TY - JOUR
KW - Regenerative Medicine
KW - Stem-cell biotechnology
KW - Stem-cell differentiation
AU - Hasan Al Reza
AU - Connie Santangelo
AU - Kentaro Iwasawa
AU - Abid Al Reza
AU - Sachiko Sekiya
AU - Kathryn Glaser
AU - Alexander Bondoc
AU - Jonathan Merola
AU - Takanori Takebe
AB - 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.
BT - Nature
DA - 2025-04-16
DO - 10.1038/s41586-025-08850-1
LA - en
N2 - 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.
PY - 2025
SP - 1
EP - 10
T2 - Nature
TI - Multi-zonal liver organoids from human pluripotent stem cells
UR - https://www.nature.com/articles/s41586-025-08850-1
Y2 - 2025-04-18
SN - 1476-4687
ER -