Conversion of human fibroblasts into multipotent cells by cell-penetrating peptides

The potential application of human induced pluripotent stem cells (hiPSCs) brings great expectations to regenerative medicine. However, several safety concerns, such as oncogenic transformation, remain. A number of methods have been developed to produce hiPSCs with potentially reduced risks. Cell-penetrating peptides (CPPs) are expected to improve the efficiency of nonviral reprogramming by delivering biologically active molecules into cells. Here, we show that the transfection of CPPs alone into normal adult human fibroblasts generated embryonic body (EB)-like cell clusters in the absence of reprogramming factors. The CPP-generated cell clusters were positive for a set of multipotency markers and differentiated into endodermal, ectodermal, and mesodermal cells in vitro. These results suggest that CPPs converted normal human adult somatic cells into multipotent cells. Moreover, we show that CPPs dissociated histone deacetylase 1 and lysine-specific demethylase 1 from the promoter/enhancer regions of reprogramming factors to reactivate their expression. This is the first report of an easy and quick method for somatic cell reprogramming by CPPs and a novel mechanism of reprogramming. The potential application of CPP-generated multipotent cells resolves several concerns, especially safety issues, in regenerative medicine.