{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T12:04:34Z","timestamp":1792929874673,"version":"4.5.0"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,12,18]],"date-time":"2021-12-18T00:00:00Z","timestamp":1639785600000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>Patient\u2010derived human\u2010induced pluripotent stem cells (hiPSCs) differentiated into hepatocytes (hiPSC\u2010Heps) have facilitated the study of rare genetic liver diseases. Here, we aimed to establish an in vitro liver disease model of the urea cycle disorder ornithine transcarbamylase deficiency (OTCD) using patient\u2010derived hiPSC\u2010Heps.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      Before modeling OTCD, we addressed the question of why hiPSC\u2010Heps generally secrete less urea than adult primary human hepatocytes (PHHs). Because hiPSC\u2010Heps are not completely differentiated and maintain some characteristics of fetal PHHs, we compared gene\u2010expression levels in human fetal and adult liver tissue to identify genes responsible for reduced urea secretion in hiPSC\u2010Heps. We found lack of aquaporin 9 (AQP9) expression in fetal liver tissue as well as in hiPSC\u2010Heps, and showed that forced expression of AQP9 in hiPSC\u2010Heps restores urea secretion and normalizes the response to ammonia challenge by increasing ureagenesis. Furthermore, we proved functional ureagenesis by challenging AQP9\u2010expressing hiPSC\u2010Heps with ammonium chloride labeled with the stable isotope [\n                      <jats:sup>15<\/jats:sup>\n                      N] (\n                      <jats:sup>15<\/jats:sup>\n                      NH\n                      <jats:sub>4<\/jats:sub>\n                      Cl) and by assessing enrichment of [\n                      <jats:sup>15<\/jats:sup>\n                      N]\u2010labeled urea. Finally, using hiPSC\u2010Heps derived from patients with OTCD, we generated a liver disease model that recapitulates the hepatic manifestation of the human disease. Restoring OTC expression\u2014together with AQP9\u2014was effective in fully correcting OTC activity and normalizing ureagenesis as assessed by\n                      <jats:sup>15<\/jats:sup>\n                      NH\n                      <jats:sub>4<\/jats:sub>\n                      Cl stable\u2010isotope challenge.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our results identify a critical role for AQP9 in functional urea metabolism and establish the feasibility of in vitro modeling of OTCD with hiPSC\u2010Heps. By facilitating studies of OTCD genotype\/phenotype correlation and drug screens, our model has potential for improving the therapy of OTCD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32247","type":"journal-article","created":{"date-parts":[[2021,11,17]],"date-time":"2021-11-17T02:56:27Z","timestamp":1637117787000},"page":"646-659","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":23,"title":["Aquaporin 9 induction in human iPSC\u2010derived hepatocytes facilitates modeling of ornithine transcarbamylase deficiency"],"prefix":"10.1097","volume":"76","author":[{"given":"Alexander","family":"Laemmle","sequence":"first","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research,University of California San Francisco,San Francisco,California,USA"},{"name":"Department of Pediatrics,University Children's Hospital,Bern,Switzerland"},{"name":"University Institute of 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Research Center,University Children\u2019s Hospital,Zurich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Robinson","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research,University of California San Francisco,San Francisco,California,USA"},{"name":"Center for Reproductive Sciences,University of California San Francisco,San Francisco,California,USA"},{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences,University of California San Francisco,San Francisco,California,USA"},{"name":"Department of Pediatrics,Medical Genetics,University of California San Francisco,San Francisco,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin C.","family":"Sadowski","sequence":"additional","affiliation":[{"name":"Institute of Pathology,University of Bern,Bern,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Marc","family":"Nuoffer","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,University Children's Hospital,Bern,Switzerland"},{"name":"University Institute of Clinical Chemistry,University of Bern,Bern,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"H\u00e4berle","sequence":"additional","affiliation":[{"name":"Division of Metabolism and Children`s Research Center,University Children\u2019s Hospital,Zurich,Switzerland"},{"name":"Zurich Center for Integrative Human Physiology,University of Zurich,Zurich,Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holger","family":"Willenbring","sequence":"additional","affiliation":[{"name":"Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research,University of California San Francisco,San Francisco,California,USA"},{"name":"Department of 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