Exacerbation of Oxidative Stress-Induced Cell Death and Differentiation in Induced Pluripotent Stem Cells Lacking Heme Oxygenase-1

Embryonic stem cells (ESCs) are promising donor sources in cell therapies for various diseases. Although low levels of reactive oxygen species (ROS) are necessary for the maintenance of stem cells, increased ROS levels initiate differentiation and cell damage. We and others have previously demonstrated that heme oxygenase (HO)-1, a stress response protein with antioxidative and anti-inflammatory properties, plays critical protective functions in cardiovascular and other diseases. However, the functions of HO-1 in ESCs remain to be elucidated. Our goal was to investigate the roles of HO-1 in ESC survival and differentiation. Due to the lack of HO-1-deficient ESCs, we used Oct3/4, Sox2, c-Myc, and Klf4 retroviruses to reprogram mouse embryonic fibroblasts into induced pluripotent stem (iPS) cells of different HO-1 genotypes. These iPS-HO-1 cells exhibited characteristics of mouse ESCs (mESCs) and formed teratomas that were composed of cell types of all 3 germ layers after injected into severe combined immun...