Rethinking Liver Repair: Cellular Insights and Stem Cell Models Tackle Chronic Disease

As liver-related diseases—including fibrosis, cirrhosis, and drug-induced toxicity—continue to pose major global health and drug development challenges, researchers are working to better understand how the liver regenerates and how to model its diseases more accurately. On July 17, 2025, the Development Center for Biotechnology (DCB), in collaboration with the School of Biotechnology and Industry, hosted a special lecture in Taipei featuring two scientists from the University of Tokyo. Project Professor Atsushi Miyajima and Project Associate Professor Taketomo Kido presented complementary approaches to these problems: one exploring liver regeneration at the cellular level, the other leveraging human iPSCs to model disease and improve drug discovery.

Reframing the Regenerative Paradigm

Project Professor Atsushi Miyajima opened the seminar with a talk titled “Cellular Basis of Liver Regeneration.” His presentation examined the origins and functions of the ductular reaction, a process observed in response to liver injury and inflammation, which remains poorly understood despite its relevance to chronic liver disease.

Many regenerative strategies have focused on stimulating or transplanting liver progenitor-like cells in the hope of restoring damaged liver tissue. However, if the cells proliferating in chronic liver damage cannot become functional hepatocytes, their therapeutic value is far more limited than previously believed. This insight reshapes how researchers and companies should approach stem cell-based liver therapies, suggesting that other sources—such as hepatocyte-specific iPSCs or direct hepatocyte expansion strategies—may be more appropriate for regenerative purposes. In practical terms, this means that the ductular reaction may be a marker of injury, not a mechanism of regeneration.

Industry Impact: Targeting Fibrosis and Improving Models

The research also points to fibrosis, not failed regeneration, as the dominant concern in chronic liver disease. As Miyajima noted, hepatic stellate cells—liver-resident cells that activate in response to injury—are central to the development of liver scarring. Once activated, these cells lay down excessive extracellular matrix, stiffening the liver and impairing function.

This insight supports a shift in therapeutic focus from regeneration to fibrosis prevention and reversal, particularly through the targeted inhibition of hepatic stellate cell activation. With fibrosis still lacking effective pharmacological treatments, this area represents a high-priority opportunity for drug discovery and clinical innovation.

Additionally, the findings reinforce the importance of accurate preclinical models. Many current liver disease models may overestimate the regenerative capacity of ductular reaction cells, potentially leading to misleading data during drug screening. By clearly mapping how specific cell types respond under chronic injury, Miyajima’s work helps developers build better predictive models—particularly for drug-induced liver injury (DILI) and anti-fibrotic compound testing.

The Bigger Picture: Matching Biology to Strategy

Understanding what the liver can’t do is just as important as understanding what it can. Miyajima’s findings correct a critical misconception about liver regeneration and emphasize the importance of designing therapies aligned with actual cellular behavior. Whether building iPSC-derived liver models or screening anti-fibrotic drugs, success will depend on how closely science and industry match their tools to the biology at hand.

So what’s the bottom line? Ductular reaction cells help with bile drainage but don’t rebuild the liver. To develop meaningful therapies, the field must now pivot toward more accurate regeneration models and strategies that directly target fibrosis—a shift that could define the next generation of liver disease treatment.

“The ductular reaction reflects an adaptive response to injury, but it does not contribute to true liver regeneration—understanding this distinction is key to developing effective therapies,” said Project Professor Atsushi Miyajima at the seminar on July 17th in Taipei, Taiwan. Image: GeneOnline

From Modeling to Medicine: UTokyo’s Kido Builds Human iPSC Liver Platforms to Fight Fibrosis and Accelerate Drug Discovery

Building on the cellular insights into liver regeneration, Project Associate Professor Taketomo Kido expanded the conversation by presenting a complementary solution: the development of human iPSC-derived liver models designed for disease research, antiviral testing, and fibrosis-targeted drug discovery. In his talk, titled “Generation and Application of Human iPSC-Derived Liver Cells for Disease Modeling and Drug Discovery,” Kido outlined how his team engineered liver tissue from stem cells to create scalable, functional platforms that better reflect human liver biology and support therapeutic innovation.

As researchers seek more predictive tools for understanding liver disease and testing therapies, a major bottleneck remains: the lack of reliable human liver models. Conventional in vitro systems often fall short in mimicking true liver function, while sourcing primary human liver cells poses logistical and ethical challenges. In response, scientists are turning to induced pluripotent stem cells (iPSCs) to engineer scalable, functional models of liver tissue.

Engineering a Functional Human Liver Model

Professor Kido’s approach centers on mimicking the liver’s natural development process to generate more physiologically relevant cells. By guiding iPSCs through intermediate stages, his team successfully produced liver progenitor cells (LPCs), which were then expanded and differentiated into mature hepatocyte-like cells.

Key to this process was the identification of a novel cell surface marker, MCAM/CD146, which allowed the team to isolate a population of LPCs with high regenerative potential. These cells were shown to express liver-specific markers, store glycogen, and form bile duct-like structures, indicating successful functional differentiation.

Importantly, these iPSC-derived hepatocytes demonstrated improved drug-metabolizing enzyme activity, especially in long-term cultures. When co-cultured with other liver-relevant cells—such as hepatic stellate cells (HSCs) and sinusoidal endothelial cells—the model further enhanced liver-like functionality.

“This human liver model closes a critical gap between animal testing and clinical prediction, providing a more accurate platform for drug metabolism and toxicity studies,” said Project Associate Professor Taketomo Kido (featured) at the seminar on July 17th in Taipei, Taiwan. Image: GeneOnline

Modeling Viral Infection: Hepatitis B in a Dish

Kido’s team also applied their liver model to develop a functional HBV infection system, enabling researchers to study virus-host interactions using human-derived cells. Through co-culture with endothelial cells, they successfully promoted HBV entry and replication—demonstrating the role of host-secreted factors like EGF in modulating viral infection pathways.

This platform allows for quantitative analysis of infection dynamics, offering valuable insights for antiviral drug development and personalized medicine applications in viral hepatitis.

Targeting Fibrosis: From Modeling to Drug Discovery

Perhaps most compelling for translational medicine, Kido’s research addresses one of the liver field’s most urgent needs: new therapies for liver fibrosis. Fibrosis, the buildup of scar tissue in the liver, underlies most chronic liver diseases and currently lacks effective treatment.

To tackle this, his team developed a system to generate quiescent and activated hepatic stellate cells (qHSCs and aHSCs) from iPSCs. These cells mirror the behavior of stellate cells in vivo—remaining vitamin A–positive in the quiescent state and becoming fibrogenic upon activation.

Using gene-editing techniques and fluorescent reporters, the team established quantitative assays to monitor HSC activation, enabling high-throughput drug screening. Through this platform, they screened over 1,500 compounds and identified candidates that either:

• Inhibit HSC activation (preventing fibrosis onset), or
• Induce HSC deactivation (reversing established fibrosis)

Among these, “Compound G”—a GCR inhibitor—demonstrated strong anti-fibrotic effects in mouse models, reducing scarring and improving liver function.

Implications for Industry and Beyond

The creation of iPSC-derived liver models that include both parenchymal and non-parenchymal cells—such as hepatocytes and stellate cells—represents a major leap forward for the biotech and pharmaceutical industries. These models enable:

• More predictive drug testing for liver toxicity and metabolism
• Functional disease modeling for viral hepatitis and fibrosis
• Rational screening of anti-fibrotic compounds using human-relevant biology

Furthermore, Kido’s findings suggest that drugs targeting myofibroblast-like cells, such as activated stellate cells, may also apply to fibrosis in other organs. His team demonstrated that candidate compounds reduced fibrotic markers in models of skin, lung, and cardiac fibrosis, opening doors for broader therapeutic applications.

Bottom Line: From Cell Origin to Scalable Models, Redefining the Future of Liver Therapies

By building a liver from the ground up—using stem cells and developmental biology cues—Kido’s work brings precision and scalability to liver disease research. His team’s models don’t just replicate liver tissue; they replicate the complex behavior of cells during injury, infection, and healing.

These platforms offer the industry a powerful bridge between biology and therapy, and a path toward better drugs, fewer failures, and targeted interventions for fibrotic disease.

Together, the presentations by Professors Miyajima and Kido underscore a shift in liver research—from debating the source of regeneration to building tools that replicate liver biology with unprecedented fidelity. Their complementary approaches—one dissecting the limitations of endogenous repair, the other engineering functional human models—equip researchers and drug developers with the knowledge and tools to navigate the complexity of chronic liver disease. 

Author

Bernice Lottering

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