Innovative Lab-Grown Liver Model Enables Advanced Study of Fibrosis and Regeneration

Researchers at the Institute of Science Tokyo have developed a sophisticated miniature liver model using human induced pluripotent stem cells (iPSCs), paving the way for a deeper understanding of liver disease progression and potential therapeutic interventions. This three-dimensional organoid system closely mimics the interactions between essential liver cells, specifically hepatocytes and hepatic stellate cells, which play pivotal roles in liver repair and fibrotic processes.

Chronic liver disease remains a significant health concern worldwide, with millions affected by conditions that can ultimately lead to irreversible liver scarring, cirrhosis, and organ failure. Traditionally, the principal treatment for advanced cirrhosis has been organ transplantation, underscoring the need for innovative strategies to prevent or reverse fibrotic damage before it reaches this critical stage.

The newly engineered liver organoid, referred to as the iHSO model (iPSC-derived hepatocyte-stellate cell surrounding organoid), was meticulously designed to replicate the complex cellular environment of the human liver. By co-culturing iPSC-derived hepatocyte-like cells alongside stellate-like cells in a three-dimensional format, researchers succeeded in creating organoids where stellate cells envelop hepatocytes, accurately reflecting their natural arrangement in human tissue.

Within this model, hepatocytes are responsible for carrying out essential liver functions, while stellate cells remain in a quiescent state under healthy conditions, storing vitamin A. Upon liver injury, however, these stellate cells are activated by signals from damaged hepatocytes, as well as immune system and endothelial cells. Once activated, the stellate cells transform into myofibroblasts, producing extracellular matrix components necessary for tissue repair. However, excessive or persistent activation leads to fibrosis, contributing to the stiffening and loss of functional tissue characteristic of chronic liver disease.

A key finding from the study was the identification of the ICAM-1 molecule and the cytokine interleukin-1? as mediators of cellular communication within the organoid. These molecules facilitate bidirectional signaling between hepatocytes and stellate cells, regulating both tissue repair and regenerative processes. The iHSO model demonstrated that these interactions not only support hepatocyte proliferation but also maintain the stellate cells in a cytokine-rich but non-fibrogenic state, closely aligning with the liver's natural response to injury.

To evaluate the organoid's capacity to model liver injury, researchers exposed the iHSO system to acetaminophen, a common cause of drug-induced liver toxicity. The organoids exhibited injury responses mirroring those observed in actual human liver tissue, including activation of stellate cells in response to hepatocyte damage. This highlights the model's potential utility in preclinical studies for drug toxicity and the investigation of fibrotic mechanisms.

The prevalence of chronic liver disease is increasing, driven by factors such as metabolic disorders and alcohol use. In Japan and globally, there is a growing demand for reliable human-based systems that can accurately replicate disease progression and aid in drug development. The iHSO organoid offers a promising solution, enabling detailed studies of fibrosis onset, cellular crosstalk, and the regenerative capacity of liver tissue.

Researchers anticipate that this model will accelerate the discovery and evaluation of novel therapies targeting liver fibrosis and support regenerative medicine approaches. Ultimately, advances in organoid technology such as the iHSO system may provide viable alternatives to transplantation, offering hope for effective treatments that restore liver function without the need for donor organs.

The full study findings are available in the journal Stem Cell Reports, providing a foundation for future research in liver disease pathogenesis and therapeutic development.