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

Abstract

Induced pluripotent stem (iPS) cells are generated from mouse and human somatic cells by introduction of four genes. Efficiency of this process, however, is low. Here it is reported that up to 10% of transduced mouse embryonic fibroblasts (MEF) lacking p53 became iPS cells, even without the Myc retrovirus. In the p53-null background, iPS cells can be generated from terminally differentiated T lymphocytes. The authors propose that the p53–p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation. Induced pluripotent stem (iPS) cells are generated from mouse and human somatic cells by the introduction of four genes, but with low efficiency. Here it is reported that 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus, and iPS cells were also generated from terminally differentiated T lymphocytes in the p53-null background. 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 mouse1,2,3,4 and in human5,6,7,8. The efficiency of this process, however, is low9. Pluripotency can be induced without c-Myc, but with even lower efficiency10,11. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation12, 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.