An In Vitro Human Liver Model by iPSC-Derived Parenchymal and Non-parenchymal Cells

Abstract

Summary: During liver development, hepatoblasts and liver non-parenchymal cells (NPCs) such as liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs) constitute the liver bud where they proliferate and differentiate. Accordingly, we reasoned that liver NPCs would support the maturation of hepatocytes derived from human induced pluripotent stem cells (hiPSCs), which usually exhibit limited functions. We found that the transforming growth factor β and Rho signaling pathways, respectively, regulated the proliferation and maturation of LSEC and HSC progenitors isolated from mouse fetal livers. Based on these results, we have established culture systems to generate LSECs and HSCs from hiPSCs. These hiPSC-derived NPCs exhibited distinctive phenotypes and promoted self-renewal of hiPSC-derived liver progenitor cells (LPCs) over the long term in the two-dimensional culture system without exogenous cytokines and hepatic maturation of hiPSC-derived LPCs. Thus, a functional human liver model can be constructed in vitro from the LPCs, LSECs, and HSCs derived from hiPSCs. : Koui et al. developed efficient methods for generating LSEC and HSC from human iPS cells. These cells exhibit distinctive phenotypes and promote proliferation and differentiation of LPCs. They are useful for generation of functional liver tissue that can be utilized in drug discovery, toxicology, and disease modeling in vitro. Keywords: liver bud, liver sinusoidal endothelial cells, hepatic stellate cells, liver progenitor cells, liver development, pluripotent stem cells