Liver disease is a significant healthcare issue—when the organ fails, besides joining a long waitlist for a transplant, patient options are limited. The liver is a complex organ, and managing conditions such as hepatitis remains a challenge given much is still unknown about the cellular basis of liver disease. Three-dimensional ‘mini livers’ derived from stem cells have the potential to bridge this gap. These tissue cultures known as organoids recapitulate the liver’s complexity and can be a powerful tool for studying liver disease.
An A*STAR research team from the Genome Institute of Singapore (GIS), Institute of Medical Biology (IMB) and Skin Research Institute of Singapore (SRIS) has created the next generation of liver organoids that feature a network of canaliculi, the transport system for bile. This hepatic organoid, the first of its kind, captures a critical structural element of the liver, allowing researchers to investigate how pathologies impact liver function in a lab setting.
Under the right experimental conditions, stem cells can self-assemble into miniaturized liver tissues. “We have to mimic fetal liver development in a dish,” explained study corresponding author Winston Chan, a Senior Program Manager at GIS. “This involves the timely introduction of signaling cues in a step-wise manner to direct the stem cells towards the endoderm lineage, form the posterior foregut, and to eventually differentiate into the liver organ.”
Chan and the team first identified the precise biochemical cues required to induce the formation of specific structural components in liver organoids, such as the bile canaliculi system. They then validated the functionality of these structures by subjecting them to cholestasis-inducing drugs, which are known to disrupt bile function.
Additionally, they tested the utility of the organoids for studying liver disease by incubating the organoids with free fatty acids. Analyses revealed that the organoids’ gene expression signatures mirrored those of cells derived from patients with nonalcoholic steatohepatitis (NASH).
This tissue engineering breakthrough highlights how hepatic organoids could revolutionize the development and testing of therapies for managing liver diseases such as NASH—conditions that involve an interplay between multiple liver cell populations and external factors.
Chan and colleagues continue to push the limits of what’s possible with haptic organoids, with future studies focused on incorporating even more cell types into their organoid models. In particular, the researchers are looking at introducing immune cells and blood vessel endothelial cells, working towards eventually recreating the entire liver in a dish, said Chan.