Direct reprogramming of somatic cells with the transcription factors Oct4, Sox2, Klf4, and c-Myc1 yields induced pluripotent stem cells (iPSC) with striking similarity to embryonic stem cells from fertilized embryos (fESC). Like fESC, iPSC form teratomas, differentiated tumors with tissues from all three embryonic germ layers, and when injected into murine blastocysts contribute to all tissues, including the germ line. iPSC from mouse embryo fibroblasts generate “all-iPSC mice” following injection into tetraploid blastocysts2, thereby satisfying the most stringent criterion of pluripotency3. Embryonic tissues are the most efficiently reprogrammed, producing iPSC that are nearly identical to fESC. In contrast, reprogramming from accessible adult tissues, most applicable for modeling diseases and generating therapeutic cells, is inefficient and limited by barriers related to the differentiation state and age of the donor’s cells456. Aged cells have higher levels of Ink4/Arf, which limits the efficiency and fidelity of reprogramming5. Moreover, terminally differentiated blood cells reprogram less efficiently than blood progenitors6. As with cloning by nuclear transfer in frogs and mice, the efficiency and yield of reprogrammed genomes declines with increasing age and differentiation status of the donor cell7, and varies with the methylation state of the donor nucleus8.
