Non cell-autonomous reprogramming of adult ocular progenitors: Generation of pluripotent stem cells without exogenous transcription factors

Direct reprogramming of differentiated cells to induced pluripotent stem (iPS) cells by ectopic expression of defined transcription factors (TFs) represents a significant break-through towards the use of stem cells in regenerative medicine (Takahashi and Yamanaka Cell 2006;126:663-676). However, the virus-mediated expression of exogenous transcription factors could be potentially harmful and, therefore, represents a barrier to the clinical use of iPS cells. Several approaches, ranging from plasmid-mediated TF expression to introduction of recombinant TFs (Yamanaka Cell 2009;137:13-17; Zhou, Wu, Joo et al. Cell Stem Cell 2009;4:381-384), have been reported to address the risk associated with viral integration. We describe an alternative strategy of reprogramming somatic progenitors entirely through the recruitment of endogenous genes without the introduction of genetic materials or exogenous factors. To this end, we reprogrammed accessible and renewable progenitors from the limbal epithelium of adult rat eye by microenvironment-based induction of endogenous iPS cell genes. Non cell-autonomous reprogramming generates cells that are pluripotent and capable of differentiating into functional neurons, cardiomyocytes, and hepatocytes, which may facilitate autologous cell therapy to treat degenerative diseases.