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1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Currently, tThe overwhelming majority of studies on iPSC reprogramming utilize recombinant DNA and viral vectors, which in turn

carry involves the attendant risk of permanent genetic modification to the reprogrammed cells. This poses presents a major barrier to clinical applications of iPSCs, as there are due to serious safety concerns with regards to regarding the transplantation/transfusion of genetically modified cells into the human body. Indeed, In a previous clinical trial, for example, Ever since Yamanaka et al.’s pioneering study, tThere has been rapid progress in the iPSC field ever since the pioneering study of Yamanaka and colleagues [5, 6]. Besides Apart from the original four transcription factors (Klf4, Oct4, c-Myc, and Sox2) initially utilized by that Yamanaka and colleagueset al. utilized, another additional a further two transcription factors (Nanog & Lin28) have also been shown to be able to substitute some of the original four transcription factors in cellular reprogramming for iPSC generation [7–-10]. Various small molecules have also been identified which that can enhance reprogramming efficiency and reduce the number of different transcription factors required for reprogramming in order to reprogram to iPSCs [11–-13]. Lin et al. [12] reported that utilizing a combination of three small molecules (SB431542, PD032-5901, and thiazovivin) produced a 200-fold increase in iPSC reprogramming efficiency by utilizing a combination of three small molecules SB431542, PD032-5901 and thiazovivin. In aAnother study by Li et al. [13], it was demonstrated showed that the expression of it was only just necessary to express as few as two transcription factors (Oct4 and Klf4) was sufficient in order to reprogram primary human keratinocytes to iPSCs, in the presence of two small molecules (– CHIR99021 and Parnate). Nevertheless tTo date, however, the use of small molecules alone have has not yet been demonstrated shown to be sufficient for reprogramming somatic cells to their pluripotent state.

2 28 29 30 31 32 33 34 genetically modified cells have been reported to become became cancerous in a previous clinical trial, leading which led to the unfortunate death of the patient [14]. The PiggyBac transposon system has been used to develop Although sstrategies to for transiently inserting and remove removing transgenic elements in a precise and sitespecific manner have been devloped with the PiggyBac transposon system [15, 16]. However, such an approach is tedious and labor-intensive, and requires rigorous screening to confirm the absence of genetic modification to the cellular genome.