RSS-Feed abonnieren
DOI: 10.1055/s-0040-1709679
Hepatobiliary Differentiation: Principles from Embryonic Liver Development
Acknowledgments This study was funded by NIH R24OD017870, R01DK090311, and R01DK105198 to W.G.![](https://www.thieme-connect.de/media/sld/202004/lookinside/thumbnails/10-1055-s-0040-1709679_1900096-1.jpg)
Abstract
Hepatocytes and biliary epithelial cells (BECs), the two endodermal cell types of the liver, originate from progenitor cells called hepatoblasts. Based principally on in vitro data, hepatoblasts are thought to be bipotent stem cells with the potential to produce both hepatocytes and BECs. However, robust in vivo evidence for this model has only recently emerged. We examine the molecular mechanisms that stimulate hepatoblast differentiation into hepatocytes or BECs. In the absence of extrinsic cues, the default fate of hepatoblasts is hepatocyte differentiation. Inductive cues from the hepatic portal vein, however, initiate transcription factor expression in hepatoblasts, driving biliary specification. Defining the mechanisms of hepatobiliary differentiation provides important insights into congenital disorders, such as Alagille syndrome, and may help to better characterize the poorly understood hepatic lineage relationships observed during regeneration from liver injury.
Publikationsverlauf
Artikel online veröffentlicht:
11. Juni 2020
© 2020. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
-
References
- 1 Li L, Krantz ID, Deng Y. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet 1997; 16 (03) 243-251
- 2 Oda T, Elkahloun AG, Pike BL. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nat Genet 1997; 16 (03) 235-242
- 3 Hofmann JJ, Zovein AC, Koh H, Radtke F, Weinmaster G, Iruela-Arispe ML. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 2010; 137 (23) 4061-4072
- 4 Gordillo M, Evans T, Gouon-Evans V. Orchestrating liver development. Development 2015; 142 (12) 2094-2108
-
5
Zorn AM.
Liver development (October 31, 2008), StemBook, ed. The Stem Cell Research Community, StemBook. Doi: /10.3824/stembook.1.25.1 Available at: http://www.stembook.org . Accessed October 20, 2019
- 6 Severn CB. A morphological study of the development of the human liver. I. Development of the hepatic diverticulum. Am J Anat 1971; 131 (02) 133-158
- 7 Hutchins GM, Moore GW. Growth and asymmetry of the human liver during the embryonic period. Pediatr Pathol 1988; 8 (01) 17-24
- 8 Ober EA, Verkade H, Field HA, Stainier DY. Mesodermal Wnt2b signalling positively regulates liver specification. Nature 2006; 442 (7103): 688-691
- 9 Rossi JM, Dunn NR, Hogan BL, Zaret KS. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev 2001; 15 (15) 1998-2009
- 10 Jung J, Zheng M, Goldfarb M, Zaret KS. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 1999; 284 (5422): 1998-2003
- 11 Shin D, Shin CH, Tucker J. et al. Bmp and Fgf signaling are essential for liver specification in zebrafish. Development 2007; 134 (11) 2041-2050
- 12 Lee CS, Friedman JR, Fulmer JT, Kaestner KH. The initiation of liver development is dependent on Foxa transcription factors. Nature 2005; 435 (7044): 944-947
- 13 Watt AJ, Zhao R, Li J, Duncan SA. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol 2007; 7: 37
- 14 Zhao R, Watt AJ, Li J, Luebke-Wheeler J, Morrisey EE, Duncan SA. GATA6 is essential for embryonic development of the liver but dispensable for early heart formation. Mol Cell Biol 2005; 25 (07) 2622-2631
- 15 Lokmane L, Haumaitre C, Garcia-Villalba P, Anselme I, Schneider-Maunoury S, Cereghini S. Crucial role of vHNF1 in vertebrate hepatic specification. Development 2008; 135 (16) 2777-2786
- 16 Keng VW, Yagi H, Ikawa M. et al. Homeobox gene Hex is essential for onset of mouse embryonic liver development and differentiation of the monocyte lineage. Biochem Biophys Res Commun 2000; 276 (03) 1155-1161
- 17 Yang L, Wang WH, Qiu WL, Guo Z, Bi E, Xu CR. A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation. Hepatology 2017; 66 (05) 1387-1401
- 18 Germain L, Blouin MJ, Marceau N. Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin, and cell surface-exposed components. Cancer Res 1988; 48 (17) 4909-4918
- 19 Suzuki A, Zheng Y, Kondo R. et al. Flow-cytometric separation and enrichment of hepatic progenitor cells in the developing mouse liver. Hepatology 2000; 32 (06) 1230-1239
- 20 Tanimizu N, Saito H, Mostov K, Miyajima A. Long-term culture of hepatic progenitors derived from mouse Dlk+ hepatoblasts. J Cell Sci 2004; 117 (Pt 26): 6425-6434
- 21 Suzuki A, Zheng YW, Kaneko S. et al. Clonal identification and characterization of self-renewing pluripotent stem cells in the developing liver. J Cell Biol 2002; 156 (01) 173-184
- 22 Tanimizu N, Nishikawa M, Saito H, Tsujimura T, Miyajima A. Isolation of hepatoblasts based on the expression of Dlk/Pref-1. J Cell Sci 2003; 116 (Pt 9): 1775-1786
- 23 Forbes SJ, Newsome PN. Liver regeneration - mechanisms and models to clinical application. Nat Rev Gastroenterol Hepatol 2016; 13 (08) 473-485
- 24 Gilgenkrantz H, Collin de l'Hortet A. Understanding liver regeneration: from mechanisms to regenerative medicine. Am J Pathol 2018; 188 (06) 1316-1327
- 25 Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepatology 2014; 59 (04) 1617-1626
- 26 Yanagida A, Mizuno N, Yamazaki Y. et al. Investigation of bipotent differentiation of hepatoblasts using inducible diphtheria toxin receptor-transgenic mice. Hepatol Res 2016; 46 (08) 816-828
- 27 Shiojiri N, Inujima S, Ishikawa K, Terada K, Mori M. Cell lineage analysis during liver development using the spf(ash)-heterozygous mouse. Lab Invest 2001; 81 (01) 17-25
- 28 El Sebae GK, Malatos JM, Cone ME. et al. Single-cell murine genetic fate mapping reveals bipotential hepatoblasts and novel multi-organ endoderm progenitors. Development 2018; 145 (19) dev168658
- 29 Prior N, Hindley CJ, Rost F. et al. Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool. Development 2019; 146 (12) dev174557
- 30 Schmelzer E, Wauthier E, Reid LM. The phenotypes of pluripotent human hepatic progenitors. Stem Cells 2006; 24 (08) 1852-1858
- 31 Schmelzer E, Zhang L, Bruce A. et al. Human hepatic stem cells from fetal and postnatal donors. J Exp Med 2007; 204 (08) 1973-1987
- 32 Segal JM, Kent D, Wesche DJ. et al. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors. Nat Commun 2019; 10 (01) 3350
- 33 Dan YY, Riehle KJ, Lazaro C. et al. Isolation of multipotent progenitor cells from human fetal liver capable of differentiating into liver and mesenchymal lineages. Proc Natl Acad Sci U S A 2006; 103 (26) 9912-9917
- 34 Lüdtke TH, Christoffels VM, Petry M, Kispert A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology 2009; 49 (03) 969-978
- 35 Suzuki A, Sekiya S, Büscher D, Izpisúa Belmonte JC, Taniguchi H. Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression. Development 2008; 135 (09) 1589-1595
- 36 Seth A, Ye J, Yu N. et al. Prox1 ablation in hepatic progenitors causes defective hepatocyte specification and increases biliary cell commitment. Development 2014; 141 (03) 538-547
- 37 Akai Y, Oitate T, Koike T, Shiojiri N. Impaired hepatocyte maturation, abnormal expression of biliary transcription factors and liver fibrosis in C/EBPα(Cebpa)-knockout mice. Histol Histopathol 2014; 29 (01) 107-125
- 38 Yamasaki H, Sada A, Iwata T. et al. Suppression of C/EBPalpha expression in periportal hepatoblasts may stimulate biliary cell differentiation through increased Hnf6 and Hnf1b expression. Development 2006; 133 (21) 4233-4243
- 39 Flodby P, Barlow C, Kylefjord H, Ahrlund-Richter L, Xanthopoulos KG. Increased hepatic cell proliferation and lung abnormalities in mice deficient in CCAAT/enhancer binding protein alpha. J Biol Chem 1996; 271 (40) 24753-24760
- 40 Tomizawa M, Garfield S, Factor V, Xanthopoulos KG. Hepatocytes deficient in CCAAT/enhancer binding protein alpha (C/EBP alpha) exhibit both hepatocyte and biliary epithelial cell character. Biochem Biophys Res Commun 1998; 249 (01) 1-5
- 41 Kyrmizi I, Hatzis P, Katrakili N, Tronche F, Gonzalez FJ, Talianidis I. Plasticity and expanding complexity of the hepatic transcription factor network during liver development. Genes Dev 2006; 20 (16) 2293-2305
- 42 Li J, Ning G, Duncan SA. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev 2000; 14 (04) 464-474
- 43 Duncan SA, Manova K, Chen WS. et al. 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 (16) 7598-7602
- 44 Kamiya A, Inoue Y, Gonzalez FJ. Role of the hepatocyte nuclear factor 4alpha in control of the pregnane X receptor during fetal liver development. Hepatology 2003; 37 (06) 1375-1384
- 45 Lemaigre FP. Development of the intrahepatic and extrahepatic biliary tract: a framework for understanding congenital diseases. Annu Rev Pathol 2020; 15: 1-22
- 46 Clotman F, Jacquemin P, Plumb-Rudewiez N. et al. Control of liver cell fate decision by a gradient of TGF beta signaling modulated by Onecut transcription factors. Genes Dev 2005; 19 (16) 1849-1854
- 47 Antoniou A, Raynaud P, Cordi S. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 2009; 136 (07) 2325-2333
- 48 Zong Y, Panikkar A, Xu J. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 2009; 136 (10) 1727-1739
- 49 Geisler F, Nagl F, Mazur PK. et al. Liver-specific inactivation of Notch2, but not Notch1, compromises intrahepatic bile duct development in mice. Hepatology 2008; 48 (02) 607-616
- 50 Zhang D, Gates KP, Barske L. et al. Endoderm Jagged induces liver and pancreas duct lineage in zebrafish. Nat Commun 2017; 8 (01) 769
- 51 Poncy A, Antoniou A, Cordi S, Pierreux CE, Jacquemin P, Lemaigre FP. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev Biol 2015; 404 (02) 136-148
- 52 Carpentier R, Suñer RE, van Hul N. et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 2011; 141 (04) 1432-1438 , 1438.e1–1438.e4
- 53 Decaens T, Godard C, de Reyniès A. et al. Stabilization of beta-catenin affects mouse embryonic liver growth and hepatoblast fate. Hepatology 2008; 47 (01) 247-258
- 54 Hussain SZ, Sneddon T, Tan X, Micsenyi A, Michalopoulos GK, Monga SP. Wnt impacts growth and differentiation in ex vivo liver development. Exp Cell Res 2004; 292 (01) 157-169
- 55 Monga SP, Monga HK, Tan X, Mulé K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology 2003; 124 (01) 202-216
- 56 Cordi S, Godard C, Saandi T. et al. Role of β-catenin in development of bile ducts. Differentiation 2016; 91 (1-3): 42-49
- 57 So J, Khaliq M, Evason K. et al. Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity. Hepatology 2018; 67 (06) 2352-2366
- 58 Wei W, Lotto J, Hoodless PA. Expression patterns of Yes-associated protein 1 in the developing mouse liver. Gene Expr Patterns 2018; 29: 10-17
- 59 Zhang N, Bai H, David KK. et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell 2010; 19 (01) 27-38
- 60 Lee DH, Park JO, Kim TS. et al. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat Commun 2016; 7: 11961
- 61 Hand NJ, Master ZR, Eauclaire SF, Weinblatt DE, Matthews RP, Friedman JR. The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology 2009; 136 (03) 1081-1090
- 62 Le Guen CL, Friedman JR, Hand NJ. Novel targets of miR-30, a microRNA required for biliary development. F1000 Res 2013; 2: 197
- 63 Demarez C, Gérard C, Cordi S. et al. MicroRNA-337-3p controls hepatobiliary gene expression and transcriptional dynamics during hepatic cell differentiation. Hepatology 2018; 67 (01) 313-327
- 64 Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet 2012; 20 (03) 251-257
- 65 Adams JM, Huppert KA, Castro EC. et al. Sox9 is a modifier of the liver disease severity in a mouse model of Alagille syndrome. Hepatology 2019
- 66 Farber E. 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 1956; 16 (02) 142-148
- 67 Factor VM, Radaeva SA, Thorgeirsson SS. Origin and fate of oval cells in dipin-induced hepatocarcinogenesis in the mouse. Am J Pathol 1994; 145 (02) 409-422
- 68 Wang X, Foster M, Al-Dhalimy M, Lagasse E, Finegold M, Grompe M. The origin and liver repopulating capacity of murine oval cells. Proc Natl Acad Sci U S A 2003; 100 (Suppl. 01) 11881-11888
- 69 Yanger K, Knigin D, Zong Y. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014; 15 (03) 340-349
- 70 Schaub JR, Malato Y, Gormond C, Willenbring H. Evidence against a stem cell origin of new hepatocytes in a common mouse model of chronic liver injury. Cell Rep 2014; 8 (04) 933-939
- 71 Choi TY, Ninov N, Stainier DY, Shin D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 2014; 146 (03) 776-788
- 72 He J, Lu H, Zou Q, Luo L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 2014; 146 (03) 789-800.e8
- 73 Lu WY, Bird TG, Boulter L. et al. Hepatic progenitor cells of biliary origin with liver repopulation capacity. Nat Cell Biol 2015; 17 (08) 971-983
- 74 Yanger K, Zong Y, Maggs LR. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev 2013; 27 (07) 719-724
- 75 Schaub JR, Huppert KA, Kurial SNT. et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 2018; 557 (7704): 247-251
- 76 Russell JO, Ko S, Monga SP, Shin D. Notch inhibition promotes differentiation of liver progenitor cells into hepatocytes via sox9b repression in zebrafish. Stem Cells Int 2019; 2019: 8451282
- 77 Font-Burgada J, Shalapour S, Ramaswamy S. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 2015; 162 (04) 766-779
- 78 Han X, Wang Y, Pu W. et al. Lineage tracing reveals the bipotency of SOX9+ hepatocytes during liver regeneration. Stem Cell Reports 2019; 12 (03) 624-638