Transgenic Mice with Defined Combinations of Drug Inducible Reprogramming Factors

Drug-inducible lentiviruses encoding Oct4, Sox2, Klf4 and c-Myc were used to derive “primary” iPS cells and segregated through germline transmission generating mice and fibroblasts carrying subsets of the reprogramming factors. Drug treatment of the cells resulted in “secondary ” iPS cell derivation only when the missing factor was introduced. This creates a defined platform for studying reprogramming mechanisms and allows screening of genetically homogenous cells for compounds that replace any transcription factor required for iPS cell derivation. The generation of induced pluripotent stem (iPS) cells from mouse and human somatic cells through the forced expression of defined transcription factors1–4 constitutes a major breakthrough in regenerative biology5. However, current reprogramming strategies require viral transduction with potentially oncogenic transcription factors. Understanding the molecular changes underlying iPS cell derivation will be required to devise alternative and safer strategies for reprogramming e.g., by replacing the viral transduced factors with small molecules6–8. Screening approaches using infected cells are hampered by the genetic variability caused b