Abstract
An important number of healthy and diseased tissues shows spatial variations in their metabolic capacities across the tissue. The liver is a prime example of such heterogeneity where the gradual changes in various metabolic activities across the liver sinusoid is termed as “zonation” of the liver. Here, we introduce the Metabolic Patterning on a Chip (MPOC) platform capable of dynamically creating metabolic patterns across the length of a microchamber of liver tissue via actively enforced gradients of various metabolic modulators such as hormones and inducers. Using this platform, we were able to create continuous liver tissues of both rat and human origin with gradually changing metabolic activities. The gradients we have created in nitrogen, carbohydrate and xenobiotic metabolisms recapitulated an in vivo like zonation and zonal toxic response. Beyond its application in recapitulation of liver zonation in vitro as we demonstrate here, the MPOC platform can be used and expanded for a variety of purposes including better understanding of heterogeneity in many different tissues during developmental and adult stages.
Highlights
ObjectivesThis new platform stemmed from our previous work where we aimed to mimic liver zonation in a narrow prototype microfluidic chip
We have used only one metabolic modulator at a time to investigate the individual effects of each modulator and we limited ourselves to two preliminary cases of these modulators. Even with this limited approach, our results indicate that the gradual patterns created in our MPOC device recapitulate several aspects of the liver zonation observed in vivo in a single connected tissue, similar to the liver sinusoid
The notion of microfluidic “metabolic patterning” we introduced in this work as well as the MPOC platform we build to achieve it, are versatile and applicable to almost any tissue where gradual or arbitrary patterns in metabolic processes in a continuous tissue are of interest
Summary
This new platform stemmed from our previous work where we aimed to mimic liver zonation in a narrow prototype microfluidic chip. In ongoing work where we aim to look at the effect of different zonal inducers in combination we aim to undertake such analysis. Given the recent reports which hail the Wnt/β-catenin - as the “master regulator of metabolic zonation”, and indicate the overwhelming importance of oxygen gradients in the zonation of lipid accumulation, our goal is to add these two classes of modulators into the MPOC framework
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