Recellularization of rat liver: An in vitro model for assessing human drug metabolism and liver biology

PLoS One. 2018 Jan 29;13(1):e0191892. doi: 10.1371/journal.pone.0191892. eCollection 2018.

Abstract

Liver-like organoids that recapitulate the complex functions of the whole liver by combining cells, scaffolds, and mechanical or chemical cues are becoming important models for studying liver biology and drug metabolism. The advantages of growing cells in three-dimensional constructs include enhanced cell-cell and cell-extracellular matrix interactions and preserved cellular phenotype including, prevention of de-differentiation. In the current study, biomimetic liver constructs were made via perfusion decellularization of rat liver, with the goal of maintaining the native composition and structure of the extracellular matrix. We optimized our decellularization process to produce liver scaffolds in which immunogenic residual DNA was removed but glycosaminoglycans were maintained. When the constructs were recellularized with rat or human liver cells, the cells remained viable, capable of proliferation, and functional for 28 days. Specifically, the cells continued to express cytochrome P450 genes and maintained their ability to metabolize a model drug, midazolam. Microarray analysis showed an upregulation of genes involved in liver regeneration and fibrosis. In conclusion, these liver constructs have the potential to be used as test beds for studying liver biology and drug metabolism.

MeSH terms

  • Animals
  • Bioreactors
  • Cell Adhesion
  • Cell Proliferation
  • Culture Media
  • Extracellular Matrix
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • In Vitro Techniques
  • Liver / cytology*
  • Models, Animal*
  • Pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Culture Media

Grants and funding

The authors received no specific funding for this work.