Authors: Ruben Boon, Manoj Kumar, Tine Tricot, Ilaria Elia, Laura Ordovas, Frank Jacobs, Jennifer One, Jonathan De Smedt, Guy Eelen, Matthew Bird, Philip Roelandt, Ginevra Doglioni, Kim Vriens, Matteo Rossi, Marta Aguirre Vazquez, Thomas Vanwelden, François Chesnais, Adil El Taghdouini, Mustapha Najimi, Etienne Sokal, David Cassiman, Jan Snoeys, Mario Monshouwer, Wei-Shou Hu, Christian Lange, Peter Carmeliet, Sarah-Maria Fendt, Catherine M. Verfaillie
Published: 2020-03-13
DOI: 10.1038/s41467-020-15058-6
Source: Full article
AbstractPredicting drug-induced liver injury in a preclinical setting remains challenging, as cultured primary human hepatocytes (PHHs), pluripotent stem cell-derived hepatocyte-like cells (HLCs), and hepatoma cells exhibit poor drug biotransformation capacity. We here demonstrate that hepatic functionality depends more on cellular metabolism and extracellular nutrients than on developmental regulators. Specifically, we demonstrate that increasing extracellular amino acids beyond the nutritional need of HLCs and HepG2 cells induces glucose independence, mitochondrial function, and the acquisition of a transcriptional profile that is closer to PHHs. Moreover, we show that these high levels of amino acids are sufficient to drive HLC and HepG2 drug biotransformation and liver-toxin sensitivity to levels similar to those in PHHs. In conclusion, we provide data indicating that extracellular nutrient levels represent a major determinant of cellular maturity and can be utilized to guide stem cell differentiation to the hepatic lineage.