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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

1
Institute of Molecular and Cell Biology, Proteos, Singapore.
2
Institute of Bioengineering and Nanotechnology, Nanos, Singapore.
3
The Anne McLaren Laboratory of Regenerative Medicine, Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
4
Division of Cardiovascular Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
5
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
6
Mechanobiology Institute, Singapore.
7
Singapore-MIT Alliance for Research and Technology, BioSyM, Singapore.
8
Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

Abstract

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.

KEYWORDS:

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

PMID:
28297582
PMCID:
PMC5442778
DOI:
10.5966/sctm.2016-0129
[Indexed for MEDLINE]
Free PMC Article

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