Intestine-liver interaction affects hepatocyte function in multi-organ chip

Everyone can pipette conditioned media of an intestinal cell culture into a hepatocyte model to study intestine–liver interaction. But what if you could use the same cell models and not only to make this process automatic (save money), but also to control the cross-talk (more flexibility)? Enjoy this paper from Shinohara et al. at the University of Tokyo, co-culturing human iPSC intestine cells with human liver hepatocytes freshly derived from a PXB mouse in an organ on a chip. In this study, the medium is circulated between the basal side of a Transwell®-based intestinal model and hepatocytes culture in 2D.

Results

While the intestinal cells exhibited similar phenotypes in the mono- vs. co-culture, the authors found that the hepatocytes were maintained better (morphology), and showed higher CYP activity and albumin production. Also, the authors showed an increase in protein expression in the co-culture (exposed to substrate mixture of drugs), specifically enhanced lipoprotein expression by intestinal cells.

Method

Culture media was recirculated between two compartments, one with hiPS-derived intestinal cells (differentiated off-chip) and the other primary human hepatocytes isolated from a PXB mouse.
Fabrication: PDMS microfluidic plate was fabricated by injection moulding
Sterilization: Autoclaving
Cell incorporation: The intestinal cells were cultured inside a Transwell® insert and then added to the organ on a chip system while the hepatocytes were cultured directly in the chip in 2D
Perfusion/refreshing: A pressure-based pump with a valving system to create a uni-directional circulation between the intestine and liver compartments. The culture medium was changed every two days.
On-chip read-outs: End-point microscopy
Off-chip read-outs: RT-qPCR, LC-MS, ELISA

Strong points:
+ One directional medium recirculation
+ Comprehensive comparison of the mono- vs. co-culture
+ 8 Chips on one plate, relatively higher throughput
+ Relatively easy sampling and cell incorporation methods
+ The authors are aware of adsorption/absorption of molecules in PDMS and have performed control experiments without cells

Nothing is perfect! The system can also improve:
– Non-specific binding of enzymes onto PDMS, the same true for a class of drugs tested without cells.
– No direct shear stress on intestinal cells

Conclusion and outlook
The multi-organ on a chip model investigates the intestineal–liver interactions. In future studies, the model can be further developed to study enterohepatic circulation to achieve more physiological relevance.

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