{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:12:03Z","timestamp":1790291523812,"version":"4.1.0"},"reference-count":71,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the medical faculty of Heinrich Heine University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Bilirubin-induced neurological damage (BIND), which might progress to kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus enabling albumin-unbound free bilirubin (BF) to cross the blood\u2013brain barrier and accumulate within. A defect in the UGT1A1 enzyme-encoding gene, which is directly responsible for bilirubin conjugation, can cause Crigler\u2013Najjar syndrome (CNS) and Gilbert\u2019s syndrome. We used human-induced pluripotent stem cell (hiPSC)-derived 3D brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of BF in the developing human brain. Healthy and patient-derived iPSCs were differentiated into day-20 brain organoids, and then stimulated with 200 nM BF. Analyses at 24 and 72 h post-treatment point to BF-induced neuro-inflammation in both cell lines. Transcriptome, associated KEGG, and Gene Ontology analyses unveiled the activation of distinct inflammatory pathways, such as cytokine\u2013cytokine receptor interaction, MAPK signaling, and NF\u03baB activation. Furthermore, the mRNA expression and secretome analysis confirmed an upregulation of pro-inflammatory cytokines such as IL-6 and IL-8 upon BF stimulation. This novel study has provided insights into how a human iPSC-derived 3D brain organoid model can serve as a prospective platform for studying the etiology of BIND kernicterus.<\/jats:p>","DOI":"10.3390\/cells12182277","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T03:50:10Z","timestamp":1694749810000},"page":"2277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Free Bilirubin Induces Neuro-Inflammation in an Induced Pluripotent Stem Cell-Derived Cortical Organoid Model of Crigler-Najjar Syndrome"],"prefix":"10.3390","volume":"12","author":[{"given":"Abida Islam","family":"Pranty","sequence":"first","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9153-7051","authenticated-orcid":false,"given":"Wasco","family":"Wruck","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6075-6761","authenticated-orcid":false,"given":"James","family":"Adjaye","sequence":"additional","affiliation":[{"name":"Institute for Stem Cell Research and Regenerative Medicine, Medical Faculty, Heinrich-Heine University D\u00fcsseldorf, 40225 D\u00fcsseldorf, Germany"},{"name":"Zayed Centre for Research into Rare Diseases in Children (ZCR), University College London (UCL)\u2014EGA Institute for Women\u2019s Health, 20 Guilford Street, London WC1N 1DZ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/21678707.2018.1495558","article-title":"Advances in understanding disease mechanisms and potential treatments for Crigler\u2013Najjar syndrome","volume":"6","author":"Bortolussi","year":"2018","journal-title":"Expert Opin. 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