{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:30:10Z","timestamp":1793118610321,"version":"4.5.0"},"reference-count":36,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is caused by pathogenic\n                    <jats:italic>SERPING1<\/jats:italic>\n                    mutations that disrupt production of the plasma protease inhibitor C1INH. However, the molecular mechanisms and consequences of patient\u2010specific mutations remain poorly understood due to the lack of physiologically relevant human models. Here, we established a personalized, isogenic, stem\u2010cell\u2010derived hepatocyte platform to investigate the underlying mutation\u2010specific mechanisms of HAE. Specifically, peripheral blood mononuclear cell (PBMC)\u2010expanded erythroblasts from four representative HAE\u2010C1INH\u2010Type1 patients containing distinct point, insertion, deletion, or large fragment\n                    <jats:italic>SERPING1<\/jats:italic>\n                    mutations were reprogrammed into expanded potential stem cells (EPSCs) and further differentiated into hepatocyte\u2010like cells (HLCs). These HLCs exhibited appropriate transcriptional transitions, mature hepatic features, and C1INH secretion comparable to that observed in human plasma. All patient\u2010derived HLCs demonstrated impaired C1INH secretion with mutation\u2010specific differences in both\n                    <jats:italic>SERPING1<\/jats:italic>\n                    transcription and intracellular accumulation. Moreover, to verify that the mutations directly drive the phenotype, we performed CRISPR\/Cas9\u2010mediated genome repair, which restored\n                    <jats:italic>SERPING1<\/jats:italic>\n                    mRNA expression and C1INH secretion. Conversely, identical patient mutations installed into healthy EPSCs showed the same transcriptional and secretory defects, confirming sufficiency. Collectively, we have established a robust human hepatocyte model that accurately recapitulates key hepatocyte\u2010specific aspects of HAE pathophysiology and provides a scalable foundation for investigation of future precision therapies.\n                  <\/jats:p>","DOI":"10.1111\/all.70419","type":"journal-article","created":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T03:20:12Z","timestamp":1782012012000},"page":"2858-2873","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modeling Hereditary Angioedema With Personalized Expanded Potential Stem Cell\u2010Derived Hepatocytes: A\n                    <scp>CRISPR<\/scp>\n                    \u2010Validated Platform for Mutation\u2010Specific Mechanisms and Therapeutic Innovation"],"prefix":"10.1111","volume":"81","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3756-9172","authenticated-orcid":false,"given":"Xueyan","family":"Liu","sequence":"first","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"},{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9603-5533","authenticated-orcid":false,"given":"Yuxin","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane C. Y.","family":"Wong","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2369-5267","authenticated-orcid":false,"given":"Xiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cuixi","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"},{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"},{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhi","family":"Yang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-9678","authenticated-orcid":false,"given":"Pentao","family":"Liu","sequence":"additional","affiliation":[{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"},{"name":"School of Biomedical Sciences University of Hong Kong  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6698-8355","authenticated-orcid":false,"given":"Chak Sing","family":"Lau","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"},{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Cook","sequence":"additional","affiliation":[{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"},{"name":"School of Clinical Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9155-9162","authenticated-orcid":false,"given":"Philip Hei","family":"Li","sequence":"additional","affiliation":[{"name":"Division of Rheumatology and Clinical Immunology, Department of Medicine Queen Mary Hospital, University of Hong Kong  Hong Kong SAR China"},{"name":"InnoHK Centre for Translational Stem Cell Biology Hong Kong Science Park  Hong Kong SAR China"},{"name":"School of Clinical Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1808012"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.15214"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10092023"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-025-09027-4"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2025.102653"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2024.03.024"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacig.2023.100179"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-025-03382-6"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23917"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-021-08834-9"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00547"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI98869"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.04.023"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2022.11.027"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13023\u2010022\u201002536\u2010x"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1159\/000370106"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.02.020"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95125-0"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13836"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.07.041"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-019-0333-2"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.11.914"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2018.05.029"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2008.05.007"},{"issue":"2","key":"e_1_2_9_26_1","first-page":"308","article-title":"Exhaustive Mutation Scanning by Fluorescence\u2010Assisted Mismatch Analysis Discloses New Genotype\u2010Phenotype Correlations in Angiodema","volume":"59","author":"Verpy E.","year":"1996","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1398-9995.2010.02456.x"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1159\/000323915"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2017.03.010"},{"issue":"5","key":"e_1_2_9_30_1","first-page":"1055","article-title":"Recombinational Biases in the Rearranged C1\u2010Inhibitor Genes of Hereditary Angioedema Patients","volume":"49","author":"Stoppa\u2010Lyonnet D.","year":"1991","journal-title":"American Journal of Human Genetics"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-021-08836-7"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08346-4"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1159\/000486312"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0142174"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2020.06.026"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2023-331742"}],"container-title":["Allergy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.70419","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/all.70419","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/all.70419","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:05:43Z","timestamp":1786557943000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/all.70419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,20]]},"references-count":36,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1111\/all.70419"],"URL":"https:\/\/doi.org\/10.1111\/all.70419","archive":["Portico"],"relation":{},"ISSN":["0105-4538","1398-9995"],"issn-type":[{"value":"0105-4538","type":"print"},{"value":"1398-9995","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,20]]},"assertion":[{"value":"2026-02-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-20","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}