Modelling foetal exposure to maternal smoking using hepatoblasts from pluripotent stem cells
JournalArchives of Toxicology
MetadataShow full item record
AbstractThe liver is a dynamic organ which is both multifunctional and highly regenerative. A major role of the liver is to process both endo and xenobiotics. Cigarettes are an example of a legal and widely used drug which can cause major health problems for adults and constitute a particular risk to the foetus, if the mother smokes during pregnancy. Cigarette smoke contains a complex mixture of thousands of different xenobiotics, including nicotine and polycyclic aromatic hydrocarbons. These affect foetal development in a sex-specific manner, inducing sex-dependant molecular responses in different organs. To date, the effect of maternal smoking on the foetal liver has been studied in vitro using cell lines, primary tissue and animal models. While these models have proven to be useful, poor cell phenotype, tissue scarcity, batch-to-batch variation and species differences have led to difficulties in data extrapolation toward human development. Therefore, in this study we have employed hepatoblasts, derived from pluripotent stem cells, to model the effects of xenobiotics from cigarette smoke on human hepatocyte development. Highly pure hepatocyte populations (>90%) were produced in vitro and exposed to factors present in cigarette smoke. Analysis of ATP levels revealed that, independent of the sex, the majority of smoking derivatives tested individually did not deplete ATP levels below 50%. However, following exposure to a cocktail of smoking derivatives, ATP production fell below 50% in a sex-dependent manner. This was paralleled by a loss metabolic activity and secretory ability in both female and male hepatocytes. Interestingly, cell depletion was less pronounced in female hepatocytes, whereas caspase activation was ~twofold greater, indicating sex differences in cell death upon exposure to the smoking derivatives tested. Copyright 2017, The Author(s).
SponsorsThe project was funded by awards from the Medical Research Council MR/L010011/1, MR/K026666/1 and MR/L022974/1. We are grateful to Professor Sue Kimber for providing the Man12 hESC line used in these studies.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85019216839&doi=10.1007%2fs00204-017-1983-0&partnerID=40&md5=90562203083115b57e0a7c4ff20da2c9; http://hdl.handle.net/10713/10020
- Isolation and expansion of human pluripotent stem cell-derived hepatic progenitor cells by growth factor defined serum-free culture conditions.
- Authors: Fukuda T, Takayama K, Hirata M, Liu YJ, Yanagihara K, Suga M, Mizuguchi H, Furue MK
- Issue date: 2017 Mar 15
- Feeder-free and serum-free production of hepatocytes, cholangiocytes, and their proliferating progenitors from human pluripotent stem cells: application to liver-specific functional and cytotoxic assays.
- Authors: Nakamura N, Saeki K, Mitsumoto M, Matsuyama S, Nishio M, Saeki K, Hasegawa M, Miyagawa Y, Ohkita H, Kiyokawa N, Toyoda M, Akutsu H, Umezawa A, Yuo A
- Issue date: 2012 Apr
- Microbial-derived lithocholic acid and vitamin K2 drive the metabolic maturation of pluripotent stem cells-derived and fetal hepatocytes.
- Authors: Avior Y, Levy G, Zimerman M, Kitsberg D, Schwartz R, Sadeh R, Moussaieff A, Cohen M, Itskovitz-Eldor J, Nahmias Y
- Issue date: 2015 Jul
- Generation of functional hepatocytes from mouse induced pluripotent stem cells.
- Authors: Li W, Wang D, Qin J, Liu C, Zhang Q, Zhang X, Yu X, Lahn BT, Mao FF, Xiang AP
- Issue date: 2010 Mar
- In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling.
- Authors: Fowler PA, Childs AJ, Courant F, MacKenzie A, Rhind SM, Antignac JP, Le Bizec B, Filis P, Evans F, Flannigan S, Maheshwari A, Bhattacharya S, Monteiro A, Anderson RA, O'Shaughnessy PJ
- Issue date: 2014 Jul