The generation of induced pluripotent stem cells (iPSCs) often causes genetic and epigenetic defects, which may limit their clinical applications. Here, we show that reprogramming in the presence of small molecules preserved the genomic stability of iPSCs by inhibiting DNA double-strand breaks (DSBs) and activating Zscan4 gene. Surprisingly, the small molecules protected normal karyotype by facilitating repair of the DSBs that occurred during the early reprogramming process and long-term culture of iPSCs. The stemness and cell growth of iPSCs(+) were normally sustained with high expression of pluripotency genes compared that of iPSCs(-). Moreover, small molecules maintained the differentiation potential of iPSCs(+) for the three germ layers, whereas it was lost in iPSCs(-). Our results demonstrate that the defined small molecules are potent factors for generation of high quality iPSCs with preservation of genomic integrity by facilitating the reprogramming process.
