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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Culture Media, Conditioned / pharmacology
  • Dietary Supplements*
  • Endothelial Progenitor Cells / cytology*
  • Endothelial Progenitor Cells / drug effects
  • Endothelial Progenitor Cells / metabolism
  • Genistein / pharmacology
  • Hepatocytes / cytology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Human Embryonic Stem Cells / cytology
  • Human Embryonic Stem Cells / drug effects
  • Human Embryonic Stem Cells / metabolism
  • Humans
  • Inflammation / pathology
  • Interleukin-1beta / metabolism
  • Liver / cytology*
  • Metabolome* / drug effects
  • Pluripotent Stem Cells / cytology*
  • Pluripotent Stem Cells / drug effects
  • Pluripotent Stem Cells / metabolism
  • Protective Agents / pharmacology*
  • Quercetin / pharmacology

Substances

  • Culture Media, Conditioned
  • Interleukin-1beta
  • Protective Agents
  • Quercetin
  • Genistein