Liver development entails induction of definitive endoderm, specification of the endoderm to a hepatic fate, generation of hepatoblasts, and differentiation of these hepatic progenitors into mature hepatocytes. To date, efforts to generate mature hepatocytes from human pluripotent stem cells (hPSCs) have mainly produced immature hepatocytes. Now, on , Gordon Keller and co-workers investigate the mechanisms underlying hepatocyte maturation by manipulating specific signalling pathways at different stages of hepatocyte development in hPSC cultures. The researchers report that sustained activin/nodal signalling is required to pattern the definitive endoderm for hepatic specification. Three-dimensional aggregation of hepatoblasts initiates the maturation of these progenitor cells, and cAMP signalling within the hepatoblast aggregates promotes further maturation to a hepatocyte-like population that expresses metabolic enzymes at levels comparable to those of primary human hepatocytes. These results provide new insights into the pathways regulating hepatocyte maturation from hPSCs, as well as a simple method for generating functional hepatocytes for use in drug metabolism studies and cell-based therapy of liver diseases.
