Suppression of induced pluripotent stem cell generation by the p53-p21 pathway

Induced pluripotent stem(iPS) cells can be generated from somatic cells by the introduction of Oct3/4 ( also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse(1-4) and in human(5-8). The efficiency of this process, however, is low(9). Pluripotency can be induced without c-Myc, but with even lower efficiency(10,11). A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation(12), but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53-p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.