Abstract
ABSTRACTHepatocyte-like cells (HLCs) differentiated from human induced pluripotent stem cells (iPSCs) offer an alternative model to primary human hepatocytes to study lipid aberrations. However, the detailed lipid profile of HLCs is yet unknown. In the current study, functional HLCs were differentiated from iPSCs generated from dermal fibroblasts of three individuals by a three-step protocol through the definitive endoderm (DE) stage. In parallel, detailed lipidomic analyses as well as gene expression profiling of a set of lipid-metabolism-related genes were performed during the entire differentiation process from iPSCs to HLCs. Additionally, fatty acid (FA) composition of the cell culture media at different stages was determined. Our results show that major alterations in the molecular species of lipids occurring during DE and early hepatic differentiation stages mainly mirror the quality and quantity of the FAs supplied in culture medium at each stage. Polyunsaturated phospholipids and sphingolipids with a very long FA were produced in the cells at a later stage of differentiation. This work uncovers the previously unknown lipid composition of iPSC-HLCs and its alterations during the differentiation in conjunction with the expression of key lipid-associated genes. Together with biochemical, functional and gene expression measurements, the lipidomic analyses allowed us to improve our understanding of the concerted influence of the exogenous metabolite supply and cellular biosynthesis essential for iPSC-HLC differentiation and function. Importantly, the study describes in detail a cell model that can be applied in exploring, for example, the lipid metabolism involved in the development of fatty liver disease or atherosclerosis.
Highlights
The liver is the main metabolic and synthetic organ in the human body, carrying out more than 500 different functions
FOXA2, a transcription factor involved in liver metabolism (Wolfrum et al, 2004), had a continuous expression pattern starting around day 5 and continuing until the end of differentiation
Low-density lipoprotein receptor (LDL-R), asialoglycoprotein receptor (ASGR), alpha fetoprotein (AFP) as well as albumin (ALB) were all expressed in Hepatocyte-like cells (HLCs) (Fig. 1C,D)
Summary
The liver is the main metabolic and synthetic organ in the human body, carrying out more than 500 different functions. It is mainly composed of hepatocytes, which constitute approximately 60% of the cells in the liver and possess many important functions. Liver has a central role in lipid metabolism as it is the major site for the generation of plasma lipoproteins (Godoy et al, 2013)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
