Two-organ chip to answer the fatty liver question

(Nanowerk News) A new chip that houses different types of cells in small, interconnected spaces could allow scientists to better understand physiological and disease interactions between organs. The integrated-gut-liver-on-a-chip (iGLC) platform was designed by scientists at Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS), to enhance the understanding of non-alcoholic fatty liver disease (NAFLD).

The researchers, along with colleagues in Japan, published their findings in the journal Communication Biology (“Integrated-gut-liver-on-a-chip platform as an in vitro human model of non-alcoholic fatty liver disease”).

“NAFLD affects a significant percentage of the population, but no effective treatment has been established,” explained iCeMS bioengineer Ken-ichiro Kamei, who led the study. This is because NAFLD is a complex condition, involving multiple interactions within and between the gut and liver, known as the gut-liver axis. It is very difficult to model these interactions using animals, such as mice, because of the many differences between species.

NAFLD involves the accumulation of fat in the liver, which can be severe. Currently, the only way to treat severe cases is with a liver transplant. Scientists need a better approach to studying the condition in order to find better treatment options.

This isn’t the first time scientists have developed an organ-on-a-chip platform, nor is it the first gut-liver platform, but previous devices weren’t perfect. The platform developed by Kamei and his colleagues overcomes some but not all of the problems with previous attempts.

The scientists tested their iGLC platform by placing cells from a liver cancer cell line and from a colon cancer cell line into separate chambers. The chambers are connected by small fluid passages with strategically positioned valves which can be opened and closed. The platform also includes a pump to push fluid between the chambers. They allow a fluid medium to pass through both chambers while keeping cells separate, mimicking the circulation that moves between the intestines and liver in the human body. It also allows scientists to introduce new substances onto the platform, for example free fatty acids to test their impact on two interacting “organs”.

Importantly, the platform is made of a silicone material, called polydimethylsiloxane (PDMS), which is coated with two other substances: one prevents the chip from absorbing fat molecules that could affect the experiment, and another promotes cell growth.

Significant changes in gene expression were seen in intestinal and liver cells cultured on the iGLC platform when compared to the same cells cultured alone. Scientists have also documented specific changes that occur inside cells when free fatty acids are introduced for one or seven days. One day free fatty acids lead to the initiation of DNA damage in cells. Seven days of circulating free fatty acids causes their accumulation in cells until DNA damage leads to cell death, similar to the case of severe NAFLD.

The platform does not take into account the impact of gut microbes or other factors on the gut-liver axis. The experiments also used cancer cell lines, which are not representative of the full diversity or function of cells in living human tissue, but the platform is a significant step forward.

“We next plan to use liver and gut organoids derived from human stem cells so that we can investigate NAFLD under precisely controlled conditions that are more similar to the patient’s physiological context,” said iCeMS mechanical engineering researcher Yoshikazu Hirai, corresponding author of the study. .