Human induced pluripotent stem cell derived hepatocytes provide insights on parenteral nutrition associated cholestasis in the immature liver

Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined develo...

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Bibliographic Details
Published in:Scientific reports 2021-06, Vol.11 (1), p.12386-12386, Article 12386
Main Authors: Nghiem-Rao, T. Hang, Pfeifer, Courtney, Asuncion, Michelle, Nord, Joshua, Schill, Daniel, Pulakanti, Kirthi, Patel, Shailendra B., Cirillo, Lisa A., Rao, Sridhar
Format: Article
Language:English
Subjects:
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Bile
Cholestasis
Cholestasis - diet therapy
Computer applications
Female
Fetuses
Gallbladder diseases
Gene expression
Hepatocytes
Hepatocytes - cytology
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells - cytology
Infant, Newborn
Infants
Intravenous administration
Lipid metabolism
Lipids
Liver
Liver - physiopathology
Male
Metabolism
Morbidity
multidisciplinary
Nutrition
Parenteral Nutrition
Pluripotency
Science
Science (multidisciplinary)
Stem cells
Sterols
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Summary:Parenteral nutrition-associated cholestasis (PNAC) significantly limits the safety of intravenous parenteral nutrition (PN). Critically ill infants are highly vulnerable to PNAC-related morbidity and mortality, however the impact of hepatic immaturity on PNAC is poorly understood. We examined developmental differences between fetal/infant and adult livers, and used human induced pluripotent stem cell-derived hepatocyte-like cells (iHLC) to gain insights into the contribution of development to altered sterol metabolism and PNAC. We used RNA-sequencing and computational techniques to compare gene expression patterns in human fetal/infant livers, adult liver, and iHLC. We identified distinct gene expression profiles between the human feta/infant livers compared to adult liver, and close resemblance of iHLC to human developing livers. Compared to adult, both developing livers and iHLC had significant downregulation of xenobiotic, bile acid, and fatty acid metabolism; and lower expression of the sterol metabolizing gene ABCG8. When challenged with stigmasterol, a plant sterol found in intravenous soy lipids, lipid accumulation was significantly higher in iHLC compared to adult-derived HepG2 cells. Our findings provide insights into altered bile acid and lipid metabolizing processes in the immature human liver, and support the use of iHLC as a relevant model system of developing liver to study lipid metabolism and PNAC.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-021-90510-1