Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases

Sci Adv. 2021 Jan 29;7(5):eabd1707. doi: 10.1126/sciadv.abd1707. Print 2021 Jan.

Abstract

Slow progress in the fight against neurodegenerative diseases (NDs) motivates an urgent need for highly controlled in vitro systems to investigate organ-organ- and organ-immune-specific interactions relevant for disease pathophysiology. Of particular interest is the gut/microbiome-liver-brain axis for parsing out how genetic and environmental factors contribute to NDs. We have developed a mesofluidic platform technology to study gut-liver-cerebral interactions in the context of Parkinson's disease (PD). It connects microphysiological systems (MPSs) of the primary human gut and liver with a human induced pluripotent stem cell-derived cerebral MPS in a systemically circulated common culture medium containing CD4+ regulatory T and T helper 17 cells. We demonstrate this approach using a patient-derived cerebral MPS carrying the PD-causing A53T mutation, gaining two important findings: (i) that systemic interaction enhances features of in vivo-like behavior of cerebral MPSs, and (ii) that microbiome-associated short-chain fatty acids increase expression of pathology-associated pathways in PD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / metabolism
  • Humans
  • Induced Pluripotent Stem Cells*
  • Liver / metabolism
  • Neurodegenerative Diseases* / etiology
  • Neurodegenerative Diseases* / metabolism
  • Parkinson Disease* / genetics
  • Parkinson Disease* / metabolism