Free Bilirubin Induces Neuro-Inflammation in an Induced Pluripotent Stem Cell-Derived Cortical Organoid Model of Crigler-Najjar Syndrome.
Cells
; 12(18)2023 09 14.
Article
em En
| MEDLINE
| ID: mdl-37759499
ABSTRACT
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-brain barrier and accumulate within. A defect in the UGT1A1 enzyme-encoding gene, which is directly responsible for bilirubin conjugation, can cause Crigler-Najjar syndrome (CNS) and Gilbert's 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-cytokine receptor interaction, MAPK signaling, and NFκB 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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Crigler-Najjar
/
Células-Tronco Pluripotentes Induzidas
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Kernicterus
Limite:
Humans
Idioma:
En
Revista:
Cells
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Alemanha