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Stem Cells Transl Med. 2017 Mar;6(3):851-863. doi: 10.5966/sctm.2016-0129. Epub 2016 Oct 7.

Human Stem Cell-Derived Endothelial-Hepatic Platform for Efficacy Testing of Vascular-Protective Metabolites from Nutraceuticals.

Narmada BC1, Goh YT1, Li H2, Sinha S3,4, Yu H2,5,6,7, Cheung C1,8.

Author information

Institute of Molecular and Cell Biology, Proteos, Singapore.
Institute of Bioengineering and Nanotechnology, Nanos, Singapore.
The Anne McLaren Laboratory of Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
Division of Cardiovascular Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Mechanobiology Institute, Singapore.
Singapore-MIT Alliance for Research and Technology, BioSyM, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.


Atherosclerosis underlies many cardiovascular and cerebrovascular diseases. Nutraceuticals are emerging as a therapeutic moiety for restoring vascular health. Unlike small-molecule drugs, the complexity of ingredients in nutraceuticals often confounds evaluation of their efficacy in preclinical evaluation. It is recognized that the liver is a vital organ in processing complex compounds into bioactive metabolites. In this work, we developed a coculture system of human pluripotent stem cell-derived endothelial cells (hPSC-ECs) and human pluripotent stem cell-derived hepatocytes (hPSC-HEPs) for predicting vascular-protective effects of nutraceuticals. To validate our model, two compounds (quercetin and genistein), known to have anti-inflammatory effects on vasculatures, were selected. We found that both quercetin and genistein were ineffective at suppressing inflammatory activation by interleukin-1β owing to limited metabolic activity of hPSC-ECs. Conversely, hPSC-HEPs demonstrated metabolic capacity to break down both nutraceuticals into primary and secondary metabolites. When hPSC-HEPs were cocultured with hPSC-ECs to permit paracrine interactions, the continuous turnover of metabolites mitigated interleukin-1β stimulation on hPSC-ECs. We observed significant reductions in inflammatory gene expressions, nuclear translocation of nuclear factor κB, and interleukin-8 production. Thus, integration of hPSC-HEPs could accurately reproduce systemic effects involved in drug metabolism in vivo to unravel beneficial constituents in nutraceuticals. This physiologically relevant endothelial-hepatic platform would be a great resource in predicting the efficacy of complex nutraceuticals and mechanistic interrogation of vascular-targeting candidate compounds. Stem Cells Translational Medicine 2017;6:851-863.


Coculture; Endothelial cells; Hepatocytes; Human pluripotent stem cells; Metabolism; Nutraceutical testing

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