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

Mitochondrial 3243A > G mutation confers pro-atherogenic and pro-inflammatory properties in MELAS iPS derived endothelial cells

“…Endothelial cells were derived from three hPSC cell lines, namely H9, MELAS and cMELAS iPSCs using an established protocol 15 (Fig. 1a, S1a).…”

Determination of critical shear stress for maturation of human pluripotent stem cell‐derived endothelial cells towards an arterial subtype

“…Endothelial cells were derived from human embryonic stem cell line (H9; WiCell) according to protocols previously reported in Narmada et al (). Briefly, H9 embryonic stem cells were first induced into early mesoderm followed by lateral plate mesoderm induction.…”

Sprouts and Microgreens: Trends, Opportunities, and Horizons for Novel Research

“…This was clearly illustrated when quercetin and genistein, two polyphenols with proven anti-inflammatory properties, were used as positive controls to counteract the inflammatory response provoked by interleukin 1β in human pluripotent stem cell-derived endothelial cells (hPSC-EC). Notably, both polyphenols were inactive when tested in these cells, but displayed a powerful anti-inflammatory response when hPSC-EC were co-cultured with their hepatocytic counterpart hPSC-HEP that, unlike hPSC-EC, retains a metabolic capacity to breakdown quercetin and genistein into bioactive molecules [234]. Finally, it should be noted that organoids and 3D cell-based assays, despite technical challenges [235], represent the most recent advance in tissue culture to recapitulate the cellular and biological complexities of tissues and organs.…”