Hypoimmunogenic iPSC-derived hepatic organoids featuring a functional vascular network.

The current management of end-stage liver diseases relies on organ transplantation but is constrained by donor scarcity and immune rejection. Induced pluripotent stem cell (iPSC)-derived cells represent a promising alternative, as they can be expanded indefinitely, genome-edited to reduce immunogenicity and employed to develop more mature three-dimensional cultures. Here, we combined tissue engineering with hypoimmunogenic iPSC technology to generate off-the-shelf hepatic organoids that integrate parenchymal and non-parenchymal cells: hepatocytes, cholangiocytes, hepatic stellate cells, Kupffer cells and both vascular and sinusoidal endothelial cells. Lineage identity was validated by gene and protein expression analysis, electron microscopy and single-cell RNA sequencing. The complex microenvironment obtained recapitulates native liver composition and promotes hepatic maturation, as evidenced by the secretion of liver-specific proteins, including albumin and apolipoproteins. These properties, together with the presence of a functional endothelial network, represent a step towards universal cell therapies for end-stage liver diseases and hepatic metabolic disorders.