Innovative Human Stem Cell-Derived Liver Organoids Enhance Research Potential

In a groundbreaking study published in the journal Cell Reports, researchers from the Institute of Science Tokyo, in collaboration with the Tokyo Metropolitan Institute of Medical Science and Juntendo University, have unveiled a novel method for developing three-dimensional (3D) liver organoids derived from human induced pluripotent stem cells (iPSCs). This research, led by Professor Sei Kakinuma and his colleagues, aims to address significant limitations in the study of chronic liver diseases by facilitating the long-term proliferation of hepatocyte-like cells.

The liver is crucial in detoxifying chemicals in the blood and regulating metabolic processes. However, traditional in vitro models have struggled to maintain the essential characteristics of hepatocytes over extended periods. As noted by Professor Yasuhiro Asahina, “Many aspects of the underlying mechanisms involved in liver cirrhosis and hepatocellular carcinoma remain obscure. To investigate these disease conditions, human hepatocyte-based systems are needed.”

To create these organoids, the researchers initially cultivated two-dimensional cultures of iPS-Hep cells, which were later embedded in a solubilized basement membrane to develop 3D cultures. They introduced a new culture medium, the human iPSC-derived hepatic organoid (iHO) medium, enriched with bile acids, which significantly supported the growth and proliferation of the organoids. As a result, the hepatic organoids exhibited a unique grape-like structural morphology and demonstrated a higher proliferation rate compared to those grown without bile acids.

The study revealed that these iPSC-derived hepatic organoids could be maintained for over three months while retaining their hepatocyte-like characteristics. Advanced gene expression analysis indicated that these organoids closely resembled fetal hepatocytes, providing a promising avenue for studying liver pathophysiology. Furthermore, researchers established a hepatitis C virus infection model within the organoids, showcasing their potential for elucidating chronic liver disease mechanisms.

The findings highlight the role of farnesoid X receptor (FXR) signaling in maintaining hepatocyte-like characteristics. When FXR inhibitors were introduced into the culture medium, the number of grape-like organoids significantly decreased, underscoring the importance of this signaling pathway in organoid development. This research could lead to new therapeutic strategies for liver diseases, which have historically been challenging to model in vitro.

With the development of these innovative stem cell-derived hepatic organoids, the research team is optimistic about the future of chronic liver disease studies. As Professor Kakinuma stated, “The hepatic organoids developed in our study possess the ability to support replication of hepatitis viruses, indicative of their broad potential for applications in elucidating the pathophysiology of chronic liver diseases.” This advancement represents a significant leap forward in biotechnology and regenerative medicine, potentially paving the way for new therapeutic approaches to treat liver-related ailments.