Challenges for Deriving Hepatocyte-Like Cells from Umbilical Cord Mesenchymal Stem Cells for In Vitro Toxicology Applications

The in vitro toxicology field seeks for reliable human relevant hepatic models for predicting xenobiotics metabolism and for the safety assessment of chemicals and developing drugs. The low availability and rapid loss of the phenotype or low biotransformation activity of primary hepatocytes urged the stem cell differentiation into hepatocyte-like cells (HLCs). Umbilical cord-derived mesenchymal stem cells (UC-MSC), in particular, offer a highly available cell source, with few ethical issues and higher genetic stability. However, the dynamic and complex microenvironment of liver development, including the cell-ECM and cell–cell interactions, pressure gradients (oxygen and nutrients) and growth factor signaling that are critical for the differentiation and maturation of hepatocytes, challenges the progress of in vitro hepatic models. Promising strategies like (i) cytokine and growth factor supplementation mimicking the liver development; (ii) epigenetic modification; and (iii) bioengineering techniques to recreate the liver microphysiological environment are gaining increasing importance for the development of relevant in vitro liver models to address the need for higher predictivity and cost efficiency. In this context, this chapter reviews the existing knowledge and recent advances on the approaches for deriving HLCs from UC-MSC and their application for in vitro toxicology.