{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T15:37:20Z","timestamp":1791819440811,"version":"4.3.4"},"reference-count":81,"publisher":"American Chemical Society (ACS)","issue":"7","license":[{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T00:00:00Z","timestamp":1592438400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["WI2648\/3-1"],"award-info":[{"award-number":["WI2648\/3-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,7,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Key liver functions, including protein synthesis, carbohydrate metabolism, and detoxification, are performed by specific populations of hepatocytes that are defined by their relative positions within the liver lobules. On a molecular level, the functional heterogeneity with periportal and pericentral phenotypes, so-called metabolic liver zonation, is mainly established by a gradient of canonical Wnt signaling activity. Since the relevant physiological cues are missing in in vitro liver models, they fail to reflect the functional heterogeneity and thus lack many liver functions. We synthetically re-engineered Wnt signaling in murine and human hepatocytes using a doxycycline-dependent cassette for externally controlled digital expression of stabilized \u03b2-catenin. Thereby, we achieved adjustable mosaic-like activation of Wnt signaling in in vitro-cultured hepatocytes that was resistant to negative-feedback loops. This allowed the establishment of long-term-stable periportal-like and pericentral-like phenotypes that mimic the heterogeneity observed in vivo. The in vitro-zonated hepatocytes show differential expression of drug-metabolizing enzymes and associated differential toxicity and higher levels of autophagy. Furthermore, recombinant adeno-associated virus and hepatitis C virus preferentially transduce the pericentral-like zonation phenotype, suggesting a bias of these viruses that has been unappreciated to date. These tightly controlled in vivo-like systems will be important for studies evaluating aspects of liver zonation and for the assessment of drug toxicity for mouse and man.<\/jats:p>","DOI":"10.1021\/acssynbio.9b00435","type":"journal-article","created":{"date-parts":[[2020,6,18]],"date-time":"2020-06-18T19:09:04Z","timestamp":1592507344000},"page":"1638-1649","source":"Crossref","is-referenced-by-count":18,"title":["Controlled Functional Zonation of Hepatocytes\n                    <i>In Vitro<\/i>\n                    by Engineering of Wnt Signaling"],"prefix":"10.1021","volume":"9","author":[{"given":"Tom","family":"Wahlicht","sequence":"first","affiliation":[{"name":"Helmholtz Centre for Infection Research , , ,","place":["Braunschweig, Germany, 38124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Vie\u0300yres","sequence":"additional","affiliation":[{"name":"TWINCORE, Centre for Experimental and Clinical Infection Research , , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja A.","family":"Bruns","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Infection Research , , ,","place":["Braunschweig, Germany, 38124"]},{"name":"Otto von Guericke University Magdeburg , , ,","place":["Magdeburg, Germany, 39106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadja","family":"Meumann","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF) , , ,","place":["Braunschweig, Germany, 38124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Bu\u0308ning","sequence":"additional","affiliation":[{"name":"German Center for Infection Research (DZIF) , , ,","place":["Braunschweig, Germany, 38124"]},{"name":"Hannover Medical School , , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansjo\u0308rg","family":"Hauser","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Infection Research , , ,","place":["Braunschweig, Germany, 38124"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Infection Research , , ,","place":["Braunschweig, Germany, 38124"]},{"name":"Otto von Guericke University Magdeburg , , ,","place":["Magdeburg, Germany, 39106"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Pietschmann","sequence":"additional","affiliation":[{"name":"TWINCORE, Centre for Experimental and Clinical Infection Research , , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-6251","authenticated-orcid":true,"given":"Dagmar","family":"Wirth","sequence":"additional","affiliation":[{"name":"Helmholtz Centre for Infection Research , , ,","place":["Braunschweig, Germany, 38124"]},{"name":"Medical University Hannover , , ,","place":["Hannover, Germany, 30625"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2020,6,18]]},"reference":[{"issue":"1","key":"2026081714212803600_cit1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1080\/03602530601093489","article-title":"Primary hepatocytes: current understanding of the regulation\nof metabolic enzymes and transporter proteins, and pharmaceutical\npractice for the use of hepatocytes in metabolism, enzyme induction,\ntransporter, clearance, and hepatotoxicity studies","volume":"39","author":"Hewitt","year":"2007","journal-title":"Drug Metab. Rev."},{"issue":"8","key":"2026081714212803600_cit2","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1007\/s00204-013-1078-5","article-title":"Recent advances in 2D and 3D in vitro systems using\nprimary hepatocytes, alternative hepatocyte sources and non-parenchymal\nliver cells and their use in investigating mechanisms of hepatotoxicity,\ncell signaling and ADME","volume":"87","author":"Godoy","year":"2013","journal-title":"Arch. Toxicol."},{"issue":"2","key":"2026081714212803600_cit3","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1038\/s41575-018-0075-9","article-title":"Wnt\u2212\u03b2-catenin\nsignalling in liver development, health and disease","volume":"16","author":"Perugorria","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"issue":"7647","key":"2026081714212803600_cit4","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/nature21729","article-title":"Erratum: Single-cell\nspatial reconstruction reveals global division of labour in the mammalian\nliver","volume":"543","author":"Halpern","year":"2017","journal-title":"Nature"},{"issue":"7564","key":"2026081714212803600_cit5","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1038\/nature14863","article-title":"Self-renewing\ndiploid Axin2+ cells fuel homeostatic renewal of the liver","volume":"524","author":"Wang","year":"2015","journal-title":"Nature"},{"issue":"1","key":"2026081714212803600_cit6","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/1478-811X-11-21","article-title":"Hepatic autophagy\nis differentially regulated in periportal\nand pericentral zones - a general mechanism relevant for other tissues?","volume":"11","author":"Gebhardt","year":"2013","journal-title":"Cell Commun. Signaling"},{"issue":"2","key":"2026081714212803600_cit7","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/j.jhep.2014.09.004","article-title":"Hepatitis C viral proteins\nperturb metabolic liver zonation","volume":"62","author":"Moreau","year":"2015","journal-title":"J. Hepatol."},{"issue":"6","key":"2026081714212803600_cit8","doi-asserted-by":"publisher","first-page":"2344","DOI":"10.1002\/hep.26924","article-title":"T-cell factor\n4 and beta-catenin chromatin occupancies pattern zonal liver metabolism\nin mice","volume":"59","author":"Gougelet","year":"2014","journal-title":"Hepatology (Hoboken, NJ, U. 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Biotechnol."},{"issue":"7","key":"2026081714212803600_cit12","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1002\/hep4.1196","article-title":"Endothelial\nWnts regulate beta-catenin signaling in murine liver zonation and\nregeneration: A sequel to the Wnt-Wnt situation","volume":"2","author":"Preziosi","year":"2018","journal-title":"Hepatol Commun."},{"issue":"7321","key":"2026081714212803600_cit13","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1038\/nature09493","article-title":"Inductive angiocrine signals from sinusoidal endothelium are required\nfor liver regeneration","volume":"468","author":"Ding","year":"2010","journal-title":"Nature"},{"issue":"7481","key":"2026081714212803600_cit14","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nature12681","article-title":"Divergent\nangiocrine signals from vascular niche balance liver regeneration\nand fibrosis","volume":"505","author":"Ding","year":"2014","journal-title":"Nature"},{"issue":"1","key":"2026081714212803600_cit15","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1002\/hep.23618","article-title":"Liver sinusoidal endothelium: a microenvironment-dependent\ndifferentiation program in rat including the novel junctional protein\nliver endothelial differentiation-associated protein-1","volume":"52","author":"Geraud","year":"2010","journal-title":"Hepatology (Hoboken, NJ, U. 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Pharmacol."},{"issue":"6","key":"2026081714212803600_cit19","doi-asserted-by":"publisher","first-page":"2031","DOI":"10.1002\/hep.22880","article-title":"Extracellular\nmatrix modulates sensitivity of hepatocytes to fibroblastoid dedifferentiation\nand transforming growth factor beta-induced apoptosis","volume":"49","author":"Godoy","year":"2009","journal-title":"Hepatology (Hoboken, NJ, U. S.)"},{"issue":"3","key":"2026081714212803600_cit20","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1002\/hep.21082","article-title":"Zonal gene\nexpression in murine liver: lessons from tumors","volume":"43","author":"Hailfinger","year":"2006","journal-title":"Hepatology (Hoboken, NJ, U. 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Pharmacol."},{"issue":"9","key":"2026081714212803600_cit25","doi-asserted-by":"publisher","first-page":"2963","DOI":"10.1007\/s00204-018-2271-3","article-title":"Spatio-temporal visualization of\nthe distribution of acetaminophen as well as its metabolites and adducts\nin mouse livers by MALDI MSI","volume":"92","author":"Sezgin","year":"2018","journal-title":"Arch. Toxicol."},{"issue":"16","key":"2026081714212803600_cit26","doi-asserted-by":"publisher","first-page":"e147","DOI":"10.1093\/nar\/gkx601","article-title":"Controlled re-activation of epigenetically\nsilenced Tet promoter-driven transgene expression by targeted demethylation","volume":"45","author":"Go\u0308decke","year":"2017","journal-title":"Nucleic Acids Res."},{"issue":"4","key":"2026081714212803600_cit27","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/nbt.1617","article-title":"Self-sufficient control of urate homeostasis in mice\nby a synthetic circuit","volume":"28","author":"Kemmer","year":"2010","journal-title":"Nat. Biotechnol."},{"issue":"7","key":"2026081714212803600_cit28","doi-asserted-by":"publisher","first-page":"1319","DOI":"10.1007\/s00018-016-2417-5","article-title":"Proliferation status\ndefines functional properties of endothelial cells","volume":"74","author":"Lipps","year":"2017","journal-title":"Cell. Mol. 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Biotechnol"},{"issue":"20","key":"2026081714212803600_cit33","doi-asserted-by":"publisher","first-page":"10253","DOI":"10.1128\/JVI.01059-06","article-title":"Production\nof infectious hepatitis\nC virus by well-differentiated, growth-arrested human hepatoma-derived\ncells","volume":"80","author":"Sainz","year":"2006","journal-title":"J. Virol."},{"issue":"3","key":"2026081714212803600_cit34","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1080\/00498250802613620","article-title":"Characterization of\nincreased drug metabolism activity in dimethyl\nsulfoxide (DMSO)-treated Huh7 hepatoma cells","volume":"39","author":"Choi","year":"2009","journal-title":"Xenobiotica"},{"issue":"2","key":"2026081714212803600_cit35","doi-asserted-by":"publisher","first-page":"e9370","DOI":"10.1371\/journal.pone.0009370","article-title":"Lentiviral vectors to probe and manipulate\nthe Wnt signaling pathway","volume":"5","author":"Fuerer","year":"2010","journal-title":"PLoS One"},{"issue":"2","key":"2026081714212803600_cit36","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1002\/biot.201400076","article-title":"Single-cell analysis\nreveals heterogeneity in onset of transgene\nexpression from synthetic tetracycline-dependent promoters","volume":"10","author":"Rand","year":"2015","journal-title":"Biotechnol. J."},{"key":"2026081714212803600_cit37","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1007\/978-1-4939-8730-6_4","article-title":"Stable Expression\nby Lentiviral Transduction\nof Cells","volume":"1850","author":"Go\u0308decke","year":"2018","journal-title":"Methods Mol. Biol."},{"issue":"11","key":"2026081714212803600_cit38","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1080\/15548627.2016.1226732","article-title":"Intracellular Staphylococcus\naureus eludes selective\nautophagy by activating a host cell kinase","volume":"12","author":"Neumann","year":"2016","journal-title":"Autophagy"},{"issue":"1","key":"2026081714212803600_cit39","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1002\/hep.29176","article-title":"Autophagy\ndetermines efficiency of liver-directed gene\ntherapy with adeno-associated viral vectors","volume":"66","author":"Ho\u0308sel","year":"2017","journal-title":"Hepatology (Hoboken, NJ, U. S.)"},{"key":"2026081714212803600_cit40","doi-asserted-by":"publisher","first-page":"A104","DOI":"10.1089\/hum.2017.29055.abstracts","article-title":"ESGCT XXV Anniversary Congress in\nCollaboration with the German Society for Gene Therapy, October 17\u201320,\n2017, Abstract P320: Identification and characterisation of novel\nliver-directed AAV capsid variants exhibiting highly improved liver\ntransduction features","volume":"28","author":"Meumann","year":"2017","journal-title":"Hum. Gene Ther."},{"issue":"2","key":"2026081714212803600_cit41","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.ymeth.2012.09.005","article-title":"Entry and\nreplication of recombinant hepatitis C viruses\nin cell culture","volume":"59","author":"Vieyres","year":"2013","journal-title":"Methods"},{"issue":"19","key":"2026081714212803600_cit42","doi-asserted-by":"publisher","first-page":"7408","DOI":"10.1073\/pnas.0504877103","article-title":"Construction\nand characterization of infectious intragenotypic and intergenotypic\nhepatitis C virus chimeras","volume":"103","author":"Pietschmann","year":"2006","journal-title":"Proc. Natl. Acad.\nSci. U. S. A."},{"issue":"5734","key":"2026081714212803600_cit43","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1126\/science.1114016","article-title":"Complete replication of hepatitis\nC virus in cell culture","volume":"309","author":"Lindenbach","year":"2005","journal-title":"Science (Washington,\nDC, U. 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Protoc."},{"issue":"2","key":"2026081714212803600_cit46","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1053\/j.gastro.2009.05.038","article-title":"Convergence\nof Wnt signaling on the HNF4alpha-driven transcription in controlling\nliver zonation","volume":"137","author":"Colletti","year":"2009","journal-title":"Gastroenterology"},{"issue":"12","key":"2026081714212803600_cit47","doi-asserted-by":"publisher","first-page":"e413","DOI":"10.1038\/emm.2017.226","article-title":"Dual modulation\nof human hepatic zonation via canonical and non-canonical Wnt pathways","volume":"49","author":"McEnerney","year":"2017","journal-title":"Exp. Mol. Med."},{"issue":"7165","key":"2026081714212803600_cit48","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1038\/nature06196","article-title":"Identification of stem cells in small\nintestine and colon by marker gene Lgr5","volume":"449","author":"Barker","year":"2007","journal-title":"Nature"},{"issue":"4","key":"2026081714212803600_cit49","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1128\/MCB.22.4.1172-1183.2002","article-title":"Wnt\/beta-catenin\/Tcf\nsignaling induces the transcription\nof Axin2, a negative regulator of the signaling pathway","volume":"22","author":"Jho","year":"2002","journal-title":"Mol. Cell. Biol."},{"issue":"1","key":"2026081714212803600_cit50","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1093\/toxsci\/kfr080","article-title":"Coordinate Regulation\nof Cytochrome P450 1A1 Expression in Mouse Liver by the Aryl Hydrocarbon\nReceptor and the \u03b2-Catenin Pathway","volume":"122","author":"Braeuning","year":"2011","journal-title":"Toxicol.\nSci."},{"issue":"5","key":"2026081714212803600_cit51","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.stem.2008.09.013","article-title":"Wnt signaling mediates self-organization\nand axis formation in embryoid bodies","volume":"3","author":"ten\nBerge","year":"2008","journal-title":"Cell\nstem cell"},{"issue":"7641","key":"2026081714212803600_cit52","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1038\/nature21065","article-title":"Single-cell\nspatial reconstruction reveals global division of labour in the mammalian\nliver","volume":"542","author":"Halpern","year":"2017","journal-title":"Nature"},{"issue":"6","key":"2026081714212803600_cit53","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1124\/mol.114.097402","article-title":"Activating\nand Inhibitory Functions\nof WNT\/\u03b2-Catenin in the Induction of Cytochromes P450 by Nuclear\nReceptors in HepaRG Cells","volume":"87","author":"Thomas","year":"2015","journal-title":"Mol. Pharmacol."},{"issue":"2","key":"2026081714212803600_cit54","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1124\/jpet.104.075945","article-title":"Mechanisms\nof acetaminophen-induced hepatotoxicity: role of oxidative stress\nand mitochondrial permeability transition in freshly isolated mouse\nhepatocytes","volume":"312","author":"Reid","year":"2005","journal-title":"J. Pharmacol. Exp. 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