Multi-zonal liver organoids from human pluripotent stem cells

• 成果类型: Article
• 署名作者: Al Reza, Hasan; Santangelo, Connie; Iwasawa, Kentaro; Al Reza, Abid; Sekiya, Sachiko; Glaser, Kathryn; Bondoc, Alexander; Merola, Jonathan; Takebe, Takanori
• 署名单位: Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; Cincinnati Children's Hospital Medical Center; University System of Ohio; University of Cincinnati; University of Osaka; University of Osaka; Yokohama City University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2639
• DOI: 10.1038/s41586-025-08850-1
• 发表日期: 2025-05-29
• 关键词: ascorbic-acid; zonation

摘要

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 HIF1 alpha. 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.