Genetic reprogramming to a pluripotent state of mouse somatic cells was first achieved by ectopic expression of four factors (Oct4, Sox2, Klf4 and c-Myc) using retroviruses 
. Such cells were named induced pluripotent stem cells (iPSCs). Subsequently, this method was applied to human cells using the same factors or a different combination in a lentivirus vector (Oct4, Sox2, Lin28 and Nanog) 
. Both mouse and human iPSCs are similar to embryonic stem cells (ESCs) with respect to their morphology, cell behavior, gene expression, epigenetic status and differentiation potential both in culture and in vivo
. However, to date, a comprehensive transcriptional analysis has not been reported comparing human ESCs and iPSCs. One reason is that the technology used to derived iPSCs is not “footprint-free” and thus, subjected to transcriptional interference.
Viral vectors are known to affect the transcriptional profile from target cells, altering their behavior and sometimes inducing apoptosis 
. Moreover, the reactivation of the viral transgene was also implicated in tumorigenesis from iPSC-derived chimeric mice 
. Also, random integration may influence the molecular signatures of iPSCs by interrupting regulatory regions in the human genome. Interestingly, a transcriptional analysis revealed that transgene expression from not completely silenced viral vectors could, in fact, perturb global gene expression in hiPSCs 
Several attempts were made to generate a viral-free, integration-free iPSCs. The generation of iPSCs with later excision of reprogramming factors was recently achieved; still, the genome continues to be affected by random solo-LTR insertions from viral vectors 
. Mouse iPSCs were also generated by multiple transient expression of Oct4, Sox2 and Klf4 from embryonic fibroblasts at very low efficiency 
. Recently, a two-step seamless factor removal from iPSCs using transposase-stimulated excision was recently reported 
. Although evidence that the system might work in human cells was presented, it needs further validation in more rigorous pluripotent assays 
. A “footprint-free” and highly efficient system of generating human iPSCs would help to determine the molecular mechanism of cellular reprogramming and accelerate the search for efficient compounds that will replace the original factors without side effects.
The timing of the reprogramming and the factors required seem to vary depending on cellular context 
. The susceptibility of a somatic cell to reprogram may depend on how similar its transcriptional profile is to ESCs. Of note, mouse neural stem cells (NSCs) were reprogrammed using only one (Oct4) or two factors (Oct4 and Klf4), due to the endogenously high expression of pluripotent genes, such as Sox2 and c-Myc, as well as several intermediate reprogramming markers 
. Fibroblasts that already carry the Oct4 transgene can be reprogrammed with fewer factors, facilitating the study of nuclear reprogramming 
. Moreover, although reprogramming can be achieved without c-Myc, iPSC generation is more efficient when the gene is present 
. Furthermore, recent data suggest that c-Myc expression primes cells for iPSC conversion, accelerating the initial steps of reprogramming to achieve high efficiency 
. Such observations prompted us to use human NSCs expressing c-Myc, as a model to facilitate the generation of iPSCs and to study the reprogramming steps.