New human “multi-zonal” liver organoids improve injury survival in rodents

(Press-News.org) One reason why our livers excel at clearing waste from our blood system is that the organ functions according to three key “zones” that perform specific major tasks. So, if scientists hope to create self-growing patches of liver organoid tissue that could help repair damaged organs, it’s important that the lab-grown tissue faithfully reproduce such zones.

In a groundbreaking paper published April 16, 2025, in the prestigious journal Nature, a team of organoid medicine experts at Cincinnati Children’s reports achieving just such a milestone – made from human stem cells. When these humanized organoids were transplanted into rodents whose own liver-bile duct system had been disconnected, the improved organoids nearly doubled the rodents’ survival rate.

“The research community has long needed a better model for studying human liver biology and disease, because there are outstanding hepatocyte diversity and associated functional orchestrations in the human liver that do not exist in rodents,” says Takanori Takebe, MD, PhD, the study’s corresponding author.  “This new system paves the way for studying, and eventually treating, a wide range of otherwise fatal liver disorders.”

Takebe is Director for Commercial Innovation at Cincinnati Children’s Center for Stem Cell and Organoid Medicine (CuSTOM). He has been studying methods for growing liver organoids for over 13 years. Breakthroughs from his lab include producing the first connected set of three organoids grown together, a novel way to mass produce liver organoids for research purposes, and gene-engineered liver organoids that may someday help treat severe jaundice.

In the short term, these multi-zonal liver organoids will help scientists shed new light on diseases including diabetes, drug-induced liver injury, alcohol-related liver disease, and viral hepatitis. In turn, such work could accelerate drug development and other approaches to restore liver health.

Longer-term, for people on waiting lists for liver transplantation, this study moves the medical community one step closer to “growing” a patient’s own liver replacement tissue instead of relying on organ donation.

Currently, more than 9,000 Americans are registered on waiting lists to receive a liver transplant, according to the federal Organ Procurement and Transplantation Network. Every year, an estimated 2,000 people die waiting lists, while far more people never become eligible. 

“This discovery is exciting for multiple reasons,” says Aaron Zorn, PhD, Co-Director of CuSTOM. “At one level, it shows that we have taken a significant step forward at growing liver tissue in the lab that accurately mimic human liver function. While human liver organoid transplantation remains at least several years away, in the lab, these special tissues may help us find ways to prevent people from ever needing a liver transplant.”

What’s next?

The new study lays out numerous details of how the new organoids were developed, and how they function – including genetic information down to the single-cell level. But even more research is needed to fully understand how the organoids match up with natural human organ development.  

Scientists also are working to develop chemical methods rather than genetic editing to trigger zonal development in the new organoids. This would make it more practical to study disease development and drug responses at a personal level.

In the near-term, however, using these new liver organoids in lab settings to more accurately predict drug metabolism and toxicity may be the biggest medical impact that this innovation will have, Zorn says.

About the study

Cincinnati Children’s co-authors include Hasan Al Reza, MS, Connie Santangelo, MS, Abid Al Reza, PhD, Kentaro Iwasawa, MD, PhD, Kathryn Glaser, MS, Alexander Bondoc, MD, and Jonathan Merola, MD, PhD.

This study was supported by members of several shared facilities at Cincinnati Children’s: the Confocal Imaging Core, Pathology Research Core, Pluripotent Stem Cell Facility, Transgenic Animal and Genome Editing Core, Veterinary Services Facility, and Single Cell Genomics Core.

Funding sources for this work include a Cincinnati Children’s Research Foundation CURE grant, a Falk Transformational Award, an NIH Director’s New Innovator Award (DP2 DK128799-01), NIH grant (R01DK135478), grants from the Japan Agency for Medical Research and Development, and support from the Takeda Science Foundation and the Mitsubishi Foundation.

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