Crosstalk via ICAM-1 enhances supportive phenotype of stellate cells and drives hepatocyte proliferation in iPSC-derived hepatic organoids.

The interaction between hepatic stellate cells (HSCs) and hepatocytes contributes to HSC activation and liver regeneration; however, the mechanisms in humans remain unclear, particularly the significance of their direct contact and the role of cell adhesion molecules. In this study, we established a novel contact co-culture organoids using induced pluripotent stem cell (iPSC)-derived hepatic stellate-like cells (iPS-HSCs) and hepatocyte-like cells (iPS-Heps), termed iPSC-derived hepatocyte-stellate cell surrounding organoids (iHSOs). The iHSOs exhibit a unique morphology with iPS-HSCs surrounding central iPS-Heps. The iHSO enabled the identification of ICAM-1-interleukin-1β (IL-1β)-mediated iPS-Hep proliferation supported by iPS-HSCs, which displayed a quiescent and cytokine-rich phenotype, whereas this proliferative support was not observed in primary liver cell-based co-culture organoids. Furthermore, iHSOs treated with acetaminophen allowed for the modeling of HSC activation induced by hepatocyte injury, demonstrating their application potential. Our study presents a valuable platform for studying the HSC behavior and complex interactions between HSCs and hepatocytes in humans.