Grown Up Mice From Gene-Corrected iPS Cells

Abstract

In 2008, Science named induced pluripotent stem cells (iPS) the breakthrough of the year.1 In 2009, Nature Methods called the process of generating iPS cells the “Method of the Year.“2 Two years later, although the use of iPS cells remains a bright promise for both research and regenerative medicine, concerns remain about how the epigenetic and genetic changes that occur in the creation of iPS cells will affect their utility in the treatment of heritable conditions. This summer, a team led by Tobias Cantz, at the Max-Planck-Institute for Molecular Biomedicine, published a proof-of-principle paper in PLoS Biology demonstrating that iPS cells remained pluripotent after correction of genetic defects.3 The authors chose fumarylacetoacetate hydrolase (FAH) deficiency as a disease model for an iPS-mediated correction. FAH deficiency leads to the rare clinical syndrome, tyrosinemia type I, characterized by the accumulation of succinylacetone in multiple organs, including the liver and kidneys, leading to organ failure and death. In this paper, Wu et al first generated iPS cells from FAH-deficient fibroblasts and then corrected the FAH deficiency by transducing the iPS cells with recombinant lentiviruses. Subsequently they used the genetically corrected iPS cells to produce mice that expressed FAH (Figure). Figure. Diagram demonstrating the process described by Wu et al for creating mice from gene-corrected disease-specific iPS cells. (Illustration credit: Cosmocyte/Ben Smith, adapted from an image provided by Tobias Cantz). “The study clearly showed that the gene correction procedures did not impair the full pluripotentiality of iPS cells,” said Shinya Yamanaka (director of the Center for iPS Cell Research and Application at Kyoto University). Yamanaka is the father of the iPS field. In 2006 his laboratory was the first to coax adult mouse fibroblasts into an undifferentiated state through the expression of 4 transcription factors: Oct4, Sox2, Klf4, and c-Myc.4 …