Talk:Gastrointestinal Tract - Liver Development

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Cite this page: Hill, M.A. (2020, July 13) Embryology Gastrointestinal Tract - Liver Development. Retrieved from

  • Bile acids - (Cholic acid (CA) and chenodeoxycholic acid (CDCA)) end products of cholesterol. After absorption from the intestine, bile acids return to the liver and inhibit their own synthesis in a feedback regulatory loop.
  • Alkaline phosphatase - produced by the placenta, making this an unreliable marker of liver dysfunction in pregnancy.


Popescu DM, Botting RA, Stephenson E, Green K, Webb S, Jardine L, Calderbank EF, Polanski K, Goh I, Efremova M, Acres M, Maunder D, Vegh P, Gitton Y, Park JE, Vento-Tormo R, Miao Z, Dixon D, Rowell R, McDonald D, Fletcher J, Poyner E, Reynolds G, Mather M, Moldovan C, Mamanova L, Greig F, Young MD, Meyer KB, Lisgo S, Bacardit J, Fuller A, Millar B, Innes B, Lindsay S, Stubbington MJT, Kowalczyk MS, Li B, Ashenberg O, Tabaka M, Dionne D, Tickle TL, Slyper M, Rozenblatt-Rosen O, Filby A, Carey P, Villani AC, Roy A, Regev A, Chédotal A, Roberts I, Göttgens B, Behjati S, Laurenti E, Teichmann SA & Haniffa M. (2019). Decoding human fetal liver haematopoiesis. Nature , 574, 365-371. PMID: 31597962 DOI.

Decoding human fetal liver haematopoiesis.

Department of Dermatology and NIHR Newcastle Biomedical Research Centre, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, Abstract Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells and multipotent progenitors (HSC/MPPs) but remains poorly defined in humans. Here, using single-cell transcriptome profiling of approximately 140,000 liver and 74,000 skin, kidney and yolk sac cells, we identify the repertoire of human blood and immune cells during development. We infer differentiation trajectories from HSC/MPPs and evaluate the influence of the tissue microenvironment on blood and immune cell development. We reveal physiological erythropoiesis in fetal skin and the presence of mast cells, natural killer and innate lymphoid cell precursors in the yolk sac. We demonstrate a shift in the haemopoietic composition of fetal liver during gestation away from being predominantly erythroid, accompanied by a parallel change in differentiation potential of HSC/MPPs, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a reference for harnessing the therapeutic potential of HSC/MPPs. PMCID: PMC6861135 [Available on 2020-04-09] DOI: 10.1038/s41586-019-1652-y

The contributions of mesoderm-derived cells in liver development

Semin Cell Dev Biol. 2019 Aug;92:63-76. doi: 10.1016/j.semcdb.2018.09.003. Epub 2018 Sep 10.

Yang L1, Li LC1, Lamaoqiezhong2, Wang X2, Wang WH1, Wang YC3, Xu CR4.

The liver is an indispensable organ for metabolism and drug detoxification. The liver consists of endoderm-derived hepatobiliary lineages and various mesoderm-derived cells, and interacts with the surrounding tissues and organs through the ventral mesentery. Liver development, from hepatic specification to liver maturation, requires close interactions with mesoderm-derived cells, such as mesothelial cells, hepatic stellate cells, mesenchymal cells, liver sinusoidal endothelial cells and hematopoietic cells. These cells affect liver development through precise signaling events and even direct physical contact. Through the use of new techniques, emerging studies have recently led to a deeper understanding of liver development and its related mechanisms, especially the roles of mesodermal cells in liver development. Based on these developments, the current protocols for in vitro hepatocyte-like cell induction and liver-like tissue construction have been optimized and are of great importance for the treatment of liver diseases. Here, we review the roles of mesoderm-derived cells in the processes of liver development, hepatocyte-like cell induction and liver-like tissue construction. Copyright © 2018 Elsevier Ltd. All rights reserved.

KEYWORDS: Cholangiocyte; Hepatic stellate cells; Hepatoblast; Hepatocyte; Liver; Septum transversum mesenchyme PMID: 30193996 DOI: 10.1016/j.semcdb.2018.09.003

A human liver cell atlas reveals heterogeneity and epithelial progenitors

Nature. 2019 Jul 10. doi: 10.1038/s41586-019-1373-2. [Epub ahead of print]

Aizarani N1,2,3, Saviano A4,5,6, Sagar1, Mailly L4,5, Durand S4,5, Herman JS1,2,3, Pessaux P4,5,6, Baumert TF7,8,9, Grün D10,11.

The human liver is an essential multifunctional organ. The incidence of liver diseases is rising and there are limited treatment options. However, the cellular composition of the liver remains poorly understood. Here we performed single-cell RNA sequencing of about 10,000 cells from normal liver tissue from nine human donors to construct a human liver cell atlas. Our analysis identified previously unknown subtypes of endothelial cells, Kupffer cells, and hepatocytes, with transcriptome-wide zonation of some of these populations. We show that the EPCAM+ population is heterogeneous, comprising hepatocyte-biased and cholangiocyte populations as well as a TROP2int progenitor population with strong potential to form bipotent liver organoids. As a proof-of-principle, we used our atlas to unravel the phenotypic changes that occur in hepatocellular carcinoma cells and in human hepatocytes and liver endothelial cells engrafted into a mouse liver. Our human liver cell atlas provides a powerful resource to enable the discovery of previously unknown cell types in normal and diseased livers. PMID: 31292543 DOI: 10.1038/s41586-019-1373-2

Molecular regulation of mammalian hepatic architecture

Curr Top Dev Biol. 2019;132:91-136. doi: 10.1016/bs.ctdb.2018.12.003. Epub 2018 Dec 26.

Huppert SS1, Iwafuchi-Doi M2.

Abstract The essential liver exocrine and endocrine functions require a precise spatial arrangement of the hepatic lobule consisting of the central vein, portal vein, hepatic artery, intrahepatic bile duct system, and hepatocyte zonation. This allows blood to be carried through the liver parenchyma sampled by all hepatocytes and bile produced by the hepatocytes to be carried out of the liver through the intrahepatic bile duct system composed of cholangiocytes. The molecular orchestration of multiple signaling pathways and epigenetic factors is required to set up lineage restriction of the bipotential hepatoblast progenitor into the hepatocyte and cholangiocyte cell lineages, and to further refine cell fate heterogeneity within each cell lineage reflected in the functional heterogeneity of hepatocytes and cholangiocytes. In addition to the complex molecular regulation, there is a complicated morphogenetic choreography observed in building the refined hepatic epithelial architecture. Given the multifaceted molecular and cellular regulation, it is not surprising that impairment of any of these processes can result in acute and chronic hepatobiliary diseases. To enlighten the development of potential molecular and cellular targets for therapeutic options, an understanding of how the intricate hepatic molecular and cellular interactions are regulated is imperative. Here, we review the signaling pathways and epigenetic factors regulating hepatic cell lineages, fates, and epithelial architecture. © 2019 Elsevier Inc. All rights reserved. KEYWORDS: Bile duct development; Biliary system; Cholangiocyte; Hepatoblast; Hepatocyte zonation; Liver development PMID: 30797519 DOI: 10.1016/bs.ctdb.2018.12.003


A single-cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation

Hepatology. 2017 Nov;66(5):1387-1401. doi: 10.1002/hep.29353. Epub 2017 Sep 29.

Yang L1,2, Wang WH1,2, Qiu WL1,3, Guo Z1, Bi E4, Xu CR1. Author information Abstract How bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from embryonic day 10.5 (E10.5) to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually and followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C/mitogen-activated protein kinase signaling pathway promoted cholangiocyte maturation. CONCLUSION: Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate toward specific hepatic cell fates in vitro. (Hepatology 2017;66:1387-1401). © 2017 by the American Association for the Study of Liver Diseases. PMID: 28681484 PMCID: PMC5650503 DOI: 10.1002/hep.29353

Human liver segments: role of cryptic liver lobes and vascular physiology in the development of liver veins and left-right asymmetry

Sci Rep. 2017 Dec 7;7(1):17109. doi: 10.1038/s41598-017-16840-1.

Hikspoors JPJM1, Peeters MMJP1, Kruepunga N1,2, Mekonen HK1, Mommen GMC1, Köhler SE1,3, Lamers WH4,5.


Couinaud based his well-known subdivision of the liver into (surgical) segments on the branching order of portal veins and the location of hepatic veins. However, both segment boundaries and number remain controversial due to an incomplete understanding of the role of liver lobes and vascular physiology on hepatic venous development. Human embryonic livers (5-10 weeks of development) were visualized with Amira 3D-reconstruction and Cinema 4D-remodeling software. Starting at 5 weeks, the portal and umbilical veins sprouted portal-vein branches that, at 6.5 weeks, had been pruned to 3 main branches in the right hemi-liver, whereas all (>10) persisted in the left hemi-liver. The asymmetric branching pattern of the umbilical vein resembled that of a "distributing" vessel, whereas the more symmetric branching of the portal trunk resembled a "delivering" vessel. At 6 weeks, 3-4 main hepatic-vein outlets drained into the inferior caval vein, of which that draining the caudate lobe formed the intrahepatic portion of the caval vein. More peripherally, 5-6 major tributaries drained both dorsolateral regions and the left and right ventromedial regions, implying a "crypto-lobar" distribution. Lobar boundaries, even in non-lobated human livers, and functional vascular requirements account for the predictable topography and branching pattern of the liver veins, respectively. PMID: 29214994 PMCID: PMC5719430 DOI: 10.1038/s41598-017-16840-1

The fate of the vitelline and umbilical veins during the development of the human liver

J Anat. 2017 Nov;231(5):718-735. doi: 10.1111/joa.12671. Epub 2017 Aug 8.

Hikspoors JPJM1, Peeters MMJP1, Mekonen HK1, Kruepunga N1, Mommen GMC1, Cornillie P2, Köhler SE1,3, Lamers WH1,4.


Differentiation of endodermal cells into hepatoblasts is well studied, but the remodeling of the vitelline and umbilical veins during liver development is less well understood. We compared human embryos between 3 and 10 weeks of development with pig and mouse embryos at comparable stages, and used Amira 3D reconstruction and Cinema 4D remodeling software for visualization. The vitelline and umbilical veins enter the systemic venous sinus on each side via a common entrance, the hepatocardiac channel. During expansion into the transverse septum at Carnegie Stage (CS)12 the liver bud develops as two dorsolateral lobes or 'wings' and a single ventromedial lobe, with the liver hilum at the intersection of these lobes. The dorsolateral lobes each engulf a vitelline vein during CS13 and the ventromedial lobe both umbilical veins during CS14, but both venous systems remain temporarily identifiable inside the liver. The dominance of the left-sided umbilical vein and the rightward repositioning of the sinuatrial junction cause de novo development of left-to-right shunts between the left umbilical vein in the liver hilum and the right hepatocardiac channel (venous duct) and the right vitelline vein (portal sinus), respectively. Once these shunts have formed, portal branches develop from the intrahepatic portions of the portal vein on the right side and the umbilical vein on the left side. The gall bladder is a reliable marker for this hepatic vascular midline. We found no evidence for large-scale fragmentation of embryonic veins as claimed by the 'vestigial' theory. Instead and in agreement with the 'lineage' theory, the vitelline and umbilical veins remained temporally identifiable inside the liver after being engulfed by hepatoblasts. In agreement with the 'hemodynamic' theory, the left-right shunts develop de novo. KEYWORDS: liver bud; liver primordium; portal vein; sinusoids; umbilical vein; venous duct; venous sinus; vitelline vein PMID: 28786203 DOI: 10.1111/joa.12671


Immunohistochemical Heterogeneity of the Endothelium of Blood and Lymphatic Vessels in the Developing Human Liver and in Adulthood

Cells Tissues Organs. 2016 Nov 26.

Nikolić I1, Todorović V, Petrović A, Petrović V, Jović M, Vladičić J, Puškaš N.


The endothelium of liver sinusoids in relation to the endothelium of other blood vessels has specific antigen expression similar to the endothelium of lymphatic vessels. Bearing in mind that there is no consensus as to the period or intensity of the expression of certain antigens in the endothelium of blood and lymphatic vessels in the liver, the aim of our study was to immunohistochemically investigate the dynamic patterns of the expression of CD31, CD34, D2-40, and LYVE-1 antigens during liver development and in adulthood on paraffin tissue sections of human livers of 4 embryos, 38 fetuses, 6 neonates, and 6 adults. The results show that, in a histologically immature liver at the end of the embryonic period, CD34 molecules are expressed only on vein endothelium localized in developing portal areas, whereby the difference between portal venous branches and CD34-negative central veins belongs to the collecting venous system. In the fetal period, with aging, expression of CD34 and CD31 molecules on the endothelium of central veins and blood vessels of the portal areas increases. Sinusoidal endothelium shows light and sporadic CD34 immunoreactivity in the late embryonic and fetal periods, and is lost in the neonatal and adult periods, unlike CD31 immunoreactivity, which is poorly expressed in the fetal and neonatal periods but is present in adults. The endothelium of sinusoids and lymphatic vessels express LYVE-1, and the endothelium of lymphatic vessels express LYVE-1 and D2-40 but not CD34. Similarity between the sinusoidal and lymphatic endothelium includes the fact that both types are LYVE-1 positive and CD34 negative. © 2016 S. Karger AG, Basel.

PMID 27889769


Developmental anatomy of the liver from computerized three-dimensional reconstructions of four human embryos (from Carnegie stage 14 to 23)

Ann Anat. 2015 Mar 20;200:105-113. doi: 10.1016/j.aanat.2015.02.012.

Lhuaire M1, Tonnelet R2, Renard Y3, Piardi T4, Sommacale D4, Duparc F5, Braun M2, Labrousse M6.


BACKGROUND & AIM: Some aspects of human embryogenesis and organogenesis remain unclear, especially concerning the development of the liver and its vasculature. The purpose of this study was to investigate, from a descriptive standpoint, the evolutionary morphogenesis of the human liver and its vasculature by computerized three-dimensional reconstructions of human embryos. MATERIAL & METHODS: Serial histological sections of four human embryos at successive stages of development belonging to three prestigious French historical collections were digitized and reconstructed in 3D using software commonly used in medical radiology. Manual segmentation of the hepatic anatomical regions of interest was performed section by section. RESULTS: In this study, human liver organogenesis was examined at Carnegie stages 14, 18, 21 and 23. Using a descriptive and an analytical method, we showed that these stages correspond to the implementation of the large hepatic vascular patterns (the portal system, the hepatic artery and the hepatic venous system) and the biliary system. CONCLUSION: To our knowledge, our work is the first descriptive morphological study using 3D computerized reconstructions from serial histological sections of the embryonic development of the human liver between Carnegie stages 14 and 23. Copyright © 2015 Elsevier GmbH. All rights reserved. KEYWORDS: 3D reconstruction; Biliary tract; Hepatic venous system; Human embryology; Liver; Organogenesis; Portal system

PMID 25866917

Embryonic Liver Development Timeline  
Carnegie Stage Age (days) CRL (mm) Biliary system Vascular Hepatic parenchyma
14 33 7
  • Bile duct - primordial duct links primitive intestine and liver parenchyma. Thick-walled tube (95 µm diameter) small lumen (22 µm diameter).
  • Gall bladder - elongated tube further dilated, thick wall (125 µm diameter) and a narrow lumen (43 µm diameter).
  • Hepatic sinusoids - intra-hepatic vasculature present
  • Three venous tributaries flow into the liver sinusoids - right and left placental vein and a single vitelline vein.
  • Cords of liver cells fragmented by vascular network of hepatic sinusoids.
  • Between pericardial cavity (top) and mesonephros (bottom).
  • Upper pole of the liver lies close to the septum transversum and early ventricles.
  • Liver occupies the majority of abdominal cavity.
18 46 15
  • Bile duct (future common bile duct), and a common hepatic duct, in contact with liver parenchyma without penetration.
  • Primordium of accessory bile tract is an elongated and fusiform gall bladder projecting forward and by a short cystic duct that opens into common bile duct.
  • Bile duct empties into second part of duodenum on its posterior side.
  • Portal system visible - portal vein (100 µm diameter) arises from connection of upper mesenteric vein then at region of hepatic hilum (285 µm) divides into portal branches.
  • Left umbilical vein empties into anterior extremity of the left portal branch.
  • Ductus venosus (80 µm) connects the initial portion of left portal vein to the inferior vena cava.
  • Hepatic venous system 3 branches - left hepatic vein (120 µm in diameter), middle hepatic vein (220 􏰁µm in diameter) and right hepatic vein (160 µm in diameter). Flows into the sub-cardinal vein.
  • Liver parenchyma has two anatomical lobes (right and left lobe), separated by anteroposterior plane formed by placental vein.
21 53 22.5 Bile duct morphology as earlier stage. Common bile duct empties at the level of the proximal duodenum.
  • Portal vein arises from joining of splenic vein and superior mesenteric vein. At the level of the hepatic hilum, portal vein divides into two branches, right portal branch (420 µm in diameter) and left portal branch (540 µm in diameter). Right portal branch gives rise to a thin branch to caudate lobe. Ventral branch gives rise to segmental portal veins (VIII and V). Dorsal branch gives rise to the segmental portal veins (VI and VII).
  • Ductus venosus connects initial portion of left portal vein to inferior vena cava, just upstream from hepatic vein afferents.
  • Hepatic venous system as for previous stage.
Hepatic parenchyma a large rounded mass.
23 58 27 Bile duct morphology as earlier stage.
  • Portal venous system complete.
  • Ductus venosus (40 µm) connects initial portion of portal vein to middle hepatic vein.
  • hepatic venous system has changed very little from the previous stage. Three hepatic veins empty into inferior vena cava.
  • Liver parenchyma roughly oval shape, 2 symmetrical hepatic lobes. The quadrate and caudate lobes are identifiable.
  • Upper pole of the liver bounded above by diaphragm.
Data from a recent human study[1]

Links: liver | Carnegie stage 14 | 18 | 21 | 23 | simple embryonic timeline | Timeline human development

Embryonic Liver Development Timeline
This information is from a recent study[1] of the human embryonic liver from week 5 to 8 (GA 7 to 9; Carnegie stage 14 to 23).
Carnegie Stage Age CRL (mm) Biliary system Vascular Hepatic parenchyma
14 33 7
  • Primordial bile duct (links primitive intestine and liver parenchyma) visible. Thick-walled tube (95􏰁 µm diameter) with a small lumen (22 µ􏰁m in diameter).
  • Gallbladder - elongated tube further dilated, thick wall (125􏰁 µm in diameter) and a narrow lumen (43􏰁 µm of diameter).
  • Intra-hepatic vasculature is represented by the presence of hepatic sinusoids.
  • Three venous tributaries flow into the liver sinusoids: a large right umbilical vein, a large left placental vein and a single vitelline vein.
  • Cords of liver cells are fragmented by vascular network of the hepatic sinusoids.
  • Located between the pericardial cavity at the top and the mesonephros at the bottom.
  • Upper pole of the liver lies close to the septum transversum and early ventricles.
  • Liver occupies the majority of abdominal cavity.
18 46 15
  • Bile duct (future common bile duct), and a common hepatic duct, which is in contact with the liver parenchyma without penetration.
  • Primordium of accessory bile tract is an elongated and fusiform gall bladder projecting forward and by a short cystic duct that opens into the common bile duct.
  • The bile duct empties into the second part of duodenum on its posterior side.
  • Portal system visible - portal vein (100 µ􏰁m diameter) arises from the connection of the upper mesenteric vein then at region of the hepatic hilum (285􏰁 µm) divides into portal branches.
  • Left umbilical vein empties into the anterior extremity of the left portal branch.
  • Ductus venosus (80 µm) connects the initial portion of left portal vein to the inferior vena cava.
  • Hepatic venous system 3 branches - left hepatic vein (120􏰁 µm in diameter), middle hepatic vein (220 􏰁µm in diameter) and right hepatic vein (160􏰁 µm in diameter). Flows into the sub-cardinal vein.
  • Liver parenchyma has two anatomical lobes, a right lobe and a left lobe, separated by the anteroposterior plane formed by the placental vein.
21 53 22.5 Bile duct morphology as earlier stage. Common bile duct empties at the level of the proximal duodenum.
  • Portal vein arises from the joining of the splenic vein and the superior mesenteric vein. At the level of the hepatic hilum, portal vein divides into two branches, right portal branch (420 µm in diameter) and left portal branch (540 􏰁m in diameter). Right portal branch gives rise to a thin branch to the caudate lobe. Ventral branch gives rise to segmental portal veins (VIII and V). Dorsal branch gives rise to the segmental portal veins (VI and VII).
  • Ductus venosus connects the initial portion of the left portal vein to the inferior vena cava just upstream from the hepatic vein afferents.
  • Hepatic venous system as for previous stage.
Hepatic parenchyma looks like a large rounded mass.
23 58 27 Bile duct morphology as earlier stage.
  • Portal venous system complete.
  • Ductus venosus (40 m) connects the initial portion of the portal vein to the middle hepatic vein.
  • hepatic venous system has changed very little from the previous stage. the three hepatic veins empty into the inferior vena cava.
  • Liver parenchyma has a roughly oval shape. Two symmetrical hepatic lobes are identifiable. The quadrate and caudate lobes are identifiable.
  • Upper pole of the liver is always bounded above by the diaphragm.
Links: Liver Development

Volumetric Growth of the Liver in the Human Fetus: An Anatomical, Hydrostatic, and Statistical Study

Biomed Res Int. 2015;2015:858162. doi: 10.1155/2015/858162. Epub 2015 Aug 27.

Szpinda M1, Paruszewska-Achtel M1, Woźniak A2, Mila-Kierzenkowska C2, Elminowska-Wenda G1, Dombek M1, Szpinda A1, Badura M1. Author information Abstract Using anatomical, hydrostatic, and statistical methods, liver volumes were assessed in 69 human fetuses of both sexes aged 18-30 weeks. No sex differences were found. The median of liver volume achieved by hydrostatic measurements increased from 6.57 cm(3) at 18-21 weeks through 14.36 cm(3) at 22-25 weeks to 20.77 cm(3) at 26-30 weeks, according to the following regression: y = -26.95 + 1.74 × age ± Z × (-3.15 + 0.27 × age). The median of liver volume calculated indirectly according to the formula liver volume = 0.55 × liver length × liver transverse diameter × liver sagittal diameter increased from 12.41 cm(3) at 18-21 weeks through 28.21 cm(3) at 22-25 weeks to 49.69 cm(3) at 26-30 weeks. There was a strong relationship (r = 0.91, p < 0.001) between the liver volumes achieved by hydrostatic (x) and indirect (y) methods, expressed by y = -0.05 + 2.16x ± 7.26. The liver volume should be calculated as follows liver volume = 0.26 × liver length × liver transverse diameter × liver sagittal diameter. The age-specific liver volumes are of great relevance in the evaluation of the normal hepatic growth and the early diagnosis of fetal micro- and macrosomias. PMID: 26413551 PMCID: PMC4564626 DOI: 10.1155/2015/858162


Transcriptional ontogeny of the developing liver

BMC Genomics. 2012 Jan 19;13:33.

Lee JS, Ward WO, Knapp G, Ren H, Vallanat B, Abbott B, Ho K, Karp SJ, Corton JC. Source National Health and Environmental Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, NC 27711, USA.


ABSTRACT: BACKGROUND: During embryogenesis the liver is derived from endodermal cells lining the digestive tract. These endodermal progenitor cells contribute to forming the parenchyma of a number of organs including the liver and pancreas. Early in organogenesis the fetal liver is populated by hematopoietic stem cells, the source for a number of blood cells including nucleated erythrocytes. A comprehensive analysis of the transcriptional changes that occur during the early stages of development to adulthood in the liver was carried out. RESULTS: We characterized gene expression changes in the developing mouse liver at gestational days (GD) 11.5, 12.5, 13.5, 14.5, 16.5, and 19 and in the neonate (postnatal day (PND) 7 and 32) compared to that in the adult liver (PND67) using full-genome microarrays. The fetal liver, and to a lesser extent the neonatal liver, exhibited dramatic differences in gene expression compared to adults. Canonical pathway analysis of the fetal liver signature demonstrated increases in functions important in cell replication and DNA fidelity whereas most metabolic pathways of intermediary metabolism were under expressed. Comparison of the dataset to a number of previously published microarray datasets revealed 1) a striking similarity between the fetal liver and that of the pancreas in both mice and humans, 2) a nucleated erythrocyte signature in the fetus and 3) under expression of most xenobiotic metabolism genes throughout development, with the exception of a number of transporters associated with either hematopoietic cells or cell proliferation in hepatocytes. CONCLUSIONS: Overall, these findings reveal the complexity of gene expression changes during liver development and maturation, and provide a foundation to predict responses to chemical and drug exposure as a function of early life-stages.

PMID 22260730

The biliary tree - a reservoir of multipotent stem cells

Nat Rev Gastroenterol Hepatol. 2012 Feb 28. doi: 10.1038/nrgastro.2012.23. [Epub ahead of print]

Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E, Reid LM, Alvaro D. Source Division of Gastroenterology, Department of Medico-Surgical Sciences and Biotechnology, Fondazione Eleonora Lorillard Spencer Cenci, Polo Pontino, Corso della Repubblica 79, 04100 Latina, Italy.


The biliary tree is composed of intrahepatic and extrahepatic bile ducts, lined by mature epithelial cells called cholangiocytes, and contains peribiliary glands deep within the duct walls. Branch points, such as the cystic duct, perihilar and periampullar regions, contain high numbers of these glands. Peribiliary glands contain multipotent stem cells, which self-replicate and can differentiate into hepatocytes, cholangiocytes or pancreatic islets, depending on the microenvironment. Similar cells-presumably committed progenitor cells-are found in the gallbladder (which lacks peribiliary glands). The stem and progenitor cell characteristics indicate a common embryological origin for the liver, biliary tree and pancreas, which has implications for regenerative medicine as well as the pathophysiology and oncogenesis of midgut organs. This Perspectives article describes a hypothetical model of cell lineages starting in the duodenum and extending to the liver and pancreas, and thought to contribute to ongoing organogenesis throughout life.

PMID 22371217


On the origin of the liver

J Clin Invest. 2011 Dec;121(12):4630-3. doi: 10.1172/JCI59652. Epub 2011 Nov 21.

Friedman JR, Kaestner KH. Source Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.


While it has been well established that the fetal liver originates from foregut endoderm, the identity of the mechanisms that maintain liver mass under both basal and injury conditions remains controversial. Dramatically different models have been proposed based on the experimental design employed. In this issue of the JCI, Malato and colleagues report their elegant new model for genetic lineage tracing of mature mouse hepatocytes using an adenoassociated virus-driven Cre recombinase. They show convincingly that maintenance of liver mass during normal turnover or in response to mild injury is achieved by mature hepatocytes, rather than cholangiocytes or specialized progenitor cells, as has been suggested by others. Comment on J Clin Invest. 2011 Dec;121(12):4850-60.

PMID 22105167

Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells

Gastroenterology. 2011 Oct;141(4):1432-8, 1438.e1-4. Epub 2011 Jun 25.

Carpentier R, Suñer RE, van Hul N, Kopp JL, Beaudry JB, Cordi S, Antoniou A, Raynaud P, Lepreux S, Jacquemin P, Leclercq IA, Sander M, Lemaigre FP. Source de Duve Institute, Université Catholique de Louvain, Brussels, Belgium.


BACKGROUND& AIMS: Embryonic biliary precursor cells form a periportal sheet called the ductal plate, which is progressively remodeled to generate intrahepatic bile ducts. A limited number of ductal plate cells participate in duct formation; those not involved in duct development are believed to involute by apoptosis. Moreover, cells that express the SRY-related HMG box transcription factor 9 (SOX9), which include the embryonic ductal plate cells, were proposed to continuously supply the liver with hepatic cells. We investigated the role of the ductal plate in hepatic morphogenesis. METHODS: Apoptosis and proliferation were investigated by immunostaining of mouse and human fetal liver tissue. The postnatal progeny of SOX9-expressing ductal plate cells was analyzed after genetic labeling, at the ductal plate stage, by Cre-mediated recombination of a ROSA26RYFP reporter allele. Inducible Cre expression was induced by SOX9 regulatory regions, inserted in a bacterial artificial chromosome. Livers were studied from mice under normal conditions and during diet-induced regeneration. RESULTS: Ductal plate cells did not undergo apoptosis and showed limited proliferation. They generated cholangiocytes lining interlobular bile ducts, bile ductules, and canals of Hering, as well as periportal hepatocytes. Oval cells that appeared during regeneration also derived from the ductal plate. We did not find that liver homeostasis required a continuous supply of cells from SOX9-expressing progenitors. CONCLUSIONS: The ductal plate gives rise to cholangiocytes lining the intrahepatic bile ducts, including its most proximal segments. It also generates periportal hepatocytes and adult hepatic progenitor cells. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. Comment in Gastroenterology. 2011 Oct;141(4):1152-5.

PMID 21708104

Three-dimensional reconstructions of intrahepatic bile duct tubulogenesis in human liver

BMC Dev Biol. 2011 Sep 26;11:56.

Vestentoft PS, Jelnes P, Hopkinson BM, Vainer B, Møllgård K, Quistorff B, Bisgaard HC.Source Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, The Panum Institute, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Abstract ABSTRACT: BACKGROUND: During liver development, intrahepatic bile ducts are thought to arise by a unique asymmetric mode of cholangiocyte tubulogenesis characterized by a series of remodeling stages. Moreover, in liver diseases, cells lining the Canals of Hering can proliferate and generate new hepatic tissue. The aim of this study was to develop protocols for three-dimensional visualization of protein expression, hepatic portal structures and human hepatic cholangiocyte tubulogenesis. RESULTS: Protocols were developed to digitally visualize portal vessel branching and protein expression of hepatic cell lineage and extracellular matrix deposition markers in three dimensions. Samples from human prenatal livers ranging from 7 weeks + 2 days to 15½ weeks post conception as well as adult normal and acetaminophen intoxicated liver were used. The markers included cytokeratins (CK) 7 and 19, the epithelial cell adhesion molecule (EpCAM), hepatocyte paraffin 1 (HepPar1), sex determining region Y (SRY)-box 9 (SOX9), laminin, nestin, and aquaporin 1 (AQP1).Digital three-dimensional reconstructions using CK19 as a single marker protein disclosed a fine network of CK19 positive cells in the biliary tree in normal liver and in the extensive ductular reactions originating from intrahepatic bile ducts and branching into the parenchyma of the acetaminophen intoxicated liver. In the developing human liver, three-dimensional reconstructions using multiple marker proteins confirmed that the human intrahepatic biliary tree forms through several developmental stages involving an initial transition of primitive hepatocytes into cholangiocytes shaping the ductal plate followed by a process of maturation and remodeling where the intrahepatic biliary tree develops through an asymmetrical form of cholangiocyte tubulogenesis. CONCLUSIONS: The developed protocols provide a novel and sophisticated three-dimensional visualization of vessels and protein expression in human liver during development and disease. PMID 21943389


Embryology of the biliary tract

Dig Surg. 2010;27(2):87-9. Epub 2010 Jun 10.

Ando H. Source Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.


A hepatic diverticulum appears in the ventral wall of the primitive midgut early in the 4th week of intrauterine life in the development of the human embryo. This small diverticulum is the anlage for the development of the liver, extrahepatic biliary ducts, gallbladder, and ventral pancreas. By the 5th week, all elements of the biliary tree are recognizable. Marked elongation of the common duct occurs with plugging of the lumen by epithelial cells. Recanalization of the lumen of the common duct starts at the end of the 5th week and moves slowly distally. By the 6th week, the common duct and ventral pancreatic bud rotate 180 degrees clockwise around the duodenum. Early in the 7th week, the bile and pancreatic ducts end in closed cavities of the duodenum. Between the early 8th and 12th week, hepatopancreatic ducts have both superior and inferior orifices. Of these two orifices, the inferior one is usually suppressed. The muscle of the sphincter of Oddi develops from a concentric ring of mesenchyme surrounding the preampullary portion of the bile and pancreatic ducts. At about the 10th week, the muscle of the sphincter of Oddi undergoes differentiation. In the 16th week, the muscularis propria extends from just outside the fenestra to the upper end of the ampulla. By the 28th week, the musculus proprius is differentiated almost to the distal end of the ampulla.

(c) 2010 S. Karger AG, Basel.

PMID: 20551648

Sinusoid development and morphogenesis may be stimulated by VEGF-Flk-1 signaling during fetal mouse liver development

Dev Dyn. 2010 Feb;239(2):386-97.

Sugiyama Y, Takabe Y, Nakakura T, Tanaka S, Koike T, Shiojiri N.

Department of Biology, Faculty of Science, Shizuoka University, Shizuoka City, Japan.

Abstract Early morphogenesis of hepatic sinusoids was histochemically and experimentally analyzed, and the importance of VEGF-Flk-1 signaling in the vascular development was examined during murine liver organogenesis. FITC-gelatin injection experiments into young murine fetuses demonstrated that all primitive sinusoidal structures were confluent with portal and central veins, suggesting that hepatic vessel development may occur via angiogenesis. At 12.5-14.5 days of gestation, VEGF receptors designated Flk-1, especially their mature form, were highly expressed in endothelial cells of primitive sinusoidal structures and highly phosphorylated on their tyrosine residues. At the same time, VEGF was also detected in hepatoblasts/hepatocytes, hemopoietic cells, and megakaryocytes of the whole liver parenchyma. Furthermore, the addition of VEGF to E12.5 liver cell cultures significantly induced the growth and branching morphogenesis of sinusoidal endothelial cells. Therefore, VEGF-Flk-1 signaling may play an important role in the growth and morphogenesis of primitive sinusoids during fetal liver development.

PMID: 19918884


The liver as a lymphoid organ

Annu Rev Immunol. 2009;27:147-63.

Crispe IN. Source David H. Smith Center for Vaccine Biology and Immunology, Aab Institute for Biomedical Research, University of Rochester Medical Center, Rochester, New York 14642, USA.


The liver receives blood from both the systemic circulation and the intestine, and in distinctive, thin-walled sinusoids this mixture passes over a large macrophage population, termed Kupffer cells. The exposure of liver cells to antigens, and to microbial products derived from the intestinal bacteria, has resulted in a distinctive local immune environment. Innate lymphocytes, including both natural killer cells and natural killer T cells, are unusually abundant in the liver. Multiple populations of nonhematopoietic liver cells, including sinusoidal endothelial cells, stellate cells located in the subendothelial space, and liver parenchymal cells, take on the roles of antigen-presenting cells. These cells present antigen in the context of immunosuppressive cytokines and inhibitory cell surface ligands, and immune responses to liver antigens often result in tolerance. Important human pathogens, including hepatitis C virus and the malaria parasite, exploit the liver's environment, subvert immunity, and establish persistent infection.

PMID 19302037

Dynamic signaling network for the specification of embryonic pancreas and liver progenitors

Science. 2009 Jun 26;324(5935):1707-10.

Wandzioch E, Zaret KS. Source Cell and Developmental Biology Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Abstract Studies of the formation of pancreas and liver progenitors have focused on individual inductive signals and cellular responses. Here, we investigated how bone morphogenetic protein, transforming growth factor-beta (TGFbeta), and fibroblast growth factor signaling pathways converge on the earliest genes that elicit pancreas and liver induction in mouse embryos. The inductive network was found to be dynamic; it changed within hours. Different signals functioned in parallel to induce different early genes, and two permutations of signals induced liver progenitor domains, which revealed flexibility in cell programming. Also, the specification of pancreas and liver progenitors was restricted by the TGFbeta pathway. These findings may enhance progenitor cell specification from stem cells for biomedical purposes and can help explain incomplete programming in stem cell differentiation protocols.

PMID: 19556507

Notch signaling controls liver development by regulating biliary differentiation

Development. 2009 May;136(10):1727-39. Epub 2009 Apr 15.

Zong Y, Panikkar A, Xu J, Antoniou A, Raynaud P, Lemaigre F, Stanger BZ. Source Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.


In the mammalian liver, bile is transported to the intestine through an intricate network of bile ducts. Notch signaling is required for normal duct formation, but its mode of action has been unclear. Here, we show in mice that bile ducts arise through a novel mechanism of tubulogenesis involving sequential radial differentiation. Notch signaling is activated in a subset of liver progenitor cells fated to become ductal cells, and pathway activation is necessary for biliary fate. Notch signals are also required for bile duct morphogenesis, and activation of Notch signaling in the hepatic lobule promotes ectopic biliary differentiation and tubule formation in a dose-dependent manner. Remarkably, activation of Notch signaling in postnatal hepatocytes causes them to adopt a biliary fate through a process of reprogramming that recapitulates normal bile duct development. These results reconcile previous conflicting reports about the role of Notch during liver development and suggest that Notch acts by coordinating biliary differentiation and morphogenesis.

PMID: 19369401

Excretion of biliary compounds during intrauterine life

World J Gastroenterol. 2009 Feb 21;15(7):817-28.

Macias RI, Marin JJ, Serrano MA. Source Laboratory of Experimental Hepatology and Drug Targeting, CIBERehd, University of Salamanca, Salamanca 37007, Spain.


In adults, the hepatobiliary system, together with the kidney, constitute the main routes for the elimination of several endogenous and xenobiotic compounds into bile and urine, respectively. However, during intrauterine life the biliary route of excretion for cholephilic compounds, such as bile acids and biliary pigments, is very poor. Although very early in pregnancy the fetal liver produces bile acids, bilirubin and biliverdin, these compounds cannot be efficiently eliminated by the fetal hepatobiliary system, owing to the immaturity of the excretory machinery in the fetal liver. Therefore, the potentially harmful accumulation of cholephilic compounds in the fetus is prevented by their elimination across the placenta. Owing to the presence of detoxifying enzymes and specific transport systems at different locations of the placental barrier, such as the endothelial cells of chorionic vessels and trophoblast cells, this organ plays an important role in the hepatobiliary-like function during intrauterine life. The relevance of this excretory function in normal fetal physiology is evident in situations where high concentrations of biliary compounds are accumulated in the mother. This may result in oxidative stress and apoptosis, mainly in the placenta and fetal liver, which might affect normal fetal development and challenge the fate of the pregnancy. The present article reviews current knowledge of the mechanisms underlying the hepatobiliary function of the fetal-placental unit and the repercussions of several pathological conditions on this tandem.


Vascular development and differentiation during human liver organogenesis

Anat Rec (Hoboken). 2008 Jun;291(6):614-27. doi: 10.1002/ar.20679.

Collardeau-Frachon S1, Scoazec JY.


The vascular architecture of the human liver is established at the end of a complex embryological history. The hepatic primordium emerges at the 4th week and is in contact with two major venous systems of the fetal circulation: the vitelline veins and the umbilical veins. The fetal architecture of the afferent venous circulation of the liver is acquired between the 4th and the 6th week. At the end of this process, the portal vein is formed from several distinct segments of the vitelline veins; the portal sinus, deriving from the subhepatic intervitelline anastomosis, connects the umbilical vein, which is the predominant vessel of the fetal liver, to the portal system; the ductus venosus connects the portal sinus to the vena cava inferior. At birth, the umbilical vein and the ductus venosus collapse; the portal vein becomes the only afferent vein of the liver. The efferent venous vessels of the liver derive from the vitelline veins and are formed between the 4th and the 6th week. The hepatic artery forms at the 8th week; intrahepatic arterial branches progressively extend from the central to the peripheral areas of the liver between the 10th and the 15th week. Hepatic sinusoids appear very early, as soon as hepatic cords invade the septum transversum at the 4th week. They then progressively acquire their distinctive structural and functional characters, through a multistage process. Vascular development and differentiation during liver organogenesis is, therefore, a unique process; many of the cellular and molecular mechanisms involved remain poorly understood. PMID: 18484606 DOI: 10.1002/ar.20679

Embryology of extra- and intrahepatic bile ducts, the ductal plate

Anat Rec (Hoboken). 2008 Jun;291(6):628-35.

Roskams T, Desmet V. Source Department of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium.


In the human embryo, the first anlage of the bile ducts and the liver is the hepatic diverticulum or liver bud. For up to 8 weeks of gestation, the extrahepatic biliary tree develops through lengthening of the caudal part of the hepatic diverticulum. This structure is patent from the beginning and remains patent and in continuity with the developing liver at all stages. The hepatic duct (ductus hepaticus) develops from the cranial part (pars hepatica) of the hepatic diverticulum. The distal portions of the right and left hepatic ducts develop from the extrahepatic ducts and are clearly defined tubular structures by 12 weeks of gestation. The proximal portions of the main hilar ducts derive from the first intrahepatic ductal plates. The extrahepatic bile ducts and the developing intrahepatic biliary tree maintain luminal continuity from the very start of organogenesis throughout further development, contradicting a previous study in the mouse suggesting that the extrahepatic bile duct system develops independently from the intrahepatic biliary tree and that the systems are initially discontinuous but join up later. The normal development of intrahepatic bile ducts requires finely timed and precisely tuned epithelial-mesenchymal interactions, which proceed from the hilum of the liver toward its periphery along the branches of the developing portal vein. Lack of remodeling of the ductal plate results in the persistence of an excess of embryonic bile duct structures remaining in their primitive ductal plate configuration. This abnormality has been termed the ductal plate malformation.

PMID: 18484608


Spiegel's lobe bile ducts often drain into the right hepatic duct or its branches: study using drip-infusion cholangiography-computed tomography in 179 consecutive patients

World J Surg. 2004 Oct;28(10):1001-6. Epub 2004 Sep 29.

Kitami M, Murakami G, Ko S, Takase K, Tuboi M, Saito H, Nakajima Y, Takahashi S.

Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, 980-8574, Sendai, Japan. Abstract Using drip-infusion cholangiography-computed tomography (DIC-CT), we successfully identified the bile ducts draining the caudate lobe in 138 of 179 consecutive patients with extrahepatic cholelithiasis (179 ducts from Spiegel's lobe and 154 from the paracaval portion; 1-5 ducts per patient). The dorsal subsegmental duct of S8 (B8c) was often identified and could be discriminated from the paracaval caudate ducts, thus acting as a landmark for the right margin of the caudate lobe. Notably, in more than one-third of the 138 patients, at least one of the Spiegel's lobe ducts drained into the right hepatic duct or its branches (30.2% of the 179 ducts overall; all ducts joined branches of the right lobe in 25 patients). Similarly, 34.4% of the 154 paracaval caudate lobe ducts drained into the left hepatic duct or its branches. These "anatomical left/right dissociations" between the drainage territory and route were much more frequent than previously reported. Our results confirm the effectiveness of DIC-CT as a classical, noninvasive method for presurgical evaluation of the biliary system, but they also suggest that anatomical partial resection of the dorsal liver in patients with hilar cholangioma is often impossible because of contralateral biliary drainage.

PMID: 15573255

Approximately 6,000 liver transplant operations are performed in the United States ( and about 600–700 in the UK every year (, but these numbers are limited by the availability of donor organs.


Hepatic and ductus venosus blood flows during fetal life

Hepatology. 1983 Mar-Apr;3(2):254-8.

Rudolph AM.

The course of the venous circulation in the fetal liver has been studied in fetal lambs by means of the radionuclide-labeled microsphere technique. About 50% of umbilical venous blood passes through the ductus venosus, while the remainder is distributed to both lobes of the liver. Portal venous blood is largely distributed to the right lobe of the liver, with a small proportion passing through the ductus venosus and none to the left lobe. Because of these flow patterns, oxygen saturation is lower in the right than in the left hepatic vein. Left hepatic venous blood joins the ductus venosus stream and these preferentially pass through the foramen ovale, whereas right hepatic venous blood joins the distal inferior vena caval stream and preferentially passes through the tricuspid valve. These patterns favor distribution of well-oxygenated blood to the fetal heart and brain. Hypoxia and reduced umbilical venous return are associated with reduced flow through the hepatic microcirculation with proportionately greater ductus venosus flow. In the fetus, the liver has a major role in influencing venous return to the heart and in regulating distribution of oxygen and energy substrate supply to different fetal organs. PMID: 6832717

Original Page

File:Gitbpmsm.gif This section of notes gives an overview of how the liver develops. The transverse septum (septum transversum) arises at an embryonic junctional site. The junctional region externally is where the ectoderm of the amnion meets the endoderm of the yolk sac. The junctional region internally is where the foregut meets the midgut. The mesenchymal structure of the transverse septum provides a support within which both blood vessels and the liver begin to form. This structure grows rapidly.
File:PigD3L.GIF Stage 13 embryo, the transverse septum then differentiates to form the hepatic diverticulum and the hepatic primordium, these two structures together will go on to form different components of the mature liver and gall bladder. At this stage large vascular channels can be seen coursing through th eliver primordium.
File:HumE6L.GIF Stage 22 embryo, the rapidly developing liver forms a visible surface bulge on the embryo directly under the heart bulge. The liver now occupies the entire ventral body cavity with parts of the gastrointestinal tract and urinary system "embedded" within its structure. Note in this image the large central ductus venosus.

Page Links: [#Intro Introduction] | [#Recent Some Recent Findings] | [#LiverDevelopmentStages Liver Development Stages] | [#table Components of Liver Formation] | [#ductalplate Ductal Plate] | [#bile_secretion Bile Secretion] | [#intrahepatic_bile_ducts Intrahepatic Bile Ducts] | [#HepaticStemCells Hepatic Stem Cells] | [#Kupffer Kupffer Cells] | [#Molecular Liver Molecular] | [#HepaticTranscriptionFactors Hepatic Transcription Factors] | [#Abnormalities Abnormalities] | [#References References] | [#Glossary Glossary]

Some Recent Findings

Hong S-K, Dawid IB (2008) Alpha2 Macroglobulin-Like Is Essential for Liver Development in Zebrafish. PLoS ONE 3(11): e3736. doi:10.1371/journal.pone.0003736

"This report on Alpha 2 Macroglobulin (A2ML) function in zebrafish development provides the first evidence for a specific role of an A2M family gene in liver formation during early embryogenesis in a vertebrate."


"To systematically examine the ontogenic gene expression patterns of cytochrome P450 genes (Cyps) in mice… the developmental expression of Cyps in (neonatal) mouse liver can be divided into three patterns, suggesting different mechanisms responsible for the expression of Cyps during liver maturation."

This paper in Drug Metabolism Dispos describes how the newborn liver continues to differentiate postnatally. Remember that just because the organ looks like the mature form, does not mean that it yet functions like the adult organ. This may also relate to the changes that occur in human postnatal drug clearance rates.

Huang H, Ruan H, Aw MY, Hussain A, Guo L, Gao C, Qian F, Leung T, Song H, Kimelman D, Wen Z, Peng J. Mypt1-mediated spatial positioning of Bmp2-producing cells is essential for liver organogenesis. Development. 2008 Oct;135(19):3209-18.

"Mesodermal tissues produce various inductive signals essential for morphogenesis of endodermal organs. ...Our results demonstrate that myosin phosphatase targeting subunit 1 (Mypt1) mediates coordination between mesoderm and endoderm cell movements in order to carefully position the liver primordium such that it receives a Bmp signal that is essential for liver formation in zebrafish."

Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirlì C, Fiorotto R, Okolicsanyi L, Lemaigre F, Strazzabosco M, Roskams T. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology. 2008 Feb;47(2):719-28.

"The reciprocal expression of angiogenic growth factors and receptors during development supports their involvement in the cross talk between liver epithelial cells and the portal vasculature. Cholangiocytes generate a VEGF gradient that is crucial during the migratory stage, when it determines arterial vasculogenesis in their vicinity, whereas angiopoietin-1 signaling from hepatoblasts contributes to the remodeling of the hepatic artery necessary to meet the demands of the developing epithelium."

Watt AJ, Zhao R, Li J, Duncan SA. Development of the mammalian liver and ventral pancreas is dependent on GATA4. BMC Dev Biol. 2007 Apr 23;7(1):37 (More? OMIM - GATA4)

"GATA4, a zinc finger transcription factor, is strongly expressed in these endodermal domains and molecular analyses have implicated GATA4 in potentiating liver gene expression during the onset of hepatogenesis. ...Analyses of pancreatic development revealed a complete absence of the ventral but not the dorsal pancreas in Gata4-/- embryos. Moreover, Gata6-/- embryos displayed a similar, although less dramatic phenotype, suggesting a critical role for multiple GATA factors at the earliest stages of ventral pancreas development."

Sadler KC, Krahn KN, Gaur NA, Ukomadu C. Liver growth in the embryo and during liver regeneration in zebrafish requires the cell cycle regulator, uhrf1. Proc Natl Acad Sci U S A. 2007 Jan 22

"Zebrafish uhrf1 (ubiquitin-like protein containing PHD and ring finger domains-1, Np95 in mouse, ICBP90 in human) is a cell cycle regulator and transcriptional activator of top2a expression required for liver outgrowth in both the embryo and adult."

Hepatic Stem Cells

Hepatoblasts are bipotential in that they can differentiate as either hepatocytes or cholangiocytes (bile duct cells). There are currently a number of different species bipotential hepatic stem cells available for liver development research.

Mouse - HBC-3, H-CFU-C, MMH and BMEL

Rat - rhe14321

Primate - IPFLS (Oncogene Paper)

Search PubMed Now: hepatoblasts

Kupffer Cells

File:Kupffer.jpg Kupffer Cells are a population of tissue macrophages found in the lumen of hepatic sinusoids, their role is endocytic against blood-borne materials entering the liver.

Primordial (primitive) macrophages arise in the yolk sac and then differentiate into fetal macrophages, either of these enter the blood and migrate into the developing liver.

Naito M, Hasegawa G, Ebe Y, Yamamoto T. Differentiation and function of Kupffer cells. Med Electron Microsc. 2004 Mar;37(1):16-28.

Kupffer Cells(Image: Blue Histology)

Search PubMed Now: Kupffer cell development

Intrahepatic Bile Ducts

Intrahepatic bile ducts (IHBDs) transport bile secreted from hepatocytes to the hepatic duct and are are lined with biliary epithelial cells (BECs, cholangiocytes). Biliary epithelial cells are generated from the bipotent hepatoblasts surrounding the portal vein.

Cholangiocyte Cells

Bile duct epithelial cell derived from hepatoblasts during embryonic liver development. These cells line the bile duct system and have apical cilia extending into the intrahepatic bile duct lumen.

Cholangiocytes function (mechano-, osmo-, and chemo-sensory) to regulate the fluidity and alkalinity of canalicular bile by reabsorptive and secretory events adjusting the final secreted bile composition.

Abnormalities associated with cholangiocyte cell development or function are called cholangiociliopathies.(polycystin-1, polycystin-2, and fibrocystin).

Search PubMed Now: Cholangiocyte cell development

Liver Molecular

Hepatic Transcription Factors

The following combination of transcription factors appear to be invoved in hepatic differentiation and growth program.

Homeobox gene (Hhex) multiple stages of hepatobiliary development.

Variant homeodomain-containing proteins (HNF-1 alpha, HNF-1 beta)

Winged helix family proteins HNF-3 alpha, HNF-3 beta, and HNF-3 gamma (also called FoxA1, 2, and 3)

Nuclear hormone receptor family (HNF-4, COUP-TFII, LRH-1, FXR alpha, and PXR)

Basic leucine zipper-containing factor C/EBP alpha

Onecut homeodomain protein HNF-6

Ubiquitin-like protein containing PHD and ring finger domains-1,uhrf1 in zebrafish (also called Np95 in mouse, ICBP90 in human)

4-5 weeks - liver consists of a few hepatic cords. Hematopoietic cell or blood cells were undetectable in the 4 week of gestation.

5 weeks - population of cells arise (larger, rounded) expressing VEGFA, flt-4 and Tie-2 proteins.

6 weeks - flk-1 transiently expressed.

7 weeks - greatest number of VEGFA, flt-4 and Tie-2 protein immunopositive cells.

11-12 weeks - expression decreased.

7-12 weeks - hepatic cells express VEGF-C and flt-1

Angiopoietin-1, angiopoietin-2 and Tie-2 were detectable on those cells which expressed VEGFA, flt-4 and Tie-2 from weeks 5 to 12 of gestation. The expression of angiopoietin-1 and angiopoietin-2 were weakly and Tie-2 was strongly.

All factors and their receptors were undetectable on vascular endothelial cells at 4-12 weeks of gestation.

Patterns of VEGF family on cells of liver are different before and after 7 weeks of gestation. The hematopoiesis in fetal liver may be related to development of hepatic cell.

Liver Vascular Development

Vascular Endothelial Growth Factor (VEGF) - from developing bile duct cholangiocytes regulate arterial vasculogenesis.

angiopoietin-1 - from hepatoblasts regulates remodeling of the hepatic artery.

Human Liver Gene Expression

4-5 weeks - liver consists of a few hepatic cords. Hematopoietic cell or blood cells were undetectable in the 4 week of gestation.

5 weeks - population of cells arise (larger, rounded) expressing VEGFA, flt-4 and Tie-2 proteins.

6 weeks - flk-1 transiently expressed.

7 weeks - greatest number of VEGFA, flt-4 and Tie-2 protein immunopositive cells.

11-12 weeks - expression decreased.

7-12 weeks - hepatic cells express VEGF-C and flt-1

Angiopoietin-1, angiopoietin-2 and Tie-2 were detectable on those cells which expressed VEGFA, flt-4 and Tie-2 from weeks 5 to 12 of gestation. The expression of angiopoietin-1 and angiopoietin-2 were weakly and Tie-2 was strongly. (Human Liver Gene Expression Data from: Mei Y, Li AD, Jiang JY, Zhou HY, Yang HJ, Yang SX, Hong HR, Song HR.[Expression of VEGFA, VEGFC, angiopoietin-1, angiopoietin-2 and their receptors on development liver during gestation of weeks 3-12 of human embryo.]Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2004 Oct;12(5):632-6. Chinese.)


Both liver and biliary tract developmental abnormalities can lead to severe liver disease.

Ductal Plate Malformations

Interlobular bile ducts- autosomal recessive polycystic kidney disease

Smaller interlobular ducts- von Meyenburg complexes

Larger intrahepatic bile ducts- Caroli's disease

Cholangiociliopathies - abnormalities in cholangiocyte cells in intrahepatic bile ducts either their development or function. Can be associated with the development of the apical cilia (polycystin-1, polycystin-2, and fibrocystin).

Obstetric cholestasis - (or intrahepatic cholestasis of pregnancy) remains widely disregarded as an important clinical problem, with many obstetricians still considering its main symptom, pruritus (itching), a natural association of pregnancy. Obstetric cholestasis is associated with cholesterol gallstones. It may be extremely stressful for the mother but also carries risks for the baby. Piotr Milkiewicz, Elwyn Elias, Catherine Williamson, and Judith Weaver

Milkiewicz P, Elias E, Williamson C, Weaver J. Obstetric cholestasis. BMJ. 2002 Jan 19;324(7330):123-4. BMJ Link

Alagille syndrome (AGS) - a disorder characterized by few intrahepatic bile ducts. A paper suggests that Notch signaling has a role in biliary epithelial cell differentiation and subsequent tubular formation during IHBD development.

Kodama Y, Hijikata M, Kageyama R, Shimotohno K, Chiba T. The role of notch signaling in the development of intrahepatic bile ducts. Gastroenterology. 2004 Dec;127(6):1775-86.


Huang H, Ruan H, Aw MY, Hussain A, Guo L, Gao C, Qian F, Leung T, Song H, Kimelman D, Wen Z, Peng J. Mypt1-mediated spatial positioning of Bmp2-producing cells is essential for liver organogenesis. Development. 2008 Oct;135(19):3209-18.

Fabris L, Cadamuro M, Libbrecht L, Raynaud P, Spirlì C, Fiorotto R, Okolicsanyi L, Lemaigre F, Strazzabosco M, Roskams T. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology. 2008 Feb;47(2):719-28.

Naito M, Hasegawa G, Ebe Y, Yamamoto T. Differentiation and function of Kupffer cells. Med Electron Microsc. 2004 Mar;37(1):16-28.

Delalande JM, Milla PJ, Burns AJ. Hepatic nervous system development. Anat Rec A Discov Mol Cell Evol Biol. 2004 Sep;280(1):848-53.

Kinoshita T, Miyajima A. Cytokine regulation of liver development. Biochim Biophys Acta. 2002 Nov 11;1592(3):303-12.

Crawford JM. Development of the intrahepatic biliary tree. Semin Liver Dis. 2002 Aug;22(3):213-26.

Duncan SA. Transcriptional regulation of liver development. Dev Dyn. 2000 Oct;219(2):131-42.

Shiojiri N. Development and differentiation of bile ducts in the mammalian liver. Microsc Res Tech. 1997 Nov 15;39(4):328-35.

Darlington GJ. Molecular mechanisms of liver development and differentiation. Curr Opin Cell Biol. 1999 Dec;11(6):678-82.

Costa RH, Kalinichenko VV, Holterman AX, Wang X. Transcription factors in liver development, differentiation, and regeneration. Hepatology. 2003 Dec;38(6):1331-47.

Watt AJ, Garrison WD, Duncan SA. HNF4: a central regulator of hepatocyte differentiation and function. Hepatology. 2003 Jun;37(6):1249-53.

Shen CN, Horb ME, Slack JM, Tosh D. Transdifferentiation of pancreas to liver. Mech Dev. 2003 Jan;120(1):107-16.

Strick-Marchand H, Weiss MC. Embryonic liver cells and permanent lines as models for hepatocyte and bile duct cell differentiation. Mech Dev. 2003 Jan;120(1):89-98.

Search PubMed Now: hepatic development | liver development | gall bladder development |

Earlier References

  • Darlington GJ. Molecular mechanisms of liver development and differentiation. Curr Opin Cell Biol. 1999 Dec;11(6):678-82. Review.
    • Excellent earlier review on liver development. (source for references cited below)
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  • Bossard P, Zaret KS GATA transcription factors as potentiators of gut endoderm differentiation. Development 1998, 125: 4909 - 4917.
  • Zaret K Developmental competence of the gut endoderm: Genetic potentiation by GATA and HNF3/fork head proteins.Dev Biol 1999, 209: 1 - 10.
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  • Spagnoli FM, Amicone L, Tripodii M, Weiss MC Identification of a bipotential precursor cell in hepatic cell lines derived from transgenic mice expressing cyto-met in the liver. J Cell Biol 1998, 143: 1101 - 1112.
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