SummaryStem cell-derived somatic cells represent an unlimited resource for basic and translational science. Although promising, there are significant hurdles that must be overcome. Our focus is on the generation of the major cell type of the human liver, the hepatocyte. Current protocols produce variable populations of hepatocytes that are the product of using undefined components in the differentiation process. This serves as a significant barrier to scale-up and application. To tackle this issue, we designed a defined differentiation process using recombinant laminin substrates to provide instruction. We demonstrate efficient hepatocyte specification, cell organization, and significant improvements in cell function and phenotype. This is driven in part by the suppression of unfavorable gene regulatory networks that control cell proliferation and migration, pluripotent stem cell self-renewal, and fibroblast and colon specification. We believe that this represents a significant advance, moving stem cell-based hepatocytes closer toward biomedical application.

Graphical abstract

It has been observed that there is an imperative to develop predictive human systems that more effectively study and/or prevent the onset of liver disease and decompensated organ function. A serum‐free, scalable, and shippable cell‐based model that faithfully predicts the potential for human liver injury has been developed. Such a resource has direct application in human modeling, and, in the future, could play an important role in developing renewable cell‐based therapies.