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Researchers have developed a novel “liver-on-a-chip” model that closely mimics the human liver, offering a promising new tool for studying liver regeneration and the complex process of transplant rejection. This innovative platform, described as a vascularized liver tissueoid-on-a-chip (LToC), could significantly advance our understanding of these critical areas and potentially lead to more personalized strategies for liver transplantation.

Liver transplantation remains the gold standard for patients with finish-stage liver disease, but challenges persist in optimizing outcomes and minimizing the risk of rejection. Current research is hampered by a lack of experimental models that accurately replicate the intricate architecture and immune interactions within the human liver. This new technology aims to bridge that gap, providing a more physiologically relevant system for investigation.

The LToC, engineered by researchers at the Terasaki Institute for Biomedical Innovation, is composed of human hepatic progenitor cells and intrahepatic portal vein endothelial cells. Within a week of being established in a dynamic perfusion culture, the tissueoid self-assembled into a functioning microvascular network, maturing over 49 days into a tissue resembling a human liver. The team demonstrated sustained viability, preserved vascular integrity, and active liver function, including the secretion of key proteins like albumin and urea, according to a study published in Advanced Materials.

The mature tissueoid contains a diverse range of liver cell types – hepatocytes, cholangiocytes, Kupffer cells, stellate cells, and endothelial cells – mirroring the complexity of a native human liver. This cellular diversity is crucial for accurately modeling liver function and response to injury or immune attack.

Modeling Immune-Mediated Rejection

To test the platform’s ability to simulate real-world scenarios, the researchers exposed the LToC to allogeneic T cells – immune cells from a genetically different donor. This exposure triggered responses characteristic of cellular rejection, including reduced tissue viability, disruption of the endothelial lining of blood vessels, loss of liver-specific markers, increased expression of HLA-I (a marker of immune activation), and a surge in pro-inflammatory cytokines. Specifically, levels of IL-6, TNF-α, IL-1β, IFN-γ, granzyme A and B, and perforin increased, mirroring patterns observed during clinical transplant rejection.

“This liver tissueoid-on-a-chip enables us to recreate key aspects of liver regeneration and immune-mediated rejection within a human-relevant, vascularized tissue architecture,” explained Dr. Abdul Rahim Chethikkattuveli Salih, the first author of the publication.

Dr. Vadim Jucaud, Principal Investigator and Assistant Professor at the Terasaki Institute, added, “By integrating functional vasculature, multiple liver cell types, and immune responsiveness into a single platform, this system allows us to study transplant biology in a more physiologically meaningful way. This approach has the potential to support immunosuppressive drug evaluation and advance more personalized strategies for liver transplantation.”

A Legacy of Innovation in Transplantation

This research builds upon the pioneering work of Dr. Paul I. Terasaki, a renowned figure in organ transplantation research. Dr. Terasaki’s work focused on improving the lives of transplant patients through innovation, and the Terasaki Institute continues to uphold that mission. The institute’s commitment to patient-centered, translational technologies aims to translate laboratory discoveries into tangible benefits for those awaiting or undergoing transplantation.

Dr. Jucaud, a doctoral scholar trained by Dr. Terasaki, emphasized the personal significance of carrying forward his mentor’s vision. “Dr. Terasaki believed that meaningful innovation in transplantation must always be driven by its potential to improve patients’ lives,” he said. “As one of the last doctoral scholars trained by Dr. Paul I. Terasaki, carrying forward his vision, through innovative, translational science that bridges engineering, immunology, and transplantation, holds deep personal significance to me.”

The development of this vascularized tissueoid-on-a-chip represents a significant step forward in the field of liver transplantation research. The ability to model complex biological processes in a human-relevant system opens new avenues for understanding disease mechanisms and developing more effective therapies.

Looking ahead, researchers plan to utilize the LToC platform to evaluate the efficacy of different immunosuppressive drugs and explore personalized treatment strategies for liver transplant recipients. Further refinement of the model and validation with clinical data will be crucial for translating these findings into improved patient care.

Disclaimer: This article provides informational content and should not be considered medical advice. Please consult with a qualified healthcare professional for any health concerns or before making any decisions related to your health or treatment.

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