Pek, N. M. Q., Liu, K. J., Nichane, M. & Ang, L. T. Controversies surrounding the origin of hepatocytes in adult livers and the in vitro generation or propagation of hepatocytes. Cell. Mol. Gastroenterol. Hepatol. 11, 273–290 (2021).
Martini, T., Naef, F. & Tchorz, J. S. Spatiotemporal metabolic liver zonation and consequences on pathophysiology. Annu. Rev. Pathol.: Mech. Dis. 18, 439–466 (2023).
Rinella, M. E. et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J. Hepatol. 79, 1542–1556 (2023).
Dunn, J. C., Tompkins, R. G. & Yarmush, M. L. Hepatocytes in collagen sandwich: evidence for transcriptional and translational regulation. J. Cell Biol. 116, 1043–1053 (1992).
Xiang, C. et al. Long-term functional maintenance of primary human hepatocytes in vitro. Science 364, 399–402 (2019).
Walldorf, J. et al. Expanding hepatocytes in vitro before cell transplantation: donor age‐dependent proliferative capacity of cultured human hepatocytes. Scand. J. Gastroenterol. 39, 584–593 (2004).
Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).
Cai, J. et al. Directed differentiation of human embryonic stem cells into functional hepatic cells. Hepatology 45, 1229–1239 (2007).
Sekiya, S. & Suzuki, A. Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors. Nature 475, 390–393 (2011).
Huang, P. et al. Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors. Nature 475, 386–389 (2011).
Katsuda, T. et al. Generation of human hepatic progenitor cells with regenerative and metabolic capacities from primary hepatocytes. eLife 8, e47313 (2019).
Brown, J. W., Cho, C. J. & Mills, J. C. Paligenosis: cellular remodeling during tissue repair. Annu. Rev. Physiol. 84, 461–483 (2022).
Peng, W. C. et al. Inflammatory cytokine TNFα promotes the long-term expansion of primary hepatocytes in 3D culture. Cell 175, 1607–1619.e1615 (2018).
Hu, H. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175, 1591–1606.e1519 (2018).
Marsee, A. et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell 28, 816–832 (2021).
Peng, W. C., Kraaier, L. J. & Kluiver, T. A. Hepatocyte organoids and cell transplantation: what the future holds. Exp. Mol. Med. 53, 1512–1528 (2021).
Sato, T. & Clevers, H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science 340, 1190–1194 (2013).
Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).
Ally, A. et al. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell 169, 1327–1341.e1323 (2017).
Jung, P. et al. Isolation of human colon stem cells using surface expression of PTK7. Stem Cell Rep. 5, 979–987 (2015).
Cressman, D. E. et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274, 1379–1383 (1996).
Kiuchi, N. et al. STAT3 is required for the gp130-mediated full activation of the c-myc gene. J. Exp. Med. 189, 63–73 (1999).
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.e28 (2019).
Zhang, K. et al. In vitro expansion of primary human hepatocytes with efficient liver repopulation capacity. Cell Stem Cell 23, 806–819.e804 (2018).
Poncy, A. et al. Transcription factors SOX4 and SOX9 cooperatively control development of bile ducts. Dev. Biol. 404, 136–148 (2015).
Okada, H. et al. The transcription factor Klf5 is essential for intrahepatic biliary epithelial tissue remodeling after cholestatic liver injury. J. Biol. Chem. 293, 6214–6229 (2018).
Yimlamai, D. et al. Hippo pathway activity influences liver cell fate. Cell 157, 1324–1338 (2014).
Liu, Y. et al. Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis. J. Hepatol. 76, 652–664 (2022).
Schaub, J. R. et al. De novo formation of the biliary system by TGFβ-mediated hepatocyte transdifferentiation. Nature 557, 247–251 (2018).
Wu, B. et al. A spatiotemporal atlas of cholestatic injury and repair in mice. Nat. Genet. 56, 938–952 (2024).
Bluhme, E. et al. Procurement and evaluation of hepatocytes for transplantation from neonatal donors after circulatory death. Cell Transplant. 31, 09636897211069900 (2022).
Vansaun, M. N., Mendonsa, A. M. & Lee Gorden, D. Hepatocellular proliferation correlates with inflammatory cell and cytokine changes in a murine model of nonalchoholic fatty liver disease. PLoS ONE 8, e73054 (2013).
Kaffe, E. et al. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell 186, 3793–3809.e3726 (2023).
Ardisasmita, A. I. et al. A comprehensive transcriptomic comparison of hepatocyte model systems improves selection of models for experimental use. Commun. Biol. 5, 1094 (2022).
Kim, D. S. et al. A liver‐specific gene expression panel predicts the differentiation status of in vitro hepatocyte models. Hepatology 66, 1662–1674 (2017).
García-Cañaveras, J. C., Donato, M. T., Castell, J. V. & Lahoz, A. Targeted profiling of circulating and hepatic bile acids in human, mouse, and rat using a UPLC-MRM-MS-validated method. J. Lipid Res. 53, 2231–2241 (2012).
Tilg, H., Adolph, T. E. & Trauner, M. Gut-liver axis: pathophysiological concepts and clinical implications. Cell Metab. 34, 1700–1718 (2022).
Rader, D. J. & Kastelein, J. J. P. Lomitapide and mipomersen. Circulation 129, 1022–1032 (2014).
Gerbal-Chaloin, S. et al. The WNT/beta-catenin pathway is a transcriptional regulator of CYP2E1, CYP1A2, and aryl hydrocarbon receptor gene expression in primary human hepatocytes. Mol. Pharmacol. 86, 624–634 (2014).
Zhong, Y., Yu, J. S., Wang, X., Binas, B. & Yoo, H. H. Chemical‐based primary human hepatocyte monolayer culture for the study of drug metabolism and hepatotoxicity: comparison with the spheroid model. FASEB J. 35, e21379 (2021).
Horcas-Nieto, J. M. et al. Organoids as a model to study intestinal and liver dysfunction in severe malnutrition. Biochim. Biophys. Acta, Mol. Basis Dis. 1869, 166635 (2023).
Merritt, M. E., Harrison, C., Sherry, A. D., Malloy, C. R. & Burgess, S. C. Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance. Proc. Natl Acad. Sci. USA 108, 19084–19089 (2011).
Hendriks, D. et al. Mapping of mitogen and metabolic sensitivity in organoids defines requirements for human hepatocyte growth. Nat. Commun. 15, 4034 (2024).
Baudy, A. R. et al. Liver microphysiological systems development guidelines for safety risk assessment in the pharmaceutical industry. Lab Chip 20, 215–225 (2020).
Morgan, K. et al. Oncostatin M induced α1-antitrypsin (AAT) gene expression in Hep G2 cells is mediated by a 3′ enhancer. Biochem. J. 365, 555–560 (2002).
Baumann, H., Onorato, V., Gauldie, J. & Jahreis, G. P. Distinct sets of acute phase plasma proteins are stimulated by separate human hepatocyte-stimulating factors and monokines in rat hepatoma cells. J. Biol. Chem. 262, 9756–9768 (1987).
Maione, D. et al. Coexpression of IL-6 and soluble IL-6R causes nodular regenerative hyperplasia and adenomas of the liver. EMBO J. 17, 5588–5597 (1998).
Schirmacher, P. et al. Hepatocellular hyperplasia, plasmacytoma formation, and extramedullary hematopoiesis in interleukin (IL)-6/soluble IL-6 receptor double-transgenic mice. Am. J. Pathol. 153, 639–648 (1998).
Nakamura, K., Nonaka, H., Saito, H., Tanaka, M. & Miyajima, A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 39, 635–644 (2004).
Kamiya, A. Fetal liver development requires a paracrine action of oncostatin M through the gp130 signal transducer. EMBO J. 18, 2127–2136 (1999).
Gramignoli, R. et al. Development and application of purified tissue dissociation enzyme mixtures for human hepatocyte isolation. Cell Transplant. 21, 1245–1260 (2012).
Kozakai, K. et al. Reliable high-throughput method for inhibition assay of 8 cytochrome P450 isoforms using cocktail of probe substrates and stable isotope-labeled internal standards. Drug Metab. Pharmacokinet. 27, 520–529 (2012).
Ni, X. et al. Functional human induced hepatocytes (hiHeps) with bile acid synthesis and transport capacities: a novel in vitro cholestatic model. Sci. Rep. 6, 38694 (2016).
Yamamoto, T. et al. PRMT1 sustains de novo fatty acid synthesis by methylating PHGDH to drive chemoresistance in triple-negative breast cancer. Cancer Res. 84, 1065–1083 (2024).
Tanosaki, S. et al. Fatty acid synthesis is indispensable for survival of human pluripotent stem cells. iScience 23, 101535 (2020).
Lengler, J. et al. Development of an in vitro biopotency assay for an AAV8 hemophilia B gene therapy vector suitable for clinical product release. Mol. Ther. Methods Clin. Dev. 17, 581–588 (2020).
De Castilho Fernandes, A. et al. Stable and high-level production of recombinant factor IX in human hepatic cell line. Biotechnol. Appl. Biochem. 58, 243–249 (2011).
Biron-Andréani, C., Raulet, E., Pichard-Garcia, L. & Maurel, P. in Hepatocytes. Methods in Molecular Biology, vol 640 (ed. Maurel, P.) 431–445 (Humana, 2010).
Fujii, M., Matano, M., Nanki, K. & Sato, T. Efficient genetic engineering of human intestinal organoids using electroporation. Nat. Protoc. 10, 1474–1485 (2015).
Nanki, K. et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 577, 254–259 (2020).
Hasegawa, M. et al. The reconstituted ‘humanized liver’ in TK-NOG mice is mature and functional. Biochem. Biophys. Res. Commun. 405, 405–410 (2011).
Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467.e456 (2018).
Saitou, M. et al. Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J. Cell Biol. 141, 397–408 (1998).
Schmidl, C., Rendeiro, A. F., Sheffield, N. C. & Bock, C. ChIPmentation: fast, robust, low-input ChIP-seq for histones and transcription factors. Nat. Methods 12, 963–965 (2015).
Schmidt, U., Weigert, M., Broaddus, C. & Myers, G. in Medical Image Computing and Computer Assisted Intervention – MICCAI 2018. MICCAI 2018. Lecture Notes in Computer Science, vol 11071 (eds Frangi, A. et al.) 265–273 (Springer International, 2018).
Ollion, J., Cochennec, J., Loll, F., Escudé, C. & Boudier, T. TANGO: a generic tool for high-throughput 3D image analysis for studying nuclear organization. Bioinformatics 29, 1840–1841 (2013).
Poell, J. B. et al. ACE: absolute copy number estimation from low-coverage whole-genome sequencing data. Bioinformatics 35, 2847–2849 (2019).
Scheinin, I. et al. DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res. 24, 2022–2032 (2014).
Martin, M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet.journal 17, 10 (2011).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Li, B. & Dewey, C. N. RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinf. 12, 323 (2011).
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
Langmead, B. & Salzberg, S. L. Fast gapped-read alignment with Bowtie 2. Nat. Methods 9, 357–359 (2012).
Zhang, Y. et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 9, R137 (2008).
Zhu, L. J. et al. ChIPpeakAnno: a Bioconductor package to annotate ChIP-seq and ChIP-chip data. BMC Bioinf. 11, 237 (2010).
Ramírez, F. et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 44, W160–W165 (2016).
Robinson, J. T. et al. Integrative genomics viewer. Nat. Biotechnol. 29, 24–26 (2011).
Mayakonda, A., Lin, D.-C., Assenov, Y., Plass, C. & Koeffler, H. P. Maftools: efficient and comprehensive analysis of somatic variants in cancer. Genome Res. 28, 1747–1756 (2018).
