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  • Review Article
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Fetal liver development and implications for liver disease pathogenesis

Nature Reviews Gastroenterology & Hepatology volume 20, pages 561–581 (2023)Cite this article

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Abstract

The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver’s specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ’s small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.

Key points

  • Liver function is dependent on the coordinated development of parenchymal and non-parenchymal cell lineages.

  • Single-cell genomics reveals rare populations and distinct cell states during hepatogenesis.

  • In vitro models that more closely mimic the embryonic niche enable better outcomes for mature tissue formation.

  • Adult resident and emerging regenerative hepatobiliary hybrid cells share an oncofetal regenerative signature, but mature parenchymal cells can also contribute to regeneration without upregulation of this signature.

  • An oncofetal regenerative phenotype of liver sinusoidal endothelial cells and Kupffer cells results in a microenvironment that is favourable for regeneration and oncogenesis.

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Fig. 1: Assembly of the mouse liver.
Fig. 2: 3D organization of the emergent mouse liver.
Fig. 3: Mouse liver cell lineage hierarchies.
Fig. 4: Embryological sources of hepatic cell lineages.
Fig. 5: In vitro and ex vivo models of fetal liver development.
Fig. 6: Hepatic cell origins in injury and disease.
Fig. 7: Differentiation potential of resident and pathogenic adult liver cells.

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References

  1. Ben-Moshe, S. et al. The spatiotemporal program of zonal liver regeneration following acute injury. Cell Stem Cell 29, 973–989.e10 (2022). This article describes the use of spatially resolved single-cell RNA-seq to profile regeneration following drug-induced acute pericentral damage, and shows a transient upregulation of oncofetal genes while hepatocytes proliferate and are zonally reprogrammed to replace necrotic pericentral hepatocytes.

    Article  CAS  PubMed  Google Scholar 

  2. Font-Burgada, J. et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162, 766–779 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tarlow, B. D. et al. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15, 605–618 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Deng, X. et al. Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23, 114–122.e3 (2018).

    Article  CAS  PubMed  Google Scholar 

  5. Cheemerla, S. & Balakrishnan, M. Global epidemiology of chronic liver disease. Clin. Liver Dis. 17, 365–370 (2021).

    Article  Google Scholar 

  6. Tremblay, K. D. & Zaret, K. S. Distinct populations of endoderm cells converge to generate the embryonic liver bud and ventral foregut tissues. Dev. Biol. 280, 87–99 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Wang, J., Rhee, S., Palaria, A. & Tremblay, K. D. FGF signaling is required for anterior but not posterior specification of the murine liver bud. Dev. Dyn. 244, 431–443 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Palaria, A., Angelo, J. R., Guertin, T. M., Mager, J. & Tremblay, K. D. Patterning of the hepato‐pancreatobiliary boundary by BMP reveals heterogeneity within the murine liver bud. Hepatology 68, 274–288 (2018).

    Article  CAS  PubMed  Google Scholar 

  9. Houssaint, E. Differentiation of the mouse hepatic primordium. I. An analysis of tissue interactions in hepatocyte differentiation. Cell Differ. 9, 269–279 (1980).

    Article  CAS  PubMed  Google Scholar 

  10. Gualdi, R. et al. Hepatic specification of the gut endoderm in vitro: cell signaling and transcriptional control. Genes Dev. 10, 1670–1682 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Jung, J., Zheng, M., Goldfarb, M. & Zaret, K. S. Initiation of mammalian liver development from endoderm by fibroblast growth factors. Science 284, 1998–2003 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. Bort, R., Signore, M., Tremblay, K., Barbera, J. P. M. & Zaret, K. S. Hex homeobox gene controls the transition of the endoderm to a pseudostratified, cell emergent epithelium for liver bud development. Dev. Biol. 290, 44–56 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Margagliotti, S. et al. Role of metalloproteinases at the onset of liver development. Dev. Growth Differ. 50, 331–338 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Alder, O. et al. Hippo signaling influences HNF4A and FOXA2 enhancer switching during hepatocyte differentiation. Cell Rep. 9, 261–271 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Iwafuchi-Doi, M. et al. The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation. Mol. Cell 62, 79–91 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gordillo, M., Evans, T. & Gouon-Evans, V. Orchestrating liver development. Development 142, 2094–2108 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hikspoors, J. P. J. M. et al. The fate of the vitelline and umbilical veins during the development of the human liver. J. Anat. 231, 718–735 (2017). This article describes a comprehensive examination of the fate of mouse, pig and human vitelline and umbilical vein during hepatogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lotto, J. et al. Single-cell transcriptomics reveals early emergence of liver parenchymal and non-parenchymal cell lineages. Cell 183, 702–716.e14 (2020). This article describes a comprehensive single-cell atlas of hepatic cell development, detailing diversity and differentiation of parenchymal and non-parenchymal cell types, including a distinct hepatic cell type displaying a hybrid hepatic–mesenchymal phenotype.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, H. et al. Genetic lineage tracing identifies endocardial origin of liver vasculature. Nat. Genet. 48, 537–543 (2016). Using intersectional genetics and lineage tracing, this article shows that a considerable number of liver endothelial cells originate from the dorsal aspect of the endocardium in mice.

    Article  PubMed  Google Scholar 

  20. Lee, L. K. et al. LYVE1 marks the divergence of yolk sac definitive hemogenic endothelium from the primitive erythroid lineage. Cell Rep. 17, 2286–2298 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Swartley, O. M., Foley, J. F., Livingston, D. P., Cullen, J. M. & Elmore, S. A. Histology atlas of the developing mouse hepatobiliary hemolymphatic vascular system with emphasis on embryonic days 11.5–18.5 and early postnatal development. Toxicol. Pathol. 44, 705–725 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sugiyama, Y. et al. Sinusoid development and morphogenesis may be stimulated by VEGF‐Flk‐1 signaling during fetal mouse liver development. Dev. Dyn. 239, 386–397 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. DeSesso, J. M. Vascular ontogeny within selected thoracoabdominal organs and the limbs. Reprod. Toxicol. 70, 3–20 (2017).

    Article  CAS  PubMed  Google Scholar 

  24. Lassau, J. P. & Bastian, D. Organogenesis of the venous structures of the human liver: a hemodynamic theory. Anat. Clin. 5, 97–102 (1983).

    Article  Google Scholar 

  25. Ema, H. & Nakauchi, H. Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood 95, 2284–2288 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Johnson, G. R. & Moore, M. A. S. Role of stem cell migration in initiation of mouse foetal liver haemopoiesis. Nature 258, 726–728 (1975).

    Article  CAS  PubMed  Google Scholar 

  27. Zovein, A. C. et al. Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell 3, 625–636 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Hirsch, E., Iglesias, A., Potocnik, A. J., Hartmann, U. & Fässler, R. Impaired migration but not differentiation of haematopoietic stem cells in the absence of β1 integrins. Nature 380, 171–175 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Emambokus, N. R. & Frampton, J. The glycoprotein IIb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity 19, 33–45 (2003).

    Article  CAS  PubMed  Google Scholar 

  31. Ara, T. et al. Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity 19, 257–267 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Khan, J. A. et al. Fetal liver hematopoietic stem cell niches associate with portal vessels. Science 351, 176–180 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. Ceredig, R., Rolink, A. G. & Brown, G. Models of haematopoiesis: seeing the wood for the trees. Nat. Rev. Immunol. 9, 293–300 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Lorenz, L. et al. Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival. Nature 562, 128–132 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Antoniou, A. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136, 2325–2333 (2009).

    Article  PubMed  Google Scholar 

  37. Zong, Y. et al. Notch signaling controls liver development by regulating biliary differentiation. Development 136, 1727–1739 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Clotman, F. et al. Control of liver cell fate decision by a gradient of TGFβ signaling modulated by Onecut transcription factors. Genes Dev. 19, 1849–1854 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Gouysse, G. et al. Relationship between vascular development and vascular differentiation during liver organogenesis in humans. J. Hepatol. 37, 730–740 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Liedekerke, P. V. et al. Quantitative modeling identifies critical cell mechanics driving bile duct lumen formation. PLoS Comput. Biol. 18, e1009653 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Carpentier, R. et al. Embryonic ductal plate cells give rise to cholangiocytes, periportal hepatocytes, and adult liver progenitor cells. Gastroenterology 141, 1432–1438.e4 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Shiojiri, N. & Katayama, H. Secondary joining of the bile ducts during the hepatogenesis of the mouse embryo. Anat. Embryol. 177, 153–163 (1987).

    Article  CAS  Google Scholar 

  44. Tan, C. E. L. & Moscoso, G. J. The developing human biliary system at the porta hepatis level between 11 and 25 weeks of gestation: a way to understanding biliary atresia. Part 2. Pathol. Int. 44, 600–610 (1994).

    Article  CAS  PubMed  Google Scholar 

  45. Tan, C. E. L. & Moscoso, G. J. The developing human biliary system at the porta hepatis level between 29 days and 8 weeks of gestation: a way to understanding biliary atresia. Part 1. Pathol. Int. 44, 587–599 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Fabris, L. et al. Epithelial expression of angiogenic growth factors modulate arterial vasculogenesis in human liver development. Hepatology 47, 719–728 (2008).

    Article  PubMed  Google Scholar 

  47. Ben-Moshe, S. & Itzkovitz, S. Spatial heterogeneity in the mammalian liver. Nat. Rev. Gastroenterol. Hepatol. 16, 395–410 (2019).

    Article  PubMed  Google Scholar 

  48. Vidal-Vanaclocha, F. & Barberá-Guillem, E. Fenestration patterns in endothelial cells of rat liver sinusoids. J. Ultrastruct. Res. 90, 115–123 (1985).

    Article  CAS  PubMed  Google Scholar 

  49. Wisse, E. An electron microscopic study of the fenestrated endothelial lining of rat liver sinusoids. J. Ultrastruct. Res. 31, 125–150 (1970).

    Article  CAS  PubMed  Google Scholar 

  50. Wisse, E. An ultrastructural characterization of the endothelial cell in the rat liver sinusoid under normal and various experimental conditions, as a contribution to the distinction between endothelial and Kupffer cells. J. Ultrastruct. Res. 38, 528–562 (1972).

    Article  CAS  PubMed  Google Scholar 

  51. Wisse, E., Zanger, R. B., de, Charels, K., van der Smissen, P. & McCuskey, R. S. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5, 683–692 (1985).

    Article  CAS  PubMed  Google Scholar 

  52. Shetty, S. et al. Common lymphatic endothelial and vascular endothelial receptor-1 mediates the transmigration of regulatory T cells across human hepatic sinusoidal endothelium. J. Immunol. 186, 4147–4155 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. John, B. & Crispe, I. N. Passive and active mechanisms trap activated CD8+ T cells in the liver. J. Immunol. 172, 5222–5229 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Cain, J. C. & Grindlay, J. H. Lymph from liver and thoracic duct; an experimental study. Surg. Gynecol. Obstet. 85, 558–562 (1947).

    CAS  PubMed  Google Scholar 

  55. Amersfoort, J., Eelen, G. & Carmeliet, P. Immunomodulation by endothelial cells – partnering up with the immune system? Nat. Rev. Immunol. https://doi.org/10.1038/s41577-022-00694-4 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Wu, J. et al. Toll‐like receptor‐induced innate immune responses in non‐parenchymal liver cells are cell type‐specific. Immunology 129, 363–374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ohtani, O. & Ohtani, Y. Lymph circulation in the liver. Anat. Rec. 291, 643–652 (2008).

    Article  Google Scholar 

  58. Frenkel, N. C. et al. Liver lymphatic drainage patterns follow segmental anatomy in a murine model. Sci. Rep. 10, 21808 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Wareing, S., Eliades, A., Lacaud, G. & Kouskoff, V. ETV2 expression marks blood and endothelium precursors, including hemogenic endothelium, at the onset of blood development. Dev. Dyn. 241, 1454–1464 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Kisanuki, Y. Y. et al. Tie2-Cre transgenic mice: a new model for endothelial cell-lineage analysis in vivo. Dev. Biol. 230, 230–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Rasmussen, T. L. et al. ER71 directs mesodermal fate decisions during embryogenesis. Development 138, 4801–4812 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Misfeldt, A. M. et al. Endocardial cells are a distinct endothelial lineage derived from Flk1+ multipotent cardiovascular progenitors. Dev. Biol. 333, 78–89 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Kattman, S. J., Huber, T. L. & Keller, G. M. Multipotent Flk-1+ cardiovascular progenitor cells give rise to the cardiomyocyte, endothelial, and vascular smooth muscle lineages. Dev. Cell 11, 723–732 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Pardanaud, L. et al. Two distinct endothelial lineages in ontogeny, one of them related to hemopoiesis. Development 122, 1363–1371 (1996).

    Article  CAS  PubMed  Google Scholar 

  65. Stone, O. A. & Stainier, D. Y. R. Paraxial mesoderm is the major source of lymphatic endothelium. Dev. Cell 50, 247–255.e3 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Goldman, O. et al. Endoderm generates endothelial cells during liver development. Stem Cell Rep. 3, 556–565 (2014).

    Article  CAS  Google Scholar 

  67. Srinivasan, R. S. et al. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 21, 2422–2432 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Asahina, K., Zhou, B., Pu, W. T. & Tsukamoto, H. Septum transversum‐derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver. Hepatology 53, 983–995 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Zhou, B. et al. Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454, 109–113 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gómez-Salinero, J. M. et al. Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction. Cell Stem Cell 29, 593–609.e7 (2022). This article describes a single-cell transcriptomic analysis of liver endothelial cell development in mice that identifies Maf as a key regulator of LSEC identity, which when overexpressed in generic human endothelial cells induces their transdifferentiation to LSEC-like cells.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Winkler, M. et al. Endothelial GATA4 controls liver fibrosis and regeneration by preventing a pathogenic switch in angiocrine signaling. J. Hepatol. 74, 380–393 (2021).

    Article  CAS  PubMed  Google Scholar 

  72. Théret, N., Lehti, K., Musso, O. & Clément, B. MMP2 activation by collagen I and concanavalin A in cultured human hepatic stellate cells. Hepatology 30, 462–468 (1999).

    Article  PubMed  Google Scholar 

  73. Hellerbrand, C., Stefanovic, B., Giordano, F., Burchardt, E. R. & Brenner, D. A. The role of TGFβ1 in initiating hepatic stellate cell activation in vivo. J. Hepatol. 30, 77–87 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Ratziu, V. et al. Zf9, a Kruppel-like transcription factor up-regulated in vivo during early hepatic fibrosis. Proc. Natl Acad. Sci. USA 95, 9500–9505 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Asahina, K. et al. Mesenchymal origin of hepatic stellate cells, submesothelial cells, and perivascular mesenchymal cells during mouse liver development. Hepatology 49, 998–1011 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Schulte, I., Schlueter, J., Abu‐Issa, R., Brand, T. & Männer, J. Morphological and molecular left–right asymmetries in the development of the proepicardium: a comparative analysis on mouse and chick embryos. Dev. Dyn. 236, 684–695 (2007).

    Article  PubMed  Google Scholar 

  77. Komiyama, M., Ito, K. & Shimada, Y. Origin and development of the epicardium in the mouse embryo. Anat. Embryol. 176, 183–189 (1987).

    Article  CAS  Google Scholar 

  78. Nitou, M., Ishikawa, K. & Shiojiri, N. Immunohistochemical analysis of development of desmin‐positive hepatic stellate cells in mouse liver. J. Anat. 197, 635–646 (2000).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Delgado, I. et al. GATA4 loss in the septum transversum mesenchyme promotes liver fibrosis in mice. Hepatology 59, 2358–2370 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Steiniger, B., Klempnauer, J. & Wonigeit, K. Phenotype and histological distribution of interstitial dendritic cells in the rat pancreas, liver, heart, and kidney. Transplantation 38, 169–174 (1984).

    Article  CAS  PubMed  Google Scholar 

  81. Naito, M., Hasegawa, G. & Takahashi, K. Development, differentiation, and maturation of Kupffer cells. Microsc. Res. Tech. 39, 350–364 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Doherty, D. G. et al. The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J. Immunol. 4, 2314–2321 (1999).

    Article  Google Scholar 

  83. Dusseaux, M. et al. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117, 1250–1259 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Forkel, M. et al. Composition and functionality of the intrahepatic innate lymphoid cell‐compartment in human nonfibrotic and fibrotic livers. Eur. J. Immunol. 47, 1280–1294 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Prickett, T. C. R., Mckenzie, J. L. & Hart, D. N. J. Characterization of interstitial dendritic cells in human liver. Transplantation 46, 754–761 (1988).

    Article  CAS  PubMed  Google Scholar 

  86. Bilzer, M., Roggel, F. & Gerbes, A. L. Role of Kupffer cells in host defense and liver disease. Liver Int. 26, 1175–1186 (2006).

    Article  CAS  PubMed  Google Scholar 

  87. Perdiguero, E. G. et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature 518, 547–551 (2015). This article describes the use of lineage tracing to identify a distinct population of yolk sac-derived progenitors that give rise to fetal haematopoietic cells and adult tissue-resident macrophages, including Kupffer cells.

    Article  CAS  Google Scholar 

  88. Scott, C. L. et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat. Commun. 7, 10321 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Delalande, J., Milla, P. J. & Burns, A. J. Hepatic nervous system development. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 280, 848–853 (2004).

    Article  PubMed  Google Scholar 

  90. Lin, Y., Nosaka, S., Amakata, Y. & Maeda, T. Comparative study of the mammalian liver innervation: an immunohistochemical study of protein gene product 9.5, dopamine β-hydroxylase and tyrosine hydroxylase. Comp. Biochem. Physiol. A Physiol. 110, 289–298 (1995).

    Article  CAS  PubMed  Google Scholar 

  91. Shimazu, T. & Fukuda, A. Increased activities of glycogenolytic enzymes in liver after splanchnic-nerve stimulation. Science 150, 1607–1608 (1965).

    Article  CAS  PubMed  Google Scholar 

  92. Ueno, T., Bioulac‐Sage, P., Balabaud, C. & Rosenbaum, J. Innervation of the sinusoidal wall: regulation of the sinusoidal diameter. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 280, 868–873 (2004).

    Article  PubMed  Google Scholar 

  93. Alvaro, D. et al. Role and mechanisms of action of acetylcholine in the regulation of rat cholangiocyte secretory functions. J. Clin. Invest. 100, 1349–1362 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Izumi, T. et al. Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat. Commun. 9, 5300 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cassiman, D., Barlow, A., Borght, S. V., Libbrecht, L. & Pachnis, V. Hepatic stellate cells do not derive from the neural crest. J. Hepatol. 44, 1098–1104 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Koike, N. et al. Development of the nervous system in mouse liver. World J. Hepatol. 14, 386–399 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Tanimizu, N., Ichinohe, N. & Mitaka, T. Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver. Development 145, dev159095 (2018). This article shows that nerve fibres gradually extend along periportal tissue from E17.5 until postnatal stages, with nerve growth factor production in cholangiocytes stimulating nerve fibre extension during development and regeneration after injury.

    Article  PubMed  Google Scholar 

  98. Tiniakos, D. G., Lee, J. A. & Burt, A. D. Innervation of the liver: morphology and function. Liver 16, 151–160 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. MacParland, S. A. et al. Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nat. Commun. 9, 4383 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Payen, V. L. et al. Single-cell RNA sequencing of human liver reveals hepatic stellate cell heterogeneity. JHEP Rep. 3, 100278 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Aizarani, N. et al. A human liver cell atlas reveals heterogeneity and epithelial progenitors. Nature 572, 199–204 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Andrews, T. S. et al. Single‐cell, single‐nucleus, and spatial RNA sequencing of the human liver identifies cholangiocyte and mesenchymal heterogeneity. Hepatol. Commun. 6, 821–840 (2022).

    Article  CAS  PubMed  Google Scholar 

  103. Zhao, J. et al. Single-cell RNA sequencing reveals the heterogeneity of liver-resident immune cells in human. Cell Discov. 6, 22 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lei, L. et al. Portal fibroblasts with mesenchymal stem cell features form a reservoir of proliferative myofibroblasts in liver fibrosis. Hepatology 76, 1360–1375 (2022).

    Article  CAS  PubMed  Google Scholar 

  105. Wang, Z.-Y. et al. Single-cell and bulk transcriptomics of the liver reveals potential targets of NASH with fibrosis. Sci. Rep. 11, 19396 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dobie, R. et al. Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis. Cell Rep. 29, 1832–1847.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019). This article identifies non-parenchymal cell subtypes specific to the fibrotic niche, as well as several pro-fibrogenic ligand-receptor interactions, using single-cell RNA-seq comparing healthy and cirrhotic human livers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Alvarez, M. et al. Human liver single nucleus and single cell RNA sequencing identify a hepatocellular carcinoma-associated cell-type affecting survival. Genome Med. 14, 50 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Meng, Y. et al. Single cell transcriptional diversity and intercellular crosstalk of human liver cancer. Cell Death Dis. 13, 261 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pepe-Mooney, B. J. et al. Single-cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for YAP in homeostasis and regeneration. Cell Stem Cell 25, 23–38.e8 (2019). This article demonstrates transcriptional heterogeneity within healthy adult biliary epithelium instead of a clearly defined progenitor-like cell state and identify YAP as an important driver of this heterogeneity as well as during hepatocyte regeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Halpern, K. B. et al. Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells. Nat. Biotechnol. 36, 962–970 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Halpern, K. B. et al. Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. Nature 542, 352–356 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Hildebrandt, F. et al. Spatial transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver. Nat. Commun. 12, 7046 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Nowotschin, S. et al. The emergent landscape of the mouse gut endoderm at single-cell resolution. Nature 569, 361–367 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pijuan-Sala, B. et al. A single-cell molecular map of mouse gastrulation and early organogenesis. Nature 566, 490–495 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kwon, G. S., Viotti, M. & Hadjantonakis, A.-K. The endoderm of the mouse embryo arises by dynamic widespread intercalation of embryonic and extraembryonic lineages. Dev. Cell 15, 509–520 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Han, L. et al. Single cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis. Nat. Commun. 11, 4158 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Willnow, D. et al. Quantitative lineage analysis identifies a hepato-pancreato-biliary progenitor niche. Nature 597, 87–91 (2021). This article shows plasticity between hepatopancreatobiliary cell fates, identifying a multipotent progenitor population that is sustained past organ anlage formation in a specialized niche.

    Article  CAS  PubMed  Google Scholar 

  120. Mu, T. et al. Embryonic liver developmental trajectory revealed by single-cell RNA sequencing in the Foxa2eGFP mouse. Commun. Biol. 3, 642 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Su, X. et al. Single-cell RNA-seq analysis reveals dynamic trajectories during mouse liver development. BMC Genomics 18, 946 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Yang, L. et al. A single‐cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation. Hepatology 66, 1387–1401 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Prior, N. et al. Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool. Development 146, dev174557 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Wang, X. et al. Comparative analysis of cell lineage differentiation during hepatogenesis in humans and mice at the single-cell transcriptome level. Cell Res. 30, 1109–1126 (2020). This article compares single-cell transcriptomic data from mouse and human livers during development, showing general conservation of cell differentiation programmes, including the development of a unique population of ID3+ hepatoblasts in both species, and increased metabolic heterogeneity in human versus mouse fetal hepatocytes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Segal, J. M. et al. Single cell analysis of human foetal liver captures the transcriptional profile of hepatobiliary hybrid progenitors. Nat. Commun. 10, 3350 (2019). This article identifies a hepatobiliary hybrid progenitor in human fetal liver, residing in the ductal plate.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Liang, Y. et al. Temporal analyses of postnatal liver development and maturation by single-cell transcriptomics. Dev. Cell 57, 398–414.e5 (2022). This article catalogues parenchymal and non-parenchymal hepatic cells from neonatal to adult mouse livers, enabling insights into the zonation of the liver.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wesley, B. T. et al. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates. Nat. Cell Biol. https://doi.org/10.1038/s41556-022-00989-7 (2022). This article describes the use of single-cell genomics data from developing human fetal livers to generate a bipotential hepatoblast organoid model and test candidate factors to improve the functionality of HLCs generated from human PSCs.

    Article  PubMed  Google Scholar 

  128. Dong, J. et al. Single-cell RNA-seq analysis unveils a prevalent epithelial/mesenchymal hybrid state during mouse organogenesis. Genome Biol. 19, 31 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Cordero-Espinoza, L. et al. Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation. Cell Stem Cell 28, 1907–1921.e8 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Popescu, D.-M. et al. Decoding human fetal liver haematopoiesis. Nature 574, 365–371 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Vanuytsel, K. et al. Multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment. Nat. Commun. 13, 1103 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Bian, Z. et al. Deciphering human macrophage development at single-cell resolution. Nature 582, 571–576 (2020).

    Article  CAS  PubMed  Google Scholar 

  133. Gao, S. et al. Identification of HSC/MPP expansion units in fetal liver by single-cell spatiotemporal transcriptomics. Cell Res. 32, 38–53 (2022).

    Article  CAS  PubMed  Google Scholar 

  134. Young, M. D. & Behjati, S. SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data. Gigascience 9, giaa151 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Rossi, J. M., Dunn, N. R., Hogan, B. L. & Zaret, K. S. Distinct mesodermal signals, including BMPs from the septum transversum mesenchyme, are required in combination for hepatogenesis from the endoderm. Genes Dev. 15, 1998–2009 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Matsumoto, K., Yoshitomi, H., Rossant, J. & Zaret, K. S. Liver organogenesis promoted by endothelial cells prior to vascular function. Science 294, 559–563 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Aguilera-Castrejon, A. et al. Ex utero mouse embryogenesis from pre-gastrulation to late organogenesis. Nature 593, 119–124 (2021). This article describes the development of a protocol to culture mouse E5.5 embryos up to hindlimb formation stage (E11 equivalent) ex vivo, showing accurate recapitulation of in vivo development using single-cell RNA-seq, histology and morphology.

    Article  CAS  PubMed  Google Scholar 

  138. Wadman, M. Medical research: cell division. Nature 498, 422–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  139. Wadman, M. The truth about fetal tissue research. Nature 528, 178–181 (2015).

    Article  CAS  PubMed  Google Scholar 

  140. Lovell-Badge, R. et al. ISSCR guidelines for stem cell research and clinical translation: the 2021 update. Stem Cell Rep. 16, 1398–1408 (2021).

    Article  Google Scholar 

  141. Rabesandratana, T. E.U. Commission rejects plea to block stem cell research funding. SCIENCEINSIDER https://www.science.org/content/article/eu-commission-rejects-plea-block-stem-cell-research-funding (2014).

  142. Ishii, T. & Eto, K. Fetal stem cell transplantation: past, present, and future. World J. Stem Cell 6, 404 (2014).

    Article  Google Scholar 

  143. Ang, L. T. et al. A roadmap for human liver differentiation from pluripotent stem cells. Cell Rep. 22, 2190–2205 (2018). This article describes an in vitro protocol to efficiently derive HLCs from pluripotent stem cells by including dynamic signals driving hepatic fate and blocking alternate fates.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Tayeb, K. S. et al. Highly efficient generation of human hepatocyte-like cells from induced pluripotent stem cells. Hepatology 51, 297–305 (2010).

    Article  Google Scholar 

  145. Loh, K. M. et al. Efficient endoderm induction from human pluripotent stem cells by logically directing signals controlling lineage bifurcations. Cell Stem Cell 14, 237–252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Takebe, T. et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Rep. 21, 2661–2670 (2017).

    Article  CAS  PubMed  Google Scholar 

  147. Zhao, D. et al. Promotion of the efficient metabolic maturation of human pluripotent stem cell-derived hepatocytes by correcting specification defects. Cell Res. 23, 157–161 (2013).

    Article  CAS  PubMed  Google Scholar 

  148. Wang, A. et al. Epigenetic priming of enhancers predicts developmental competence of hESC-derived endodermal lineage intermediates. Cell Stem Cell 16, 386–399 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Siller, R., Greenhough, S., Naumovska, E. & Sullivan, G. J. Small-molecule-driven hepatocyte differentiation of human pluripotent stem cells. Stem Cell Rep. 4, 939–952 (2015).

    Article  CAS  Google Scholar 

  150. Gage, B. K. et al. Generation of functional liver sinusoidal endothelial cells from human pluripotent stem-cell-derived venous angioblasts. Cell Stem Cell 27, 254–269.e9 (2020).

    Article  CAS  PubMed  Google Scholar 

  151. Marsee, A. et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell 28, 816–832 (2021).

    Article  CAS  PubMed  Google Scholar 

  152. Hu, H. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175, 1591–1606.e19 (2018). This article shows successful growth of human and mouse hepatic cells as 3D organoids, enabling long-term culture while maintaining functional resemblance to in vivo hepatocytes.

    Article  CAS  PubMed  Google Scholar 

  153. Hendriks, D. et al. Establishment of human fetal hepatocyte organoids and CRISPR–Cas9-based gene knockin and knockout in organoid cultures from human liver. Nat. Protoc. 16, 182–217 (2021).

    Article  CAS  PubMed  Google Scholar 

  154. Ramli, M. N. B. et al. Human pluripotent stem cell-derived organoids as models of liver disease. Gastroenterology 159, 1471–1486.e12 (2020).

    Article  CAS  PubMed  Google Scholar 

  155. Guan, Y. et al. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight 2, e94954 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Artegiani, B. et al. Fast and efficient generation of knock-in human organoids using homology-independent CRISPR–Cas9 precision genome editing. Nat. Cell Biol. 22, 321–331 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  158. Raggi, C. et al. Leveraging interacting signaling pathways to robustly improve the quality and yield of human pluripotent stem cell-derived hepatoblasts and hepatocytes. Stem Cell Rep. 17, 584–598 (2022).

    Article  CAS  Google Scholar 

  159. Takeishi, K. et al. Assembly and function of a bioengineered human liver for transplantation generated solely from induced pluripotent stem cells. Cell Rep. 31, 107711 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Koike, H. et al. Engineering human hepato-biliary-pancreatic organoids from pluripotent stem cells. Nat. Protoc. 16, 919–936 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Koike, H. et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary. Nature 574, 112–116 (2019). This article describes the combination of anterior and posterior foregut spheroids into a multi-organ 3D culture resulting in hepatic, biliary and pancreatic structures invaginating from the foregut–midgut boundary, enabling the study of early organ morphogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Ouchi, R. et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab. 30, 374–384.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Tarlow, B. D., Finegold, M. J. & Grompe, M. Clonal tracing of Sox9+ liver progenitors in mouse oval cell injury. Hepatology 60, 278–289 (2014).

    Article  CAS  PubMed  Google Scholar 

  164. Malato, Y. et al. Fate tracing of mature hepatocytes in mouse liver homeostasis and regeneration. J. Clin. Invest. 121, 4850–4860 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Español–Suñer, R. et al. Liver progenitor cells yield functional hepatocytes in response to chronic liver injury in mice. Gastroenterology 143, 1564–1575.e7 (2012).

    Article  PubMed  Google Scholar 

  166. Español–Suñer, R., Lemaigre, F. P. & Leclercq, I. A. Reply: To PMID 22922013. Gastroenterology 145, 255–256 (2013).

    Article  PubMed  Google Scholar 

  167. Yanger, K. et al. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27, 719–724 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Michalopoulos, G. K., Barua, L. & Bowen, W. C. Transdifferentiation of rat hepatocytes into biliary cells after bile duct ligation and toxic biliary injury. Hepatology 41, 535–544 (2005).

    Article  CAS  PubMed  Google Scholar 

  169. Michalopoulos, G. K. & Bhushan, B. Liver regeneration: biological and pathological mechanisms and implications. Nat. Rev. Gastroenterol. Hepatol. 18, 40–55 (2021).

    Article  PubMed  Google Scholar 

  170. Michalopoulos, G. K. The liver is a peculiar organ when it comes to stem cells. Am. J. Pathol. 184, 1263–1267 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Schaub, J. R., 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. 8, 933–939 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Yanger, K. et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 15, 340–349 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Turner, R. et al. Human hepatic stem cell and maturational liver lineage biology. Hepatology 53, 1035–1045 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Carpino, G. et al. Biliary tree stem/progenitor cells in glands of extrahepatic and intraheptic bile ducts: an anatomical in situ study yielding evidence of maturational lineages. J. Anat. 220, 186–199 (2012).

    Article  PubMed  Google Scholar 

  175. Lesage, G. et al. Regrowth of the rat biliary tree after 70% partial hepatectomy is coupled to increased secretin-induced ductal secretion. Gastroenterology 111, 1633–1644 (1996).

    Article  CAS  PubMed  Google Scholar 

  176. Walesky, C. M. et al. Functional compensation precedes recovery of tissue mass following acute liver injury. Nat. Commun. 11, 5785 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Fan, B. et al. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Invest. 122, 2911–2915 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Sekiya, S. & Suzuki, A. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Invest. 122, 3914–3918 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Chen, Y.-J., Shen, C.-J., Yu, S.-H., Lin, C.-L. & Shih, H.-M. Increased risk of hepatocellular carcinoma in patients with traumatic liver injury. Medicine 101, e28837 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. He, G. et al. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155, 384–396 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Ning, B.-F. et al. Hepatocyte nuclear factor 4α suppresses the development of hepatocellular carcinoma. Cancer Res. 70, 7640–7651 (2010).

    Article  CAS  PubMed  Google Scholar 

  182. Chen, T. et al. AFP promotes HCC progression by suppressing the HuR-mediated Fas/FADD apoptotic pathway. Cell Death Dis. 11, 822 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Goeroeg, D., Regoely-Merei, J., Paku, S., Kopper, L. & Nagy, P. Alpha-fetoprotein expression is a potential prognostic marker in hepatocellular carcinoma. World J. Gastroenterol. 11, 5015–5018 (2005).

    Article  Google Scholar 

  184. Muguti, G., Tait, N., Richardson, A. & Little, J. M. Alpha‐fetoprotein expression in hepatocellular carcinoma: a clinical study. J. Gastroenterol. Hepatol. 7, 374–378 (1992).

    Article  CAS  PubMed  Google Scholar 

  185. Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).

    Article  PubMed  Google Scholar 

  186. Li, Y., Wang, J. & Asahina, K. Mesothelial cells give rise to hepatic stellate cells and myofibroblasts via mesothelial–mesenchymal transition in liver injury. Proc. Natl Acad. Sci. USA 110, 2324–2329 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Chu, A. S. et al. Lineage tracing demonstrates no evidence of cholangiocyte epithelial‐to‐mesenchymal transition in murine models of hepatic fibrosis. Hepatology 53, 1685–1695 (2011).

    Article  PubMed  Google Scholar 

  188. Scholten, D. et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology 139, 987–998 (2010).

    Article  CAS  PubMed  Google Scholar 

  189. Taura, K. et al. Hepatocytes do not undergo epithelial‐mesenchymal transition in liver fibrosis in mice. Hepatology 51, 1027–1036 (2010).

    Article  PubMed  Google Scholar 

  190. Auvinen, K. et al. Fenestral diaphragms and PLVAP associations in liver sinusoidal endothelial cells are developmentally regulated. Sci. Rep. 9, 15698 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  191. Lu, Y. et al. Spatial transcriptome profiling by MERFISH reveals fetal liver hematopoietic stem cell niche architecture. Cell Discov. 7, 47 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Sharma, A. et al. Onco-fetal reprogramming of endothelial cells drives immunosuppressive macrophages in hepatocellular carcinoma. Cell 183, 377–394.e21 (2020). This article describes the use of single-cell RNA-seq of human fetal liver, HCC and mouse liver showing fetal-like reprogramming of endothelial cells and macrophages in HCC, suggesting a shared oncofetal immunosuppressive microenvironment.

    Article  CAS  PubMed  Google Scholar 

  193. Maretti‐Mira, A. C., Wang, X., Wang, L. & DeLeve, L. D. Incomplete differentiation of engrafted bone marrow endothelial progenitor cells initiates hepatic fibrosis in the rat. Hepatology 69, 1259–1272 (2019).

    Article  PubMed  Google Scholar 

  194. Wang, L. et al. Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats. J. Clin. Invest. 122, 1567–1573 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Liu, K., Jin, H. & Zhou, B. Genetic lineage tracing with multiple DNA recombinases: a user’s guide for conducting more precise cell fate mapping studies. J. Biol. Chem. 295, 6413–6424 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Masuyama, N., Mori, H. & Yachie, N. DNA barcodes evolve for high-resolution cell lineage tracing. Curr. Opin. Chem. Biol. 52, 63–71 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Rao, A., Barkley, D., França, G. S. & Yanai, I. Exploring tissue architecture using spatial transcriptomics. Nature 596, 211–220 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Ma, X. et al. Deterministically patterned biomimetic human iPSC-derived hepatic model via rapid 3D bioprinting. Proc. Natl Acad. Sci. USA 113, 2206–2211 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Ren, Y. et al. Developments and opportunities for 3D bioprinted organoids. Int. J. Bioprinting 7, 364 (2021).

    Article  Google Scholar 

  200. Kang, D. et al. Bioprinting of multiscaled hepatic lobules within a highly vascularized construct. Small 16, 1905505 (2020).

    Article  CAS  Google Scholar 

  201. Postic, C. & Magnuson, M. A. DNA excision in liver by an albumin–Cre transgene occurs progressively with age. Genesis 26, 149–150 (2000).

    Article  CAS  PubMed  Google Scholar 

  202. Schuler, M., Dierich, A., Chambon, P. & Metzger, D. Efficient temporally controlled targeted somatic mutagenesis in hepatocytes of the mouse. Genesis 39, 167–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  203. Wang, Y. et al. Genetic tracing of hepatocytes in liver homeostasis, injury, and regeneration. J. Biol. Chem. 292, 8594–8604 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Kellendonk, C., Opherk, C., Anlag, K., Schütz, G. & Tronche, F. Hepatocyte‐specific expression of Cre recombinase. Genesis 26, 151–153 (2000).

    Article  CAS  PubMed  Google Scholar 

  205. Uetzmann, L., Burtscher, I. & Lickert, H. A mouse line expressing Foxa2‐driven Cre recombinase in node, notochord, floorplate, and endoderm. Genesis 46, 515–522 (2008).

    Article  CAS  PubMed  Google Scholar 

  206. Park, E. J. et al. System for tamoxifen‐inducible expression of cre‐recombinase from the Foxa2 locus in mice. Dev. Dyn. 237, 447–453 (2008).

    Article  CAS  PubMed  Google Scholar 

  207. Sebae, G. K. E. et al. Single-cell murine genetic fate mapping reveals bipotential hepatoblasts and novel multi-organ endoderm progenitors. Development 145, dev168658 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Lee, C. S., Friedman, J. R., Fulmer, J. T. & Kaestner, K. H. The initiation of liver development is dependent on Foxa transcription factors. Nature 435, 944–947 (2005).

    Article  CAS  PubMed  Google Scholar 

  209. Solar, M. et al. Pancreatic exocrine duct cells give rise to insulin-producing β cells during embryogenesis but not after birth. Dev. Cell 17, 849–860 (2009).

    Article  CAS  PubMed  Google Scholar 

  210. Rodrigo‐Torres, D. et al. The biliary epithelium gives rise to liver progenitor cells. Hepatology 60, 1367–1377 (2014).

    Article  PubMed  Google Scholar 

  211. Means, A. L., Xu, Y., Zhao, A., Ray, K. C. & Gu, G. A CK19CreERT knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Genesis 46, 318–323 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Tannour‐Louet, M., Porteu, A., Vaulont, S., Kahn, A. & Vasseur‐Cognet, M. A tamoxifen‐inducible chimeric Cre recombinase specifically effective in the fetal and adult mouse liver. Hepatology 35, 1072–1081 (2002).

    Article  PubMed  Google Scholar 

  213. Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E. & Speck, N. A. Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature 457, 887–891 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Wohlfeil, S. A. et al. Hepatic endothelial Notch activation protects against liver metastasis by regulating endothelial-tumor cell adhesion independent of angiocrine signaling. Cancer Res. 79, 598–610 (2019).

    Article  CAS  PubMed  Google Scholar 

  215. Bianchi, R. et al. A transgenic Prox1-Cre-tdTomato reporter mouse for lymphatic vessel research. PLoS ONE 10, e0122976 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  216. Géraud, C. et al. GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis. J. Clin. Invest. 127, 1099–1114 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Kitto, L. J. & Henderson, N. C. Hepatic stellate cell regulation of liver regeneration and repair. Hepatol. Commun. 5, 358–370 (2021).

    Article  PubMed  Google Scholar 

  218. Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc. Natl Acad. Sci. USA 109, 9448–9453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Kosar, K. et al. WNT7B regulates cholangiocyte proliferation and function during murine cholestasis. Hepatol. Commun. 5, 2019–2034 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. He, J., Lu, H., Zou, Q. & Luo, L. Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology 146, 789–800.e8 (2014).

    Article  CAS  PubMed  Google Scholar 

  221. Choi, T., Ninov, N., Stainier, D. Y. R. & Shin, D. Extensive conversion of hepatic biliary epithelial cells to hepatocytes after near total loss of hepatocytes in zebrafish. Gastroenterology 146, 776–788 (2014).

    Article  CAS  PubMed  Google Scholar 

  222. Portmann, B. C. & Roberts, E. A. in Macsween’s Pathology of the Liver 6th edn (eds Burt, A. D., Portmann, B. C. & Ferrell, L. D.) 101–156 (Elsevier, 2012).

  223. Alagille, D., Odièvre, M., Gautier, M. & Dommergues, J. P. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J. Pediatr. 86, 63–71 (1975).

    Article  CAS  PubMed  Google Scholar 

  224. Alagille, D. et al. Syndromic paucity of interlobular bile ducts (Alagille syndrome or arteriohepatic dysplasia): review of 80 cases. J. Pediatr. 110, 195–200 (1987).

    Article  CAS  PubMed  Google Scholar 

  225. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat. Genet. 16, 243–251 (1997).

    Article  CAS  PubMed  Google Scholar 

  226. McDaniell, R. et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch signaling pathway. Am. J. Hum. Genet. 79, 169–173 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Hofmann, J. J. et al. Jagged1 in the portal vein mesenchyme regulates intrahepatic bile duct development: insights into Alagille syndrome. Development 137, 4061–4072 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Hartley, J. L., Davenport, M. & Kelly, D. A. Biliary atresia. Lancet 374, 1704–1713 (2009).

    Article  PubMed  Google Scholar 

  229. Arikan, C. et al. Polymorphisms of the ICAM-1 gene are associated with biliary atresia. Dig. Dis. Sci. 53, 2000–2004 (2008).

    Article  CAS  PubMed  Google Scholar 

  230. Arikan, C. et al. Positive association of macrophage migration inhibitory factor gene-173G/C polymorphism with biliary atresia. J. Pediatr. Gastroenterol. Nutr. 42, 77–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  231. Davit-Spraul, A., Baussan, C., Hermeziu, B., Bernard, O. & Jacquemin, E. CFC1 gene involvement in biliary atresia with polysplenia syndrome. J. Pediatr. Gastr Nutr. 46, 111–112 (2008).

    Article  CAS  Google Scholar 

  232. Shih, H.-H. et al. Promoter polymorphism of the CD14 endotoxin receptor gene is associated with biliary atresia and idiopathic neonatal cholestasis. Pediatrics 116, 437–441 (2005).

    Article  PubMed  Google Scholar 

  233. Huang, Y.-H. et al. Upstream stimulatory factor 2 is implicated in the progression of biliary atresia by regulation of hepcidin expression. J. Pediatr. Surg. 43, 2016–2023 (2008).

    Article  PubMed  Google Scholar 

  234. Yokoyama, T. et al. Reversal of left-right asymmetry: a situs inversus mutation. Science 260, 679–682 (1993).

    Article  CAS  PubMed  Google Scholar 

  235. Shimadera, S. et al. The inv mouse as an experimental model of biliary atresia. J. Pediatr. Surg. 42, 1555–1560 (2007).

    Article  PubMed  Google Scholar 

  236. Heslop, J. A., Pournasr, B., Liu, J.-T. & Duncan, S. A. GATA6 defines endoderm fate by controlling chromatin accessibility during differentiation of human-induced pluripotent stem cells. Cell Rep. 35, 109145 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Zaret, K. S. & Carroll, J. S. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 25, 2227–2241 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Geusz, R. J. et al. Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors. Nat. Commun. 12, 6636 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Reizel, Y. et al. Collapse of the hepatic gene regulatory network in the absence of FoxA factors. Genes Dev. 34, 1039–1050 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. DeLaForest, A. et al. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 138, 4143–4153 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Hayhurst, G. P., Lee, Y.-H., Lambert, G., Ward, J. M. & Gonzalez, F. J. Hepatocyte nuclear factor 4α (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol. Cell Biol. 21, 1393–1403 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Sosa-Pineda, B., Wigle, J. T. & Oliver, G. Hepatocyte migration during liver development requires Prox1. Nat. Genet. 25, 254–255 (2000).

    Article  CAS  PubMed  Google Scholar 

  243. Lüdtke, T. H. W., Christoffels, V. M., Petry, M. & Kispert, A. Tbx3 promotes liver bud expansion during mouse development by suppression of cholangiocyte differentiation. Hepatology 49, 969–978 (2009).

    Article  PubMed  Google Scholar 

  244. Mukherjee, S., French, D. L. & Gadue, P. Loss of TBX3 enhances pancreatic progenitor generation from human pluripotent stem cells. Stem Cell Rep. 16, 2617–2627 (2021).

    Article  CAS  Google Scholar 

  245. Thakur, A. et al. Hepatocyte nuclear factor 4‐alpha is essential for the active epigenetic state at enhancers in mouse liver. Hepatology 70, 1360–1376 (2019).

    Article  CAS  PubMed  Google Scholar 

  246. Li, J., Ning, G. & Duncan, S. A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4α. Genes Dev. 14, 464–474 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Horisawa, K. et al. The dynamics of transcriptional activation by hepatic reprogramming factors. Mol. Cell 79, 660–676.e8 (2020).

    Article  CAS  PubMed  Google Scholar 

  248. Poncy, A. et al. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev. Biol. 404, 136–148 (2015).

    Article  CAS  PubMed  Google Scholar 

  249. Coffinier, C. et al. Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1β. Development 129, 1829–1838 (2002).

    Article  CAS  PubMed  Google Scholar 

  250. Clotman, F. et al. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development 129, 1819–1828 (2002).

    Article  CAS  PubMed  Google Scholar 

  251. Campbell, S. A. et al. Signalling pathways and transcriptional regulators orchestrating liver development and cancer. Development 148, dev199814 (2021).

    Article  CAS  PubMed  Google Scholar 

  252. Macchi, F. & Sadler, K. C. Unraveling the epigenetic basis of liver development, regeneration and disease. Trends Genet. 36, 587–597 (2020).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank K. Stevens and K. Tremblay for constructive discussions and helpful comments. The authors of this work were supported by the Canadian Institutes of Health Research (FRN 159512 to P.A.H.) and Natural Sciences and Engineering Research Council (NSERC) (RGPIN-2018-05018 to P.A.H.). J.L. is the recipient of an NSERC PGSD scholarship and T.L.S. is the recipient of a Faculty of Medicine Graduate scholarship of the University of British Columbia.

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  1. These authors contributed equally: Jeremy Lotto, Tabea L. Stephan.

Authors and Affiliations

  1. Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada

    Jeremy Lotto, Tabea L. Stephan & Pamela A. Hoodless

  2. Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada

    Jeremy Lotto, Tabea L. Stephan & Pamela A. Hoodless

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  1. Jeremy Lotto
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Correspondence to Pamela A. Hoodless.

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Glossary

Central veins

The main draining vessels of the liver, receiving blood from the liver sinusoids and returning de-oxygenated blood to the heart via the vena cava.

Cholangiocytes

The epithelial cells lining the liver’s network of bile ducts, regulating the flow of bile and altering bile composition.

Fetal-like bipotential progenitor cells

A collective term to describe parenchymal hepatic cells that share a gene expression signature with fetal hepatoblasts and have the potential to differentiate into both hepatocytes and cholangiocytes.

Haemogenic endothelium of the aorta–gonad–mesonephros

A unique intraembryonic region where early in development, specialized endothelial cells, termed haemogenic endothelium, give rise to haematopoietic stem and progenitor cells, which subsequently enter the circulation and migrate to the liver.

HCC progenitor cells

Pathological cells with the potential to give rise to hepatocellular carcinoma (HCC) cells that are likely to have high proliferative potential and can be found in precancerous lesions as well as in HCC.

Hepatic parenchymal and non-parenchymal cell types

Parenchymal cells, including hepatocytes and cholangiocytes, are the functional cell types of the liver, while non-parenchymal cells include supportive cell populations, such as stromal cells, endothelial cells, resident immune cells and neurons.

Hepatobiliary hybrid cells

Hepatic parenchymal cells that both exist developmentally and persist into adulthood. They arise early in liver development (E13.5 in mice) with the potential to give rise to cholangiocytes and periportal hepatocytes. Adult resident hepatobiliary hybrid cells are defined by their periportal location, EPCAM+TROP2int in human and SOX9+HNF4α+ expression in mice, and have been shown via lineage tracing to replenish the parenchymal niche upon injury. These cells are termed hybrid periportal hepatocytes, hepatobiliary hybrid progenitor and bipotential epithelial progenitors in the original publications.

Hepatoblast

A bipotential population derived from endoderm that differentiate during development to form the liver parenchymal cell types hepatocytes and cholangiocytes.

Hepatocytes

The main population of the mature liver. They perform over 500 different metabolic and homeostatic functions.

Liver sinusoids

A specialized capillary lined by liver sinusoidal endothelial cells that serves as the location for intermixing of oxygen-rich blood from the hepatic artery and nutrient-rich blood from the portal vein, and whose fenestrations and lack of a basement membrane facilitate the free flow of blood plasma into the liver’s interstitial space, enabling easy nutrient exchange for hepatocytes.

Liver stem cells

Hepatic cells with the potential to self-renew, to persist into adulthood and to give rise to hepatocytes and cholangiocytes, replenishing the parenchymal niche upon injury. The term does not refer to a well-defined cell type, and is used ambiguously in different publications.

Liver zonation

Zonation enables the division of metabolic and synthetic functions of the liver across the portocentral axis among hepatocytes and non-parenchymal cells.

Organoid

A self-organizing 3D tissue culture derived from either stem cells or tissue explants that contains more than one cell type and recapitulates various aspects of in vivo tissue complexity.

Oval cells

A type of hepatic cell that arise in the liver upon injury when hepatocyte proliferation is inhibited, and which are named after the oval shape of their nucleus. The characteristics and functions of this cell type are poorly defined, but they are suggested to be bipotential and have the ability to proliferate and replenish the parenchymal niche.

Portal vein

The vein that transports nutrient-rich and toxin-rich but de-oxygenated blood from the gastrointestinal tract. It is one of the main blood vessels draining into the hepatic sinusoid.

Progenitor-like cells

General term for cells that share characteristics with developmental progenitor cells.

Pseudostratification

The process by which cells in a tightly packed epithelium become elongated, giving the appearance of multiple layers when examined by histological analysis, while still maintaining attachment to the basement membrane.

Septum transversum mesenchyme

The mesenchymal tissue, derived from lateral plate mesoderm, lying ventral to the developing liver, supplying cues promoting induction of hepatic identity and substrate into which primitive parenchymal cells migrate.

Sinus venosus

Embryonic cavity preceding the atrium of the right side of the developing heart, adjacent to the septum transversum mesenchyme, receiving venous blood from the embryonic circulation.

Spheroids

Cell aggregates containing one cell type with limited heterogeneity that self-organize into spheres when cultured in 3D.

Vitelline veins

The veins that drain blood from the yolk sac and gut tube into the heart of an embryo.

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Lotto, J., Stephan, T.L. & Hoodless, P.A. Fetal liver development and implications for liver disease pathogenesis. Nat Rev Gastroenterol Hepatol 20, 561–581 (2023). https://doi.org/10.1038/s41575-023-00775-2

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