Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-5cf477f64f-54txb Total loading time: 0 Render date: 2025-04-02T13:43:43.917Z Has data issue: false hasContentIssue false

1 - Liver Development: From Endoderm to Hepatocyte

from SECTION I - PATHOPHYSIOLOGY OF PEDIATRIC LIVER DISEASE

Published online by Cambridge University Press:  18 December 2009

By
Torsten Wuestefeld Ph.D.  and
Kenneth S. Zaret Ph.D.
Edited by
Frederick J. Suchy ,
Ronald J. Sokol  and
William F. Balistreri
Torsten Wuestefeld Ph.D.
Affiliation:
Postdoctoral Fellow, Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Kenneth S. Zaret Ph.D.
Affiliation:
Senior Member and Program Leader, Cell and Developmental Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania
Frederick J. Suchy
Affiliation:
Mount Sinai School of Medicine, New York
Ronald J. Sokol
Affiliation:
University of Colorado, Denver
William F. Balistreri
Affiliation:
University of Cincinnati
Get access

Summary

The liver is derived from the endoderm, one of the three germ layers formed during gastrulation. The initial endodermal epithelium consists of approximately 500 cells in the mouse [1], from which cells will be apportioned to the thyroid, lung, stomach, liver, pancreas, esophagus, and intestines. How is the endoderm patterned to generate such diverse tissues? Once the hepatic primordium is formed, how are the different hepatic cell types generated? How do they generate a proper liver architecture? And how do the principles of liver development apply to liver regeneration and the possibility of generating hepatocytes from stem cells? This chapter focuses on all of these questions.

A BRIEF OVERVIEW OF EMBRYONIC LIVER DEVELOPMENT

By late gastrulation in the mouse (embryonic day of gestation 7.5 [E7.5]) the anteroposterior pattern of the endoderm is already established [2], so that during E8.5–9.5 (mouse) the anterior-ventral domain develops the organ buds for the liver, lung, thyroid, and the ventral rudiment of the pancreas [3]. This corresponds to about 2–3 weeks' gestation in humans. The specification of liver progenitors occurs through a combination of positive inductive signals from the cardiogenic mesoderm and septum transversum mesenchyme and repressive signals from the trunk mesoderm [4–6]. This occurs at about 8.5 days gestation in the mouse, when the embryo contains six to seven pairs of somites, which are clusters of skeletal and muscle progenitors. The cells adopting the hepatic fate are characterized by the expression of two of the liver-specific markers, albumin and α-fetoprotein (AFP).

Type
Chapter
Information
Liver Disease in Children , pp. 3 - 13
Publisher: Cambridge University Press
Print publication year: 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Wells, J M, Melton, D A. Early mouse endoderm is patterned by soluble factors from adjacent germ layers. Development 2000;127:1563–72.Google ScholarPubMed
Lawson, K A, Meneses, J J, Pedersen, R A. Cell fate and cell lineage in the endoderm of the presomite mouse embryo, studied with an intracellular tracer. Dev Biol 1986;115:325–39.CrossRefGoogle ScholarPubMed
Wells, J M, Melton, D A. Vertebrate endoderm development. Annu Rev Cell Dev Biol 1999;15:393–410.CrossRefGoogle ScholarPubMed
Fukuda-Taira, S. Hepatic induction in the avian embryo: specificity of reactive endoderm and inductive mesoderm. J Embryol Exp Morph 1981;63:111–25.Google ScholarPubMed
Gualdi, R, Bossard, P, Zheng, M. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev 1996;10:1670–82.CrossRefGoogle ScholarPubMed
Douarin, N M. An experimental analysis of liver development. Med Biol 1975;53:427–55.Google ScholarPubMed
Kinoshita, T, Miyajima, A. Cytokine regulation of liver development. Biochim Biophys Acta 2002;1592:303–12.CrossRefGoogle ScholarPubMed
Kinoshita, T, Sekiguchi, T, Xu, M J. Hepatic differentiation induced by oncostatin M attenuates fetal liver hematopoiesis. Proc Natl Acad Sci U S A 1999;96:7265–70.CrossRefGoogle ScholarPubMed
Kamiya, A, Kinoshita, T, Miyajima, A. Oncostatin M and hepatocyte growth factor induce hepatic maturation via distinct signaling pathways. FEBS Lett 2001;492:90–4.CrossRefGoogle ScholarPubMed
Kamiya, A, Gonzalez, F J. TNF-alpha regulates mouse fetal hepatic maturation induced by oncostatin M and extracellular matrices. Hepatology 2004;40:527–36.CrossRefGoogle ScholarPubMed
Tremblay, K D, Zaret, K S. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev Biol 2005;280:87–99.CrossRefGoogle ScholarPubMed
Fukuda, S. The development of hepatogenic potency in the endoderm of quail embryos. J Embryol Exp Morph 1979;52:49–62.Google ScholarPubMed
Douarin, N. Etude expérimentale de l'organogenèse du tube digestif et du foie chez l'embryon de poulet. Bull Biol Fr Belg 1964;98:543–676.Google Scholar
Douarin, N. Synthese du glycogene dans les hepatocytes en voie de differentiation: role des mesenchymes homologue et heterologues. Dev Biol 1968;17:101–14.CrossRefGoogle Scholar
Douarin, N M, Jotereau, F V. (1975). Tracing of cells of the avian thymus through embryonic life in interspecific chimeras. J Exp Med 1975;142:17–40.CrossRefGoogle ScholarPubMed
Houssaint, E. Differentiation of the mouse hepatic primordium. I. An analysis of tissue interactions in hepatocyte differentiation. Cell Differ 1980;9:269–79.Google ScholarPubMed
Jung, J, Zheng, M, Goldfarb, M, Zaret, K S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 1999;284:1998–2003.CrossRefGoogle ScholarPubMed
Deutsch, G, Jung, J, Zheng, M. A bipotential precursor population for pancreas and liver within the embryonic endoderm. Development 2001;128:871–81.Google ScholarPubMed
Serls, A E, Doherty, S, Parvatiyar, P. Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 2005;132:35–47.CrossRefGoogle Scholar
Miller, D L, Ortega, S, Bashayan, O. Compensation by fibroblast growth factor 1 (FGF1) does not account for the mild phenotypic defects observed in FGF2 null mice. Mol Cell Biol 2000;20:2260–8.CrossRefGoogle Scholar
Cai, C L, Liang, X, Shi, Y. Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 2003;5:877–89.CrossRefGoogle ScholarPubMed
Fair, J H, Cairns, B A, Lapaglia, M. Induction of hepatic differentiation in embryonic stem cells by co-culture with embryonic cardiac mesoderm. Surgery 2003;134:189–96.CrossRefGoogle ScholarPubMed
Rossi, J M, Dunn, N R, Hogan, B L M, Zaret, K S. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 2001;15:1998–2009.CrossRefGoogle ScholarPubMed
Furuta, Y, Piston, D W, Hogan, B L. Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development. Development 1997;124:2203–12.Google ScholarPubMed
Barron, M, Gao, M, Lough, J. Requirement for BMP and FGF signaling during cardiogenic induction in non-precardiac mesoderm is specific, transient, and cooperative. Dev Dyn 2000;218:383–93.3.0.CO;2-P>CrossRefGoogle ScholarPubMed
Lough, J, Barron, M, Brogley, M. Combined BMP-2 and FGF-4, but neither factor alone, induces cardiogenesis in non-precardiac embryonic mesoderm. Dev Biol 1996;178:198–202.CrossRefGoogle ScholarPubMed
Lee, K C, Crowe, A J, Barton, M C. p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding. Mol Cell Biol 1999;19:1279–88.CrossRefGoogle ScholarPubMed
Ang, S L, Wierda, A, Wong, D. The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development 1993; 119:1301–15.Google ScholarPubMed
Monaghan, A P, Kaestner, K H, Grau, E, Schutz, G. Postimplantation expression patterns indicate a role for the mouse forkhead/HNF-3 alpha, beta, and gamma genes in determination of the definitive endoderm, chordamesoderm and neuroectoderm. Development 1993;119:567–78.Google ScholarPubMed
Sasaki, H, Hogan, B L M. Differential expression of multiple fork head related genes during gastrulation and pattern formation in the mouse embryo. Development 1993;118:47–59.Google ScholarPubMed
Kaestner, K H, Katz, J, Liu, Y. (1999). Inactivation of the winged helix transcription factor HNF3alpha affects glucose homeostasis and islet glucagon gene expression in vivo. Genes Dev 1999;13:495–504.CrossRefGoogle ScholarPubMed
Shih, D Q, Navas, M A, Kuwajima, S. Impaired glucose homeostasis and neonatal mortality in hepatocyte nuclear factor 3alpha-deficient mice. Proc Natl Acad Sci U S A 1999;96: 10152–7.CrossRefGoogle ScholarPubMed
Ang, S-L, Rossant, J. HNF-3b is essential for node and notochord formation in mouse development. Cell 1994;78:561–74.CrossRefGoogle ScholarPubMed
Dufort, D, Schwartz, L, Harpal, K, Rossant, J. The transcription factor HNF3b is required in visceral endoderm for normal primitive streak morphogenesis. Development 1998;125:3015–25.Google Scholar
Weinstein, D C, Altaba, Ruizi A, Chen, W S. The winged-helix transcription factor HNF-3b is required for notochord development in the mouse embryo. Cell 1994;78:575–88.CrossRefGoogle ScholarPubMed
Sund, N J, Ang, S L, Sackett, S D. Hepatocyte nuclear factor 3beta (Foxa2) is dispensable for maintaining the differentiated state of the adult hepatocyte. Mol Cell Biol 2000;20:5175–83.CrossRefGoogle ScholarPubMed
Lee, C S, Friedman, J R, Fulmer, J T, Kaestner, K H. The initiation of liver development is dependent on Foxa transcription factors. Nature 2005;435:944–7.CrossRefGoogle ScholarPubMed
Narita, N, Bielinska, M, Wilson, D B. Cardiomyocyte differentiation by GATA-4 deficient embryonic stem cells. Development 1997;122:3755–64.Google Scholar
Bossard, P, Zaret, K S. GATA transcription factors as potentiators of gut endoderm differentiation. Development 1998;125:4909–17.Google ScholarPubMed
Kuo, C T, Morrisey, E E, Anandappa, R. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev 1997;11:1048–1060.CrossRefGoogle ScholarPubMed
Molkentin, J D, Lin, Q, Duncan, S A, Olson, E N. Requirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis. Genes Dev 1997;11:1061–72.CrossRefGoogle ScholarPubMed
Rojas, A, Val, S, Heidt, A B. Gata4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors through a distal enhancer element. Development 2005;132:3405–17.CrossRefGoogle ScholarPubMed
Zaret, K. Identifying specific protein-DNA interactions within living cells, or in “in vivo footprinting.”Methods 1997;11:149–50.CrossRefGoogle ScholarPubMed
Cirillo, L A, McPherson, C E, Bossard, P. Binding of the winged-helix transcription factor HNF3 to a linker histone site on the nucleosome. EMBO J 1998;17:244–54.CrossRefGoogle ScholarPubMed
Chaya, D, Hayamizu, T, Bustin, M, Zaret, K S. Transcription factor FoxA (HNF3) on a nucleosome at an enhancer complex in liver chromatin. J Biol Chem 2001;276:44385–9.CrossRefGoogle ScholarPubMed
Cirillo, L, Lin, F R, Cuesta, I. Opening of compacted chromatin by early developmental transcription factors HNF3 (FOXA) and GATA-4. Mol Cell 2002;9:279–89.CrossRefGoogle ScholarPubMed
Ogden, S K, Lee, K C, Wernke-Dollries, K. p53 targets chromatin structure alteration to repress alpha-fetoprotein gene expression. J Biol Chem 2001;276:42057–62.CrossRefGoogle ScholarPubMed
Wilkinson, D S, Ogden, S K, Stratton, S A. A direct intersection between p53 and transforming growth factor beta pathways targets chromatin modification and transcription repression of the alpha-fetoprotein gene. Mol Cell Biol 2005;25:1200–12.CrossRefGoogle ScholarPubMed
Hiemisch, H, Schutz, G, Kaestner, K H. Transcriptional regulation in endoderm development: characterization of an enhancer controlling Hnf3g expression by transgenesis and targeted mutagenesis. EMBO J 1997;16:3995–4006.CrossRefGoogle ScholarPubMed
Kaestner, K H, Hiemisch, H, Schütz, G. Targeted disruption of the gene encoding hepatocyte nuclear factor 3g results in reduced transcription of hepatocyte-specific genes. Mol Cell Biol 1998;18:4251.CrossRefGoogle Scholar
Duncan, S A, Navas, M A, Dufort, D. Regulation of a transcription factor network required for differentiation and metabolism. Science 1998;281:692–5.CrossRefGoogle ScholarPubMed
Morrisey, E E, Tang, Z, Sigrist, K. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Genes Dev 1998;12:3579–90.CrossRefGoogle ScholarPubMed
Koutsourakis, M, Langeveld, A, Patient, R. The transcription factor GATA6 is essential for early extraembryonic development. Development 1999;126:723–32.Google ScholarPubMed
Zhao, R, Watt, A J, Li, J. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol 2005;25:2622–31.CrossRefGoogle ScholarPubMed
Holtzinger, A, Evans, T. Gata4 regulates the formation of multiple organs. Development 2005;132:4005–14.CrossRefGoogle ScholarPubMed
Wandzioch, E, Kolterud, A, Jacobsson, M. Lhx2-/- mice develop liver fibrosis. Proc Natl Acad Sci U S A 2004;101: 16549–54.CrossRefGoogle ScholarPubMed
Matsumoto, K, Yoshitomi, H, Rossant, J, Zaret, K S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 2001;294:559–63.CrossRefGoogle ScholarPubMed
Shalaby, F, Rossant, J, Yamaguchi, T P. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 1995;376:62–6.CrossRefGoogle ScholarPubMed
LeCouter, J, Moritz, D R, Li, B. Angiogenesis-independent endothelial protection of liver: role of VEGFR-1. Science 2003;299:890–3.CrossRefGoogle ScholarPubMed
Sonnenberg, E, Meyer, D, Weidner, K M, Birchmeier, C. Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development. J Cell Biol 1993;123:223–35.CrossRefGoogle ScholarPubMed
Schmidt, C, Bladt, F, Goedecke, S. Scatter factor/hepatocyte growth factor is essential for liver development. Nature 1995;373:699–702.CrossRefGoogle ScholarPubMed
Uehara, Y, Minowa, O, Mori, C. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 1995;373:702.CrossRefGoogle ScholarPubMed
Borowiak, M, Garratt, A N, Wustefeld, T. Met provides essential signals for liver regeneration. Proc Natl Acad Sci U S A 2004;101:10608–13.CrossRefGoogle ScholarPubMed
Krupczak-Hollis, K, Wang, X, Kalinichenko, V V. The mouse Forkhead Box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev Biol 2004;276: 74–88.CrossRefGoogle ScholarPubMed
Reimold, A M, Etkin, A, Clauss, I. An essential role in liver development for transcription factor XBP-1. Genes Dev 2000;14:152–7.Google ScholarPubMed
Monga, S P, Monga, H K, Tan, X. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology 2003;124: 202–16.CrossRefGoogle ScholarPubMed
Suksaweang, S, Lin, C M, Jiang, T X. Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol 2004; 266:109–22.CrossRefGoogle ScholarPubMed
Hentsch, B, Lyons, I, Ruili, L. Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. Genes Dev 1996;10:70–9.CrossRefGoogle ScholarPubMed
Lints, T J, Hartley, L, Parsons, L M, Harvey, R P. Mesoderm-specific expression of the divergent homeobox gene Hlx during murine embryogenesis. Dev Dyn 1996;205:457–70.3.0.CO;2-H>CrossRefGoogle ScholarPubMed
Keng, V W, Yagi, H, Ikawa, M. Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage. Biochem Biophys Res Commun 2000;276:1155–61.CrossRefGoogle ScholarPubMed
Martinez-Barbera, J P, Clements, M, Thomas, P. The homeobox gene hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development 2000;127:2433–45.Google ScholarPubMed
Bort, R, Martinez-Barbera, J P, Beddington, R S, Zaret, K S. Hex homeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas. Development 2004;131: 797–806.CrossRefGoogle ScholarPubMed
Bort, R, Signore, M, Tremblay, K. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev Biol 2006;290:44–56.CrossRefGoogle ScholarPubMed
Wallace, K N, Pack, M. Unique and conserved aspects of gut development in zebrafish. Dev Biol 2003;255:12–29.CrossRefGoogle ScholarPubMed
Zhang, W, Yatskievych, T A, Baker, R K, Antin, P B. Regulation of Hex gene expression and initial stages of avian hepatogenesis by Bmp and Fgf signaling. Dev Biol 2004;268:312–26.CrossRefGoogle ScholarPubMed
Zhang, W, Yatskievych, T A, Cao, X, Antin, P B. Regulation of Hex gene expression by a Smads-dependent signaling pathway. J Biol Chem 2002;277: 45435–41.CrossRefGoogle ScholarPubMed
Denson, L A, McClure, M H, Bogue, C W. HNF3b and GATA-4 transactivate the liver-enriched homeobox gene, Hex.Gene 2000;246:311–20.CrossRefGoogle Scholar
Burke, Z, Oliver, G. Prox1 is an early specific marker for the developing liver and pancreas in the mammalian foregut endoderm. Mech Dev 2002;118:147–55.CrossRefGoogle ScholarPubMed
Sosa-Pineda, B, Wigle, J T, Oliver, G. Hepatocyte migration during liver development requires Prox1. Nat Genet 2000;25:254–5.CrossRefGoogle ScholarPubMed
Dudas, J, Papoutsi, M, Hecht, M. The homeobox transcription factor Prox1 is highly conserved in embryonic hepatoblasts and in adult and transformed hepatocytes, but is absent from bile duct epithelium. Anat Embryol (Berl) 2004;208:359–66.CrossRefGoogle ScholarPubMed
Kamiya, A, Kinoshita, T, Ito, Y. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J 1999;18:2127–36.CrossRefGoogle ScholarPubMed
Kojima, N, Kinoshita, T, Kamiya, A. Cell density-dependent regulation of hepatic development by a gp130-independent pathway. Biochem Biophys Res Commun 2000;277:152–8.CrossRefGoogle ScholarPubMed
Matsui, T, Kinoshita, T, Hirano, T. STAT3 down-regulates the expression of cyclin D during liver development. J Biol Chem 2002; 277: 36167–73.CrossRefGoogle ScholarPubMed
Clotman, F, Lannoy, V J, Reber, M. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 2002;129:1819–28.Google ScholarPubMed
Coffinier, C, Gresh, L, Fiette, L. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1beta. Development 2002;129:1829–38.Google ScholarPubMed
Weinstein, M, Monga, S P, Liu, Y. Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to promote normal liver development. Mol Cell Biol 2001;21:5122–31.CrossRefGoogle ScholarPubMed
Shiojiri, N. The origin of intrahepatic bile duct cells in the mouse. J Embryol Exp Morphol 1984;79:25–39.Google ScholarPubMed
McCright, B, Lozier, J, Gridley, T. A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency. Development 2002;129:1075–82.Google ScholarPubMed
Tanimizu, N, Miyajima, A. Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors. J Cell Sci 2004;117:3165–74.CrossRefGoogle ScholarPubMed
Suzuki, A, Iwama, A, Miyashita, H. Role for growth factors and extracellular matrix in controlling differentiation of prospectively isolated hepatic stem cells. Development 2003;130:2513–24.CrossRefGoogle ScholarPubMed
Oda, T, Elkahloun, A G, Pike, B L. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997;16:235–42.CrossRefGoogle ScholarPubMed
Li, L, Krantz, I D, Deng, Y. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997;16:243–51.CrossRefGoogle ScholarPubMed
Lorent, K, Yeo, S Y, Oda, T. Inhibition of Jagged-mediated Notch signaling disrupts zebrafish biliary development and generates multi-organ defects compatible with an Alagille syndrome phenocopy. Development 2004;131:5753–66.CrossRefGoogle ScholarPubMed
Kodama, Y, Hijikata, M, Kageyama, R. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology 2004;127:1775–86.CrossRefGoogle ScholarPubMed
Sumazaki, R, Shiojiri, N, Isoyama, S. Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 2004;36:83–7.CrossRefGoogle ScholarPubMed
Hussain, S Z, Sneddon, T, Tan, X. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res 2004;292:157–69.CrossRefGoogle ScholarPubMed
Matthews, R P, Lorent, K, Russo, P, Pack, M. The zebrafish onecut gene hnf-6 functions in an evolutionarily conserved genetic pathway that regulates vertebrate biliary development. Dev Biol 2004;274:245–59.CrossRefGoogle Scholar
Matthews, R P, Plumb-Rudewiez, N, Lorent, K. Zebrafish vps33b, an ortholog of the gene responsible for human arthrogryposis-renal dysfunction-cholestasis syndrome, regulates biliary development downstream of the onecut transcription factor hnf6. Development 2005;132:5295–306.CrossRefGoogle ScholarPubMed
Rausa, F M, Tan, Y, Costa, R H. Association between hepatocyte nuclear factor 6 (HNF-6) and FoxA2 DNA binding domains stimulates FoxA2 transcriptional activity but inhibits HNF-6 DNA binding. Mol Cell Biol 2003;23:437–49.CrossRefGoogle ScholarPubMed
Odom, D T, Zizlsperger, N, Gordon, D B. Control of pancreas and liver gene expression by HNF transcription factors. Science 2004;303:1378–81.CrossRefGoogle ScholarPubMed
Chen, W S, Manova, K, Weinstein, D C. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev 1994;8:2466–77.CrossRefGoogle ScholarPubMed
Duncan, S A, Manova, K, Chen, W S. Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Proc Natl Acad Sci U S A 1994;91:7598–602.CrossRefGoogle ScholarPubMed
Duncan, S A, Nagy, A, Chan, W. Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos. Development 1997;124:279–87.Google ScholarPubMed
Li, J, Ning, G, Duncan, S A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 2000;14:464–74.Google ScholarPubMed
Parviz, F, Matullo, C, Garrison, W D. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet 2003;34:292–6.CrossRefGoogle ScholarPubMed
Hayhurst, G P, Lee, Y H, Lambert, G. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 2001;21:1393–403.CrossRefGoogle ScholarPubMed
Slack, J M, Tosh, D. Transdifferentiation and metaplasia – switching cell types. Curr Opin Genet Dev 2001;11:581–6.CrossRefGoogle ScholarPubMed
Tosh, D, Slack, J M. How cells change their phenotype. Nat Rev Mol Cell Biol 2002;3:187–94.CrossRefGoogle ScholarPubMed
Scarpelli, D G, Rao, M S. Differentiation of regenerating pancreatic cells into hepatocyte-like cells. Proc Natl Acad Sci U S A 1981;78:2577–81.CrossRefGoogle ScholarPubMed
Reddy, J K, Rao, M S, Qureshi, S A. Induction and origin of hepatocytes in rat pancreas. J Cell Biol 1984;98:2082–90.CrossRefGoogle ScholarPubMed
Rao, M S, Subbarao, V, Reddy, J K. Induction of hepatocytes in the pancreas of copper-depleted rats following copper repletion. Cell Differ 1986;18:109–17.CrossRefGoogle ScholarPubMed
Rao, M S, Dwivedi, R S, Subbarao, V. Almost total conversion of pancreas to liver in the adult rat: a reliable model to study transdifferentiation. Biochem Biophys Res Commun 1988;156:131–6.CrossRefGoogle ScholarPubMed
Krakowski, M L, Kritzik, M R, Jones, E M. Pancreatic expression of keratinocyte growth factor leads to differentiation of islet hepatocytes and proliferation of duct cells. Am J Pathol 1999;154:683–91.CrossRefGoogle ScholarPubMed
Paner, G P, Thompson, K S, Reyes, C V. Hepatoid carcinoma of the pancreas. Cancer 2000;88:1582–9.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
Longnecker, D S, Lilja, H S, French, J. Transplantation of azaserine-induced carcinomas of pancreas in rats. Cancer Lett 1979;7:197–202.CrossRefGoogle ScholarPubMed
Christophe, J. Pancreatic tumoral cell line AR42J: an amphicrine model. Am J Physiol 1994;266:G963–71.Google ScholarPubMed
Mashima, H, Shibata, H, Mine, T, Kojima, I. Formation of insulin-producing cells from pancreatic acinar AR42J cells by hepatocyte growth factor. Endocrinology 1996;137:3969–76.CrossRefGoogle ScholarPubMed
Shen, C N, Slack, J M, Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2000;2:879–87.CrossRefGoogle ScholarPubMed
Lee, B C, Hendricks, J D, Bailey, G S. Metaplastic pancreatic cells in liver tumors induced by diethylnitrosamine. Exp Mol Pathol 1989;50:104–13.CrossRefGoogle ScholarPubMed
Wolf, H K, Burchette, J L, Garcia, J A, Michalopoulos, G. Exocrine pancreatic tissue in human liver: a metaplastic process?Am J Surg Pathol 1990;14:590–5.CrossRefGoogle ScholarPubMed
Petersen, B E, Bowen, W C, Patrene, K D. Bone marrow as a potential source of hepatic oval cells. Science 1999;284:1168–70.CrossRefGoogle ScholarPubMed
Theise, N D, Nimmakayalu, M, Gardner, R. Liver from bone marrow in humans. Hepatology 2000;32:11–16.CrossRefGoogle ScholarPubMed
Alison, M R, Poulsom, R, Jeffery, R. Hepatocytes from non-hepatic adult stem cells. Nature 2000;406:257.CrossRefGoogle ScholarPubMed
Theise, N D, Badve, S, Saxena, R. Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation. Hepatology 2000;31:235–40.CrossRefGoogle ScholarPubMed
Lagasse, E, Connors, H, Al-Dhalimy, M. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229–34.CrossRefGoogle ScholarPubMed
Ishikawa, T, Terai, S, Urata, Y. Fibroblast growth factor 2 facilitates the differentiation of transplanted bone marrow cells into hepatocytes. Cell Tissue Res 2006;323:221–31.CrossRefGoogle ScholarPubMed
Willenbring, H, Bailey, A S, Foster, M. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004;10:744–8.CrossRefGoogle ScholarPubMed
Wang, X, Willenbring, H, Akkari, Y. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897–901.CrossRefGoogle ScholarPubMed
Okamura, K, Asahina, K, Fujimori, H. Generation of hybrid hepatocytes by cell fusion from monkey embryoid body cells in the injured mouse liver. Histochem Cell Biol 2006;125:247–57.CrossRefGoogle ScholarPubMed
Schwartz, R E, Reyes, M, Koodie, L. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002;109:1291–302.CrossRefGoogle ScholarPubMed
Yasunaga, M, Tada, S, Torikai-Nishikawa, S. Induction and monitoring of definitive and visceral endoderm differentiation of mouse ES cells. Nat Biotechnol 2005;23:1542–50.CrossRefGoogle ScholarPubMed
D'Amour, K A, Agulnick, A D, Eliazer, S. Efficient differentiation of human embryonic stem cells to definitive endoderm. Nat Biotechnol 2005;23:1534–41.CrossRefGoogle ScholarPubMed
Kubo, A, Shinozaki, K, Shannon, J M. Development of definitive endoderm from embryonic stem cells in culture. Development 2004;131:1651–62.CrossRefGoogle Scholar
Teratani, T, Yamamoto, H, Aoyagi, K. Direct hepatic fate specification from mouse embryonic stem cells. Hepatology 2005;41:836–46.CrossRefGoogle ScholarPubMed
Yamamoto, Y, Teratani, T, Yamamoto, H. Recapitulation of in vivo gene expression during hepatic differentiation from murine embryonic stem cells. Hepatology 2005;42:558–67.CrossRefGoogle ScholarPubMed

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×