7, 8 Over the course of differentiation, the cell lines were shown to express many appropriate stage-specific markers, but it is not clear how quantitatively similar the final “mature” hepatocytes were to primary human hepatocytes in terms

of gene expression. The residual high alpha-fetoprotein expression and the presence of two distinct cell populations, as evidenced in the flow analysis for albumin expression, make it uncertain how well the differentiation process recapitulated selleck chemicals llc normal hepatocyte development or function. Although all three disease-specific iPS-derived hepatocyte samples were analyzed for a mature hepatocyte phenotype, there were substantial differences among the final differentiated cells, particularly for albumin secretion. Further, although the authors examined several characteristics of the disease phenotypes, the immunocytochemical staining did not show the characteristic globular inclusions c-Met inhibitor of polymerized alpha-1 antitrypsin Z, which are the hallmark of A1ATD pathophysiology. It is also not known whether the degree of accumulation of mutant A1AT proteins in

hepatocytes correlates with the severity of liver disease in humans. Thus, the amount of polymers does not necessarily translate to modeling severity of disease. For the FH-iPS derived hepatocytes, the cells showed albumin expression and glycogen storage, but their albumin secretion and CYP3A4 activity were significantly lower than that of the A1ATD iPS-derived hepatocytes. Additionally, in the intracellular LDL comparisons, there were significant differences between what was seen grossly 上海皓元 by immune fluorescence and what was measured by computerized fluorescence analysis, where there was not as striking a difference between the control and diseased cells. Finally, the glucagon-induced gene expression data derived from the GSD1a-iPS derived hepatocytes were similar to those derived from HepG2 cells, but it is

unclear how this result would compare with that obtained from primary mature hepatocytes. Despite these limitations, the large array of iPS lines created in this study should permit more in-depth studies of disease phenotypes. In the second report, Espejel et al. transferred wildtype mouse iPS cells into the embryos of fumarylacetoacetate hydrolase (FAH)-deficient mice (a model for human tyrosinemia type 1) to demonstrate the ability of iPS cells to develop into hepatocytes in vivo, and to protect the FAH-deficient mice from developing hepatic failure. In doing so, the authors were able to circumvent the current limitations of in vitro hepatocyte differentiation programs by allowing the iPS cells undergo normal ontogenic development into mature hepatocytes in vivo. To accomplish this goal, the authors created iPS cells by repeatedly transfecting mouse embryonic fibroblasts with plasmids expressing Oct4, Sox2, Klf4, and Myc.