From skin cells to hepatocytes: advances in application of iPS cell technology

Abstract

The discovery several years ago that fibroblasts and other somatic cells from mice and humans can be reprogrammed to become inducible pluripotent stem (iPS) cells has created enthusiasm for their potential applications in regenerative medicine and for modeling human diseases. Two independent studies in this issue of the JCI provide evidence that iPS cells represent a promising source of hepatocytes for a wide range of applications, including cell transplantation, drug toxicity testing, patient-specific disease modeling, and even ex vivo gene therapy. But how far have we come?

Figure 1. iPS cell–derived hepatocytes restore liver function in the Fah^–/– mouse model of liver failure.

In their study, Espejel and colleagues investigated the potential for fibroblast-derived iPS cells to proliferate and restore liver function in the FAH-deficient liver failure model (18). Mouse embryonic fibroblasts were reprogrammed to become iPS cells using a plasmid method to deliver the reprogramming transcription factors KLF4, OCT4, SOX2, and c-myc. iPS cells were then injected into blastocysts from Fah^–/– mice, resulting in chimeric mice. The injected iPS cells differentiated in vivo to become hepatocytes. Upon withdrawal of NTBC in the postnatal period, Fah^–/– hepatocytes died, resulting in repopulation of the liver by the transplanted iPS cell–derived (wild-type) hepatocytes and restoration of normal liver function. The authors further tested the proliferative capacity of the iPS cell–derived hepatocytes by demonstrating that these cells proliferated in response to partial hepatectomy and repopulated a Fah^–/– liver as efficiently as did wild-type hepatocytes in a competitive repopulation assay.

Figure 2. Genetic diseases of the liver modeled in iPS cell–derived human hepatocytes.

Rashid and colleagues investigated the potential to model inborn genetic diseases of the liver in human iPS cell–derived hepatocytes (19). Skin fibroblasts were obtained from patients with 5 inborn metabolic liver diseases: AAT, FH, GSD1a, hereditary tyrosinemia, and Crigler-Najjar syndrome. Fibroblasts were reprogrammed to become iPS cells by introducing retroviral vectors expressing KLF4, OCT4, SOX2, and c-myc. iPS cells from 3 of these diseases were then differentiated in culture to become hepatocytes and analyzed for defects specific to each genetic disease.