Lab-grown organoid offers a platform to study how liver scarring develops

As chronic liver disease becomes more widespread, researchers at Science Tokyo have developed a lab-grown organoid that replicates a regenerating liver, offering new hope for future treatments. The model recreates interactions between hepatocytes and hepatic stellate cells, two cell types involved in liver repair and fibrosis. It provides a much-needed, human-based platform to study how liver scarring develops, how cells communicate during injury, and to test drugs that could halt or even reverse liver damage.  

The human body has an extraordinary ability to heal. However, sometimes, the body's repair system does more harm than good. This is the case with chronic liver disease, where repeated injury triggers cycles of damage and repair that, over time, lead to the overproduction of extracellular matrix (ECM). As healthy liver tissue is gradually replaced by stiff scar tissue-a process known as fibrosis-it can progress to cirrhosis, an irreversible stage that often results in liver failure. Currently, liver transplantation is the only treatment option for advanced cirrhosis. This highlights the urgent need for therapies that can stop or even reverse fibrosis before it becomes permanent.

To better understand how fibrosis develops, researchers at the Institute of Science Tokyo (Science Tokyo), Japan, have created a new type of human liver organoid, a miniature lab-grown model that mimics the structure and function of real liver tissue. The model, called iHSO, which stands for iPSC-derived hepatocyte–stellate cell surrounding organoid, was designed to recreate the interactions between two key cell types that regulate liver repair: hepatocytes and hepatic stellate cells (HSCs).

The research team was led by Professor Sei Kakinuma from the Department of Clinical and Diagnostic Laboratory Science, Graduate School of Medical and Dental Science, Science Tokyo, Professor Yasuhiro Asahina, Assistant Professor Masato Miyoshi, and graduate student Mr. Tomohiro Mochida from the Department of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Science Tokyo, Japan, in collaboration with Juntendo University. The study was published online in the journal Stem Cell Reports on September 18, 2025.

This study presents a novel system that helps researchers better understand the interactions between hepatocytes and stellate cells, which may lead to the development of new therapies for various liver diseases."

Professor Sei Kakinuma, Department of Clinical and Diagnostic Laboratory Science, Graduate School of Medical and Dental Science, Science Tokyo

In a healthy liver, HSCs remain quiescent, storing vitamin A in small lipid droplets. When the liver is injured, these cells receive signals from damaged hepatocytes-the main functional liver cells-as well as from immune and endothelial cells. In response, HSCs become activated and transform into myofibroblasts that produce ECM to repair the damage.

HSCs also interact closely with hepatocytes, forming a two-way communication system that regulates both repair and regeneration. HSCs can promote the growth of hepatocytes, while hepatocytes can influence stellate cells activation or death. However, most of this understanding comes from animal models, which do not fully mimic the behavior of human cells.

To address this gap, the researchers developed an organoid. Using human induced pluripotent stem cells (iPS cells), they generated hepatocyte-like (iPS-Heps) and stellate-like (iPS-HSCs) cells and co-cultured them in 3D to form spherical organoids, with stellate cells enveloping hepatocytes. Their interaction was found to be mediated by ICAM-1, an adhesion molecule, and interleukin-1β (IL-1β), a cytokine produced by HSCs. In iHSOs, iPS-HSCs exhibited a quiescent yet cytokine-rich phenotype and supported hepatocyte proliferation via ICAM-1–IL-1β axis.

The iHSOs were also able to model liver injury. When exposed to acetaminophen, a drug that can cause liver toxicity, the organoids developed injury patterns similar to those seen in human livers, including HSC activation in response to hepatocyte damage.

Chronic liver disease affects more than four million adults in the United States, and cases are rising in Japan due to factors such as alcohol consumption and metabolic disorders. By providing a realistic, human-based system for studying fibrosis, iHSOs could help scientists understand how scarring begins and identify drugs that could prevent or reverse it.

"iHSO can be applied to liver injury models and is expected to contribute to the elucidation of liver disease pathogenesis and the development of new therapeutic strategies targeting liver fibrosis and regeneration," says Asahina.

In the long term, the findings of this study could lead to treatments that stop or even repair liver damage without the need for a transplant.