Our liver's ability to efficiently remove waste products from the bloodstream is due to its unique regionalized structure - the liver consists of three key “zones” of hepatocytes working in concert, each responsible for a specific metabolic task. However, scientists have been faced with a great challenge: how to replicate this complex regionalized structure in the laboratory to develop organoids that can repair damaged livers.

In a groundbreaking study recently published in Nature, a team of researchers from Cincinnati Children's Hospital successfully constructed multi-zonal liver organoids (mZ-HLOs) using human pluripotent stem cells. These organoids significantly improved host survival when transplanted into rodents with ligated bile ducts. This achievement not only provides a novel model for studying human liver biology and disease, but also paves the way for the development of new therapies to treat fatal liver diseases.

The research team successfully induced region-specific liver precursor cells by introducing vitamin C (ascorbic acid) and bilirubin into human induced pluripotent stem cells (hiPSCs). These cells self-assembled in the laboratory to form an organoid containing features of three liver regions. Single-cell RNA sequencing analysis showed that these organoids contained hepatocytes around the portal vein (zone 1), intermediate zone (zone 2), and central vein (zone 3), as well as a variety of cell types such as cholangiocytes, endothelial cells, and macrophages.

Dr. Takanori Takebe, corresponding author of the study, said, “This new system not only mimics the complex functions of the human liver, but also provides a new perspective for studying diseases such as diabetes, drug-induced liver injury, alcoholic liver disease and viral hepatitis.” What's more, these organoids are expected to accelerate drug development and provide new treatment options for patients awaiting liver transplants.

Intracellular redox management enables CPS1+ hepatocyte specialization in HLOs

A Critical Step Toward Solving the Liver Transplant Crisis

Currently, more than 9,000 people in the U.S. are waiting for liver transplants, and about 2,000 people die each year waiting for an organ. This research offers new hope for solving this crisis. By constructing patients' own liver replacement tissue, scientists hope to reduce reliance on organ donation. While human liver organoid transplants are still years away, these organoids have shown great potential in the lab and may help scientists find ways to prevent liver disease from worsening.

Future Outlook

Despite this milestone, scientists are still working to optimize the process of regionalized organoid development. Future research will focus on developing chemical methods, rather than gene editing, to trigger region-specific development of organoids. This will make it more practical to study disease development and drug response at the individual level.

Overall, this research not only brings new hope for the treatment of liver disease, but also reinvigorates the field of organ regenerative medicine. As technology continues to advance, we are moving toward a future where we are no longer dependent on organ donation. 

References: Hasan Al Reza et al, Multi-zonal liver organoids from human pluripotent stem cells, Nature (2025). DOI: 10.1038/s41586-025-08850-1.