Vascularized liver tissueoid-on-a-chip recreates tissue regeneration and transplant rejection

Dr. Vadim Jucaud's lab at the Terasaki Institute has developed a vascularized liver tissueoid-on-a-chip (LToC) platform that recapitulates key structural, functional, and immunological features of human liver tissue, enabling the study of liver regeneration and immune-mediated allograft rejection in a physiologically relevant human system.

Liver transplantation remains the primary therapeutic option for patients with end-stage liver disease, yet progress in understanding transplant rejection and tissue regeneration has been limited by the lack of experimental models that accurately reflect human liver architecture and immune interactions. Conventional culture systems fail to capture the multicellular organization, vascular complexity, and dynamic immune responses that govern transplant outcomes, limiting their relevance for translational research.

To address these limitations, researchers in Dr. Vadim Jucaud's laboratory (VJLabs) engineered a vascularized liver tissueoid composed of donor-matched human hepatic progenitor cells and intrahepatic portal vein endothelial cells. Within the first week of dynamic perfusion culture, the tissueoid self-assembled into a perfusable microvascular network, followed by progressive maturation into a functional liver-like tissueoid over a 49-day culture period.

Using this platform, the research team demonstrated sustained tissue viability, preserved vascular integrity, and active hepatic function, including the secretion of albumin, urea, complement factors, and hepatocyte growth factor. The mature liver tissueoid contained multiple liver-relevant cell populations, including hepatocytes, cholangiocytes, Kupffer cells, stellate cells, and endothelial cells, closely reflecting the cellular diversity of native human liver tissue.

The LToC platform was further tested to model immune-mediated allograft rejection by perfusing the mature tissueoid with allogeneic T cells. This exposure induced hallmark features of cellular rejection, including reduced tissue viability, endothelial disruption, loss of hepatic markers, increased HLA-I expression, and a pronounced pro-inflammatory cytokine response. Elevated levels of IL-6, TNF-α, IL-1β, IFN-γ, granzyme A and B, and perforin mirrored immune activation 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."

Dr. Abdul Rahim Chethikkattuveli Salih, first author of the publication

"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," added Dr. Vadim Jucaud, Principal Investigator and Assistant Professor at the Terasaki Institute. "This approach has the potential to support immunosuppressive drug evaluation and advance more personalized strategies for liver transplantation."

This work contributes to the legacy of Dr. Paul I. Terasaki in organ transplantation research, with the overarching goal of improving the quality of life for transplant patients.

"Dr. Terasaki believed that meaningful innovation in transplantation must always be driven by its potential to improve patients' lives," said Dr. Jucaud. "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."

This commitment continues at the Terasaki Institute, where advancing patient-centered, translational technologies remains a guiding principle and a tribute to Dr. Terasaki's lasting impact on the field.