title: Human Stem Cell-Derived Endothelial-Hepatic Platform for Efficacy Testing of Vascular-Protective Metabolites from Nutraceuticals.
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.
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore.
authors.forename: Balakrishnan Chakrapani
authors.initials: BC
authors.lastname: Narmada
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore.
authors.forename: Yeek Teck
authors.initials: YT
authors.lastname: Goh
authors.affiliation: Institute of Bioengineering and Nanotechnology, Nanos, Singapore.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Institute of Bioengineering and Nanotechnology, Nanos, Singapore.|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.
authors.forename: Hanry
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute of Molecular and Cell Biology, Proteos, Singapore.|Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
authors.forename: Christine
authors.initials: C
authors.lastname: Cheung
mesh_terms: D017077:Culture Media, Conditioned / Q000494:pharmacology; D019587:Dietary Supplements; D066026:Endothelial Progenitor Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D008099:Liver / Q000166:cytology*; D055442:Metabolome / Q000187:drug effects; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D011794:Quercetin / Q000494:pharmacology
chemical_list: D017077:Culture Media, Conditioned; D053583:Interleukin-1beta; D020011:Protective Agents; D011794:Quercetin; D019833:Genistein
keywords: Coculture; Endothelial cells; Hepatocytes; Human pluripotent stem cells; Metabolism; Nutraceutical testing