholar 

  • Zajicek G, Oren R, Weinreb M Jr (1985) The streaming liver. Liver 5(6):293–300

    Article  CAS  PubMed  Google Scholar 

  • Zalzman M, Gupta S, Giri RK, Berkovich I, Sappal BS, Karnieli O, Zern MA, Fleischer N, Efrat S (2003) Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells. Proc Natl Acad Sci U S A 100(12):7253–7258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao R, Duncan SA (2005) Embryonic development of the liver. Hepatology 41(5):956–967

    Article  CAS  PubMed  Google Scholar 

  • Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, Stanger BZ (2009) Notch signaling controls liver development by regulating biliary differentiation. Development 136(10):1727–1739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113–0032, Japan

    Tohru Itoh, Cindy Yuet-Yin Kok & Atsushi Miyajima

  2. Department of Experimental Animal Model for Human Disease, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan

    Hinako M. Takase Ph.D.

Authors
  1. Tohru Itoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cindy Yuet-Yin Kok
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hinako M. Takase Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Atsushi Miyajima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tohru Itoh .

Editor information

Editors and Affiliations

  1. Department of Cardiac Surgery and Refere, University of Rostock, Rostock, Mecklenburg-Vorpomm., Germany

    Gustav Steinhoff

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Itoh, T., Kok, C.YY., Takase, H.M., Miyajima, A. (2016). Liver Stem Cells. In: Steinhoff, G. (eds) Regenerative Medicine - from Protocol to Patient. Springer, Cham. https://doi.org/10.1007/978-3-319-27610-6_8

Download citation

Publish with us

Policies and ethics

Search

Navigation