{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T06:06:04Z","timestamp":1790748364807,"version":"4.1.0"},"reference-count":82,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>As the resident tissue macrophage of the liver, Kupffer cells (KCs) play an important role in homeostasis and tissue support. However, current in vitro liver models often ignore the contribution of these KCs towards the proper response and function of the tissue. This is especially relevant when we consider the implications of immune-mediated drug injuries. To address this issue, we developed an isogenic co-culture system utilising iPSC-derived macrophages (iMacs) and hepatocytes (iHeps). Directly co-culturing iHeps with iMacs improved the differentiation and maturation of the iHeps, with significant downregulation of fetal hepatocyte markers as well as upregulation of cytochrome genes. Furthermore, the co-culture also imparted stronger KC identity to the iMacs in a contact-dependent manner, with iMacs cultured in iHep conditioned media alone showing weaker expression of key KC markers. Finally, challenging the iHep-iMac co-culture system with seven paradigm hepatotoxic compounds showed dose-dependent cytokine response in the five compounds associated with immune-mediated liver injuries while no significant changes were observed in the two compounds with no reported immune-dependent complications. This effect was also not recapitulated when the co-culture was instead performed with human peripheral blood monocyte-derived macrophages, suggesting that iMacs are essential for liver toxicity response. Taken together, our study shows not only the importance of macrophages in tissue systems, but also that the source of macrophages is critical to the development of accurate in vitro human models.<\/jats:p>","DOI":"10.7554\/elife.108938","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T14:30:44Z","timestamp":1763130644000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108938","source":"Crossref","is-referenced-by-count":1,"title":["Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9802-4550","authenticated-orcid":true,"given":"Christopher Zhe Wei","family":"Lee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Innovations in Food and Chemical Safety Programme (IFCS), A*STAR","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/02e7b5302","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, Nanyang Technological University","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Farah","family":"Tasnim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Innovations in Food and Chemical Safety Programme (IFCS), A*STAR","place":["Singapore, Singapore"]},{"name":"Institute of Bioengineering and Bioimaging","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Xiaozhong","family":"Huang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Innovations in Food and Chemical Safety Programme (IFCS), A*STAR","place":["Singapore, Singapore"]},{"name":"Institute of Bioengineering and Bioimaging","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/01tgyzw49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Raman","family":"Sethi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Yoohyun","family":"Song","sequence":"additional","affiliation":[{"name":"Institute of Bioengineering and Bioimaging","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Tatsuya","family":"Kozaki","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Sebastiaan","family":"De Schepper","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Nicholas","family":"Ang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Ivy","family":"Low","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"You Yi","family":"Hwang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Jinmiao","family":"Chen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR)","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR)","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0339-3685","authenticated-orcid":true,"given":"Hanry","family":"Yu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Innovations in Food and Chemical Safety Programme (IFCS), A*STAR","place":["Singapore, Singapore"]},{"name":"Institute of Bioengineering and Bioimaging","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/01tgyzw49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/01tgyzw49","id-type":"ROR","asserted-by":"publisher"}],"name":"NUS Graduate School \u2013 Integrative Sciences and Engineering Programme (ISEP)","place":["Singapore, Singapore"]},{"name":"Mechanobiology Institute","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-7755","authenticated-orcid":true,"given":"Florent","family":"Ginhoux","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/036wvzt09","id-type":"ROR","asserted-by":"publisher"}],"name":"Innovations in Food and Chemical Safety Programme (IFCS), A*STAR","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/03vmmgg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Singapore Immunology Network","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/02e7b5302","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, Nanyang Technological University","place":["Singapore, Singapore"]},{"id":[{"id":"https:\/\/ror.org\/0220qvk04","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/00xcwps97","id-type":"ROR","asserted-by":"publisher"}],"name":"Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre","place":["Singapore, Singapore"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"71","DOI":"10.14218\/JERP.2017.00024","type":"journal-article","article-title":"Induction of amodiaquine metabolism by rifampicin following concurrent administration in healthy volunteers","volume":"3","author":"Ademisoye","year":"2018","journal-title":"Journal of Exploratory Research in Pharmacology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"579","DOI":"10.3892\/mmr.2014.2258","type":"journal-article","article-title":"Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review)","volume":"10","author":"Agrogiannis","year":"2014","journal-title":"Molecular Medicine Reports"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"2190","DOI":"10.1016\/j.celrep.2018.01.087","type":"journal-article","article-title":"A roadmap for human liver differentiation from pluripotent stem cells","volume":"22","author":"Ang","year":"2018","journal-title":"Cell Reports"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"E3030","DOI":"10.1073\/pnas.1423765112","type":"journal-article","article-title":"Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy","volume":"112","author":"Babapoor-Farrokhran","year":"2015","journal-title":"PNAS"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1007\/s00418-009-0577-1","type":"journal-article","article-title":"Cellular organization of normal mouse liver: a histological, quantitative immunocytochemical, and fine structural analysis","volume":"131","author":"Baratta","year":"2009","journal-title":"Histochemistry and Cell Biology"},{"key":"bib6","first-page":"849","type":"journal-article","article-title":"Clinical pharmacokinetics and metabolism of pyrazinamide in healthy volunteers","volume":"37","author":"Bareggi","year":"1987","journal-title":"Arzneimittel-Forschung"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","type":"journal-article","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"1995","journal-title":"Journal of the Royal Statistical Society Series B"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1038\/s41586-020-2316-7","type":"journal-article","article-title":"Deciphering human macrophage development at single-cell resolution","volume":"582","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"bib9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.02694","type":"journal-article","article-title":"Understanding the heterogeneity of resident liver macrophages","volume":"10","author":"Bl\u00e9riot","year":"2019","journal-title":"Frontiers in Immunology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1016\/j.immuni.2019.08.017","type":"journal-article","article-title":"Stellate cells, hepatocytes, and endothelial cells imprint the kupffer cell identity on monocytes colonizing the liver macrophage niche","volume":"51","author":"Bonnardel","year":"2019","journal-title":"Immunity"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1089\/aivt.2014.0004","type":"journal-article","article-title":"Differential effects of trovafloxacin on TNF-\u03b1 and IL-6 profiles in a rat hepatocyte\u2013kupffer cell coculture system","volume":"1","author":"Bonzo","year":"2015","journal-title":"Applied In Vitro Toxicology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"13","DOI":"10.3824\/stembook.1.52.1","type":"journal-article","article-title":"Protocol for directed differentiation of human pluripotent stem cells toward a hepatocyte fate","volume":"16","author":"Cai","year":"2014","journal-title":"StemBook"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.tem.2018.05.003","type":"journal-article","article-title":"Roles of aldolase family genes in human cancers and diseases","volume":"29","author":"Chang","year":"2018","journal-title":"Trends in Endocrinology & Metabolism"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1177\/1535370216657901","type":"journal-article","article-title":"Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment","volume":"241","author":"Chaudhari","year":"2016","journal-title":"Experimental Biology and Medicine"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/j.drudis.2016.02.015","type":"journal-article","article-title":"DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans","volume":"21","author":"Chen","year":"2016","journal-title":"Drug Discovery Today"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1182\/blood.V95.2.543","type":"journal-article","article-title":"Domain 5 of high molecular weight kininogen (kininostatin) down-regulates endothelial cell proliferation and migration and inhibits angiogenesis","volume":"95","author":"Colman","year":"2000","journal-title":"Blood"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.it.2011.10.004","type":"journal-article","article-title":"TNF superfamily in inflammatory disease: translating basic insights","volume":"33","author":"Croft","year":"2012","journal-title":"Trends in Immunology"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"2446","DOI":"10.1016\/j.ajpath.2018.07.016","type":"journal-article","article-title":"Heparin-binding epidermal growth factor-like growth factor as a critical mediator of tissue repair and regeneration","volume":"188","author":"Dao","year":"2018","journal-title":"The American Journal of Pathology"},{"key":"bib19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-84785-7","type":"journal-article","article-title":"DAAM2 is elevated in the circulation and placenta in pregnancies complicated by fetal growth restriction and is regulated by hypoxia","volume":"11","author":"de Alwis","year":"2021","journal-title":"Scientific Reports"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1002\/cphy.c120026","type":"journal-article","article-title":"Kupffer cells in the liver","volume":"3","author":"Dixon","year":"2013","journal-title":"Comprehensive Physiology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","type":"journal-article","article-title":"STAR: ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"bib22","doi-asserted-by":"publisher","DOI":"10.3390\/cells8050403","type":"journal-article","article-title":"Current challenges of iPSC-based disease modeling and therapeutic implications","volume":"8","author":"Doss","year":"2019","journal-title":"Cells"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.1101\/442699","type":"preprint","article-title":"DNA Damage Dependent Hypomethylation Regulates the Pro-Angiogenic LncRNA MEG9","volume-title":"bioRxiv","author":"Espinosa-Diez","year":"2018"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1016\/j.cub.2014.01.067","type":"journal-article","article-title":"Proximity interactions among centrosome components identify regulators of centriole duplication","volume":"24","author":"Firat-Karalar","year":"2014","journal-title":"Current Biology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.stem.2020.06.007","type":"journal-article","article-title":"Generation of functional liver sinusoidal endothelial cells from human pluripotent stem-cell-derived venous angioblasts","volume":"27","author":"Gage","year":"2020","journal-title":"Cell Stem Cell"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3222","type":"journal-article","article-title":"An environment-dependent transcriptional network specifies human microglia identity","volume":"356","author":"Gosselin","year":"2017","journal-title":"Science"},{"key":"bib27","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-s1-s4","type":"journal-article","article-title":"GENCODE: producing a reference annotation for ENCODE","volume":"7 Suppl 1","author":"Harrow","year":"2006","journal-title":"Genome Biology"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/psp4.56","type":"journal-article","article-title":"Relationships between pharmacovigilance, molecular, structural, and pathway data: revealing mechanisms for immune-mediated drug-induced liver injury","volume":"4","author":"Ho","year":"2015","journal-title":"CPT"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1056\/NEJMra1816149","type":"journal-article","article-title":"Drug-induced liver injury - types and phenotypes","volume":"381","author":"Hoofnagle","year":"2019","journal-title":"The New England Journal of Medicine"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1248\/bpb.24.701","type":"journal-article","article-title":"Inhibitory effects of anti-inflammatory drugs on interleukin-6 bioactivity","volume":"24","author":"Kang","year":"2001","journal-title":"Biological & Pharmaceutical Bulletin"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/nrd1750","type":"journal-article","article-title":"Idiosyncratic drug hepatotoxicity","volume":"4","author":"Kaplowitz","year":"2005","journal-title":"Nature Reviews. Drug Discovery"},{"key":"bib32","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/640631","type":"journal-article","article-title":"Subtoxic concentrations of hepatotoxic drugs lead to kupffer cell activation in a human in vitro liver model: an approach to study DILI","volume":"2015","author":"Kegel","year":"2015","journal-title":"Mediators of Inflammation"},{"key":"bib33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0220974","type":"journal-article","article-title":"The variances in cytokine production profiles from non- or activated THP-1, Kupffer cell and human blood derived primary macrophages following exposure to either alcohol or a panel of engineered nanomaterials","volume":"14","author":"Kermanizadeh","year":"2019","journal-title":"PLOS ONE"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1038\/nri.2017.11","type":"journal-article","article-title":"Liver macrophages in tissue homeostasis and disease","volume":"17","author":"Krenkel","year":"2017","journal-title":"Nature Reviews. Immunology"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"830","DOI":"10.2174\/1389200219666180523095355","type":"journal-article","article-title":"Models of Drug Induced Liver Injury (DILI) - Current issues and future perspectives","volume":"19","author":"Kuna","year":"2018","journal-title":"Current Drug Metabolism"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.1242\/dev.200270","type":"journal-article","article-title":"Biology of resident tissue macrophages","volume":"149","author":"Lee","year":"2022","journal-title":"Development"},{"key":"bib37","first-page":"551","type":"journal-article","article-title":"Pharmacokinetics of leflunomide in Chinese healthy volunteers","volume":"23","author":"Li","year":"2002","journal-title":"Acta Pharmacologica Sinica"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","type":"journal-article","article-title":"featureCounts: an efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1093\/bja\/88.6.797","type":"journal-article","article-title":"Differential modulation of interleukin-6 and interleukin-10 by diclofenac in patients undergoing major surgery","volume":"88","author":"Mahdy","year":"2002","journal-title":"British Journal of Anaesthesia"},{"key":"bib40","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.4049\/jimmunol.162.4.2095","type":"journal-article","article-title":"Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression","volume":"162","author":"Manna","year":"1999","journal-title":"Journal of Immunology"},{"key":"bib41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-56024-4","type":"journal-article","article-title":"Trajectory analysis of hepatic stellate cell differentiation reveals metabolic regulation of cell commitment and fibrosis","volume":"16","author":"Mart\u00ednez Garc\u00eda de la Torre","year":"2025","journal-title":"Nature Communications"},{"key":"bib42","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf4238","type":"journal-article","article-title":"Specification of tissue-resident macrophages during organogenesis","volume":"353","author":"Mass","year":"2016","journal-title":"Science"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/S1359-6101(00)00003-4","type":"journal-article","article-title":"Role of Oncostatin M in hematopoiesis and liver development","volume":"11","author":"Miyajima","year":"2000","journal-title":"Cytokine & Growth Factor Reviews"},{"key":"bib44","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-398339-8.00003-3","type":"book","volume-title":"Animal Models of Idiosyncratic Drug Reactions","author":"Ng","year":"2012"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"236","DOI":"10.2133\/dmpk.25.236","type":"journal-article","article-title":"Secretion of albumin and induction of CYP1A2 and CYP3A4 in novel three-dimensional culture system for human hepatocytes using micro-space plate","volume":"25","author":"Nishimura","year":"2010","journal-title":"Drug Metabolism and Pharmacokinetics"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1016\/j.bcp.2009.11.010","type":"journal-article","article-title":"A microfluidic hepatic coculture platform for cell-based drug metabolism studies","volume":"79","author":"Novik","year":"2010","journal-title":"Biochemical Pharmacology"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/s41586-023-06713-1","type":"journal-article","article-title":"iPS-cell-derived microglia promote brain organoid maturation via cholesterol transfer","volume":"623","author":"Park","year":"2023","journal-title":"Nature"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/nprot.2014.006","type":"journal-article","article-title":"Full-length RNA-seq from single cells using Smart-seq2","volume":"9","author":"Picelli","year":"2014","journal-title":"Nature Protocols"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/s41586-019-1652-y","type":"journal-article","article-title":"Decoding human fetal liver haematopoiesis","volume":"574","author":"Popescu","year":"2019","journal-title":"Nature"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.jhep.2010.04.017","type":"journal-article","article-title":"Early growth response-1 attenuates liver injury and promotes hepatoprotection after carbon tetrachloride exposure in mice","volume":"53","author":"Pritchard","year":"2010","journal-title":"Journal of Hepatology"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.bbrc.2005.03.133","type":"journal-article","article-title":"Macrophages overexpressing tartrate-resistant acid phosphatase show altered profile of free radical production and enhanced capacity of bacterial killing","volume":"331","author":"R\u00e4is\u00e4nen","year":"2005","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/toxsci\/kfl173","type":"journal-article","article-title":"Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis","volume":"96","author":"Roberts","year":"2007","journal-title":"Toxicological Sciences"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","type":"journal-article","article-title":"edgeR: a Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"950","DOI":"10.1016\/S0022-3549(15)00192-6","type":"journal-article","article-title":"Co-culture of hepatocytes and kupffer cells as an in vitro model of inflammation and drug-induced hepatotoxicity","volume":"105","author":"Rose","year":"2016","journal-title":"Journal of Pharmaceutical Sciences"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41576-019-0100-z","type":"journal-article","article-title":"Induced pluripotent stem cells in disease modelling and drug discovery","volume":"20","author":"Rowe","year":"2019","journal-title":"Nature Reviews. Genetics"},{"key":"bib56","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms10321","type":"journal-article","article-title":"Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells","volume":"7","author":"Scott","year":"2016","journal-title":"Nature Communications"},{"key":"bib57","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00322","type":"journal-article","article-title":"Hepatic macrophages in liver injury","volume":"11","author":"Shan","year":"2020","journal-title":"Frontiers in Immunology"},{"key":"bib58","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/toxsci\/kfm218","type":"journal-article","article-title":"Lipopolysaccharide and trovafloxacin coexposure in mice causes idiosyncrasy-like liver injury dependent on tumor necrosis factor-alpha","volume":"100","author":"Shaw","year":"2007","journal-title":"Toxicological Sciences"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.cbi.2004.09.001","type":"journal-article","article-title":"Animal models of idiosyncratic drug reactions","volume":"150","author":"Shenton","year":"2004","journal-title":"Chemico-Biological Interactions"},{"key":"bib60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024228","type":"journal-article","article-title":"Efficient differentiation of embryonic stem cells into hepatic cells in vitro using a feeder-free basement membrane substratum","volume":"6","author":"Shiraki","year":"2011","journal-title":"PLOS ONE"},{"key":"bib61","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0081974","type":"journal-article","article-title":"Profiles of serum cytokines in acute drug-induced liver injury and their prognostic significance","volume":"8","author":"Steuerwald","year":"2013","journal-title":"PLOS ONE"},{"key":"bib62","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/j.immuni.2017.06.017","type":"journal-article","article-title":"Induced-pluripotent-stem-cell-derived primitive macrophages provide a platform for modeling tissue-resident macrophage differentiation and function","volume":"47","author":"Takata","year":"2017","journal-title":"Immunity"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1016\/j.biomaterials.2012.11.029","type":"journal-article","article-title":"3D spheroid culture of hESC\/hiPSC-derived hepatocyte-like cells for drug toxicity testing","volume":"34","author":"Takayama","year":"2013","journal-title":"Biomaterials"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.biomaterials.2015.08.002","type":"journal-article","article-title":"Cost-effective differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules","volume":"70","author":"Tasnim","year":"2015","journal-title":"Biomaterials"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1021\/acs.molpharmaceut.6b00119","type":"journal-article","article-title":"Functionally enhanced human stem cell derived hepatocytes in galactosylated cellulosic sponges for hepatotoxicity testing","volume":"13","author":"Tasnim","year":"2016","journal-title":"Molecular Pharmaceutics"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.biomaterials.2018.11.016","type":"journal-article","article-title":"Generation of mature kupffer cells from human induced pluripotent stem cells","volume":"192","author":"Tasnim","year":"2019","journal-title":"Biomaterials"},{"key":"bib67","doi-asserted-by":"publisher","DOI":"10.3389\/ftox.2021.605392","type":"journal-article","article-title":"Recent advances in models of immune-mediated drug-induced liver injury","volume":"3","author":"Tasnim","year":"2021","journal-title":"Frontiers in Toxicology"},{"key":"bib68","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.drudis.2019.09.022","type":"journal-article","article-title":"Drug-induced liver injury severity and toxicity (DILIst): binary classification of 1279 drugs by human hepatotoxicity","volume":"25","author":"Thakkar","year":"2020","journal-title":"Drug Discovery Today"},{"key":"bib69","doi-asserted-by":"publisher","first-page":"041","DOI":"10.4172\/1948-593X.1000009","type":"journal-article","article-title":"Pharmacokinetic modelling of lamotrigine from plasma concentrations in healthy volunteers","volume":"01","author":"Tuba Incecayir","year":"2009","journal-title":"Journal of Bioanalysis & Biomedicine"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1016\/j.tiv.2006.04.005","type":"journal-article","article-title":"Modeling inflammation-drug interactions in vitro: a rat Kupffer cell-hepatocyte coculture system","volume":"20","author":"Tukov","year":"2006","journal-title":"Toxicology in Vitro"},{"key":"bib71","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00837","type":"journal-article","article-title":"Mechanistic studies of idiosyncratic DILI: clinical implications","volume":"10","author":"Uetrecht","year":"2019","journal-title":"Frontiers in Pharmacology"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1136\/gut.2008.163675","type":"journal-article","article-title":"Diagnosis, management and prevention of drug-induced liver injury","volume":"58","author":"Verma","year":"2009","journal-title":"Gut"},{"key":"bib73","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41423-020-00558-8","type":"journal-article","article-title":"Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities","volume":"18","author":"Wen","year":"2021","journal-title":"Cellular & Molecular Immunology"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1002\/jat.3189","type":"journal-article","article-title":"Cytochrome P450 induction response in tethered spheroids as a three-dimensional human hepatocyte in vitro model","volume":"36","author":"Xia","year":"2016","journal-title":"Journal of Applied Toxicology"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1093\/toxsci\/kfn109","type":"journal-article","article-title":"Cellular imaging predictions of clinical drug-induced liver injury","volume":"105","author":"Xu","year":"2008","journal-title":"Toxicological Sciences"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"1608","DOI":"10.3748\/wjg.v10.i11.1608","type":"journal-article","article-title":"Leflunomide attenuates hepatocyte injury by inhibiting Kupffer cells","volume":"10","author":"Yao","year":"2004","journal-title":"World Journal of Gastroenterology"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1110\/ps.04951405","type":"journal-article","article-title":"Ligand-binding regulation of LXR\/RXR and LXR\/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation","volume":"14","author":"Yue","year":"2005","journal-title":"Protein Science"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"30222","DOI":"10.18632\/oncotarget.4997","type":"journal-article","article-title":"Histidine-rich glycoprotein function in hepatocellular carcinoma depends on its N-glycosylation status, and it regulates cell proliferation by inhibiting Erk1\/2 phosphorylation","volume":"6","author":"Zhang","year":"2015","journal-title":"Oncotarget"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1124\/jpet.109.156331","type":"journal-article","article-title":"Sulindac metabolism and synergy with tumor necrosis factor-alpha in a drug-inflammation interaction model of idiosyncratic liver injury","volume":"331","author":"Zou","year":"2009","journal-title":"The Journal of Pharmacology and Experimental Therapeutics"},{"key":"dataset1","type":"dataset","article-title":"Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation","volume-title":"NCBI Gene Expression Omnibus","author":"Lee","year":"2025","unstructured":"Lee CZW, Tasnim F, Sethi R, Chen J, Yu H. 2025. Direct contact between iPSC-derived macrophages and hepatocytes drives reciprocal acquisition of Kupffer cell identity and hepatocyte maturation. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE307755. GSE307755."},{"key":"dataset2","type":"dataset","article-title":"Human fetal liver, skin and kidney single cell transcriptome data","volume-title":"E-MTAB-7407","author":"Polanski","year":"2019","unstructured":"Polanski K, Haniffa M, Stephenson E, Popescu DM. 2019. Human fetal liver, skin and kidney single cell transcriptome data. E-MTAB-7407. https:\/\/www.ebi.ac.uk\/biostudies\/ArrayExpress\/studies\/E-MTAB-7407. ArrayExpress."},{"key":"dataset3","type":"dataset","article-title":"Deciphering human macrophage development at single-cell resolution","volume-title":"NCBI Gene Expression Omnibus","author":"Bian","year":"2020","unstructured":"Bian Z, Huang T, Gong Y, Lee CZW, Shi H. 2020. Deciphering human macrophage development at single-cell resolution. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE133345. GSE133345."}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108938\/elife-108938-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/108938\/elife-108938-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/108938","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:55:26Z","timestamp":1787561726000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/108938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,29]]},"references-count":82,"alternative-id":["10.7554\/eLife.108938"],"URL":"https:\/\/doi.org\/10.7554\/elife.108938","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.08.26.672295","asserted-by":"subject"}],"references":[{"id-type":"accession","id":"ArrayExpress","asserted-by":"subject"},{"id-type":"accession","id":"GSE133345","asserted-by":"subject"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.108938.3","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.108938.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.108938.2","asserted-by":"subject"}],"is-supplemented-by":[{"id-type":"accession","id":"GSE307755","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,29]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP108938"}}