Journal
SCIENCE ADVANCES
Volume 7, Issue 5, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abd1707
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Funding
- DARPA [W911NF-12-2-0039]
- NIH/NIBIB [R01EB021908]
- National Institute of Environmental Health Sciences of the NIH [P30-ES002109]
- Koch Institute Support (core) Grant from the National Cancer Institute [P30-CA14051]
- NIH [P30DK034854]
- Army Research Office Institute for Collaborative Biotechnologies [W911NF-19-2-0026]
- Deutsche Forschungsgemeinschaft [WO 2255/1-1]
- National Science Foundation Graduate Research Fellowship [1745302]
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The research has developed a mesofluidic platform technology to study gut-liver-cerebral interactions, aiming to explore the pathophysiology of neurodegenerative diseases. Experimental results using a patient-derived Parkinson's disease brain model show that systemic interactions and microbiome-associated short-chain fatty acids are related to pathology-associated pathways in PD.
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.
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