Breaking new ground: Novel human stem cell-derived liver organoids

Adding bile acids as farnesoid X receptor agonists to the culture medium supported the growth and development of unique stem cell-derived hepatic organoids, report researchers from Japan. These three-dimensional liver organoids were capable of sustained, long-term proliferation while retaining hepatocyte-like features. Their findings could have the potential to drive future research on chronic liver disease and result in newer therapeutic approaches to treat it.

The liver plays a critical role in the detoxification of chemicals in the blood, supports digestion, and regulates key metabolic processes. Central to the unique and diverse functions of the liver are hepatocytes-parenchymal liver cells. Recent advancements in biotechnology and cell culture practices have enabled the development of hepatocyte-like cells from human induced pluripotent stem cells (iPSCs).

At present, these iPSC-derived hepatocyte-like cells (iPS-Heps) are widely utilized for the screening of drugs, disease modeling, and regenerative medicine. However, altered hepatic characteristics and poor long-term proliferation limit their use in research on liver diseases. To address these limitations, scientists from Institute of Science Tokyo (Science Tokyo), Japan, in collaboration with the Tokyo Metropolitan Institute of Medical Science and Juntendo University, have developed novel three-dimensional (3D) liver organoids in a groundbreaking study.

The research team comprised Professor Sei Kakinuma from the Department of Clinical and Diagnostic Laboratory Science, Professor Yasuhiro Asahina, Assistant Professor Masato Miyoshi, and Project Researcher Taro Shimizu from the Department of Gastroenterology and Hepatology, Science Tokyo, Japan. Their research findings were published in Volume 44, Issue 5 of Cell Reports on May 27, 2025.

Elaborating on the need for novel hepatic organoids, Asahina states, “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. However, it has been difficult to both maintain hepatocyte characteristics and propagate the cells in long-term in vitro cultures. This limitation significantly affects the modeling of chronic liver diseases, which require long-term observation.”

In their study, the researchers initially developed two-dimensional cultures of iPS-Hep cells from human iPSCs. Subsequently, the iPS-Heps were embedded in a solubilized basement membrane to create 3D cultures. To support the growth and proliferation of the 3D hepatic organoids, they further established a new culture medium, called the human iPSC-derived hepatic organoid (iHO) medium, which contained bile acids in addition to other growth factors.

Remarkably, hepatic organoids grown using the iHO medium had a unique grape-like structural morphology and demonstrated a higher proliferation rate. On the other hand, organoids grown in the absence of bile acids predominantly formed spherical and cyst-like structures. Notably, iPSC-derived hepatic organoids could be maintained as cultures for more than three months, while retaining their hepatocyte-like characteristics.

Following the development of 3D hepatic organoids, the scientists shifted their focus to determining the intrinsic hepatic characteristics. Through comprehensive analyses of gene expression profiles, they revealed a distinct gene expression profile that closely resembled fetal hepatocytes in iPSC-derived hepatic organoids.

Additionally, the results of advanced gene sequencing analysis indicated the role of farnesoid X receptor (FXR) signaling in the sustained expression of hepatocyte-like characteristics seen in the organoids. To confirm the impact of FXR signaling, the researchers added FXR inhibitors to the culture medium. The addition of FXR inhibitors significantly reduced the number of grape-like organoids within the culture.

Inspired by their findings, the research team went a step further and successfully established a hepatitis C virus infection model in the organoids. “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—an area that has been difficult to study until now,” comments Kakinuma.

The development of stem cell-derived hepatic organoids by researchers from Science Tokyo signals the beginning of a new era for future research on liver diseases and could result in newer therapeutic strategies.

Authors:

Taro Shimizu¹, Masato Miyoshi¹, Sei Kakinuma^1,2*, Jun Tsuchiya¹, Daisuke Yamane³, Keiya Watakabe¹, Tomohiro Mochida¹, Kento Inada¹, Kaho Yamada², Kotomi Shinozaki³, Ayako Sato¹, Shun Kaneko¹, Fukiko Kawai-Kitahata¹, Miyako Murakawa¹, Sayuri Nitta¹, Mina Nakagawa¹, Mamoru Watanabe⁴, Yasuhiro Asahina^1,5*, and Ryuichi Okamoto¹

Title:

Bile acid-FXR signaling facilitates the long-term maintenance of hepatic characteristics in human iPSC-derived organoids

Journal:

Cell Reports

DOI:

10.1016/j.celrep.2025.115675

Affiliations:

¹Department of Gastroenterology and Hepatology, Institute of Science Tokyo, Japan
²Department of Clinical and Diagnostic Laboratory Science, Institute of Science Tokyo, Japan
³Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Japan
⁴School of Medicine, Juntendo University, Japan
⁵Division of Hepatic Medical Science, Institute of Science Tokyo, Japan

• KAKINUMA Sei | Science Tokyo Research Information DB
• ASAHINA Yasuhiro | Science Tokyo Research Information DB
• MIYOSHI Masato | Science Tokyo Research Information DB
• SHIMIZU Taro | Science Tokyo Research Information DB
• OKAMOTO Ryuichi | Science Tokyo Research Information DB
• Graduate School of Medical and Dental Sciences

• Juntendo University
• Tokyo Metropolitan Institute of Medical Science