The Effects of Bilirubin and Lumirubin on the Differentiation of Human Pluripotent Cell-Derived Neural Stem Cells
Nikola Capková,
Veronika Pospíšilová,
Veronika Fedorová,
Jan Raška,
Kateřina Pospíšilová,
Matteo Dal Ben,
Aleš Dvořák,
Jitka Viktorová,
Dáša Bohačiaková,
Libor Vítek
Affiliations
Nikola Capková
Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 110 00 Prague, Czech Republic
Veronika Pospíšilová
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 601 77 Brno, Czech Republic
Veronika Fedorová
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 601 77 Brno, Czech Republic
Jan Raška
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 601 77 Brno, Czech Republic
Kateřina Pospíšilová
Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 110 00 Prague, Czech Republic
Matteo Dal Ben
Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 110 00 Prague, Czech Republic
Aleš Dvořák
Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 110 00 Prague, Czech Republic
Jitka Viktorová
Department of Biochemistry and Microbiology, University of Chemistry and Technology, 166 28 Prague, Czech Republic
Dáša Bohačiaková
Department of Histology and Embryology, Faculty of Medicine, Masaryk University, 601 77 Brno, Czech Republic
Libor Vítek
Institute of Medical Biochemistry and Laboratory Diagnostics, Faculty General Hospital and 1st Faculty of Medicine, Charles University, 110 00 Prague, Czech Republic
The ‘gold standard’ treatment of severe neonatal jaundice is phototherapy with blue–green light, which produces more polar photo-oxidation products that are easily excreted via the bile or urine. The aim of this study was to compare the effects of bilirubin (BR) and its major photo-oxidation product lumirubin (LR) on the proliferation, differentiation, morphology, and specific gene and protein expressions of self-renewing human pluripotent stem cell-derived neural stem cells (NSC). Neither BR nor LR in biologically relevant concentrations (12.5 and 25 µmol/L) affected cell proliferation or the cell cycle phases of NSC. Although none of these pigments affected terminal differentiation to neurons and astrocytes, when compared to LR, BR exerted a dose-dependent cytotoxicity on self-renewing NSC. In contrast, LR had a substantial effect on the morphology of the NSC, inducing them to form highly polar rosette-like structures associated with the redistribution of specific cellular proteins (β-catenin/N-cadherin) responsible for membrane polarity. This observation was accompanied by lower expressions of NSC-specific proteins (such as SOX1, NR2F2, or PAX6) together with the upregulation of phospho-ERK. Collectively, the data indicated that both BR and LR affect early human neurodevelopment in vitro, which may have clinical relevance in phototherapy-treated hyperbilirubinemic neonates.
