Multi-zonal liver organoids from human pluripotent stem cells

Hasan Al Reza, Connie Santangelo, Kentaro Iwasawa, Abid Al Reza, Sachiko Sekiya, Kathryn Glaser, Alexander Bondoc, Jonathan Merola and Takanori Takebe ()
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Hasan Al Reza: Cincinnati Children’s Hospital Medical Center
Connie Santangelo: Cincinnati Children’s Hospital Medical Center
Kentaro Iwasawa: Cincinnati Children’s Hospital Medical Center
Abid Al Reza: Cincinnati Children’s Hospital Medical Center
Sachiko Sekiya: Institute of Science Tokyo (Science Tokyo)
Kathryn Glaser: Medical Center
Alexander Bondoc: Medical Center
Jonathan Merola: Medical Center
Takanori Takebe: Cincinnati Children’s Hospital Medical Center

Nature, 2025, vol. 641, issue 8065, 1258-1267

Abstract: Abstract Distinct hepatocyte subpopulations are spatially segregated along the portal–central axis and are critical to understanding metabolic homeostasis and injury in the liver1. Although several bioactive molecules, including ascorbate and bilirubin, have been described as having a role in directing zonal fates, zonal liver architecture has not yet been replicated in vitro2,3. Here, to evaluate hepatic zonal polarity, we developed a self-assembling zone-specific liver organoid by co-culturing ascorbate- and bilirubin-enriched hepatic progenitors derived from human induced pluripotent stem cells. We found that preconditioned hepatocyte-like cells exhibited zone-specific functions associated with the urea cycle, glutathione synthesis and glutamate synthesis. Single-nucleus RNA-sequencing analysis of these zonally patterned organoids identifies a hepatoblast differentiation trajectory that dictates periportal, interzonal and pericentral human hepatocytes. Epigenetic and transcriptomic analysis showed that zonal identity is orchestrated by ascorbate- or bilirubin-dependent binding of EP300 to TET1 or HIF1α. Transplantation of the self-assembled zonally patterned human organoids improved survival of immunodeficient rats who underwent bile duct ligation by ameliorating the hyperammonaemia and hyperbilirubinaemia. Overall, this multi-zonal organoid system serves as an in vitro human model to better recapitulate hepatic architecture relevant to liver development and disease.

Date: 2025
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DOI: 10.1038/s41586-025-08850-1

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