The iPS cells were then injected into FAH-deficient blastocysts to generate a number of mosaic offspring. Because liver cells from FAH-deficient mice are dependent on the presence of the drug 2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) for survival,

a small number of hepatocytes originating from the wildtype iPS can replace the entire liver of these animals following NTBC withdrawal. Thus, upon withdrawal of NTBC, the chimeric offspring underwent near complete liver cell repopulation with iPS-derived cells that the authors showed were not the consequence of a fusion event. The animals with iPS-derived chimeric livers were protected from liver failure that would be normally associated with NTBC withdrawal. Importantly, the iPS-derived

hepatocytes learn more were able to respond BYL719 chemical structure to postnatal liver injury with the same efficiency as primary hepatocytes. This finding of equivalence is critically important if pluripotent stem cells are to be useful in regenerative medicine. Interestingly, the renal proximal tubulopathy associated with FAH-deficiency was also corrected because iPS-derived proximal tubular epithelial cells substantially replaced the FAH-deficient cells by a similar process of positive selection and expansion. Although the correction of a metabolic disease by blastocyst injection of iPS cells cannot be translated to the treatment of human metabolic diseases, this study clearly demonstrates that iPS cells can give rise to fully functional somatic cells in vivo. Application of the iPS technology to study human disease in experimental animals will require transplantation of in vitro-differentiated human iPS-derived hepatocytes. Together these two novel proof-of-principle studies

demonstrate the great potential that exists for using iPS-derived hepatocytes in investigating the pathophysiology find more of metabolic liver diseases, discovering new drugs, and devising strategies for tissue regeneration. Because most inherited liver disease phenotypes are observed only in lineage-committed or fully differentiated cells, the degree to which disease-specific iPS cells can be differentiated into hepatocytes will affect the extent to which the disease can be modeled in vitro. Moreover, variability in response to differentiation among iPS cell lines, derived either from a single individual or from different individuals, will need to be carefully addressed. The study reported by Espejel et al. proves that mouse iPS cells are able to follow a normal developmental pathway and are able to fully differentiate into mature hepatocytes in chimeric mice. Whether human hepatocytes generated by differentiating iPS cells in culture will exhibit similar levels of function after transplantation into experimental animals remains to be evaluated.