Induction of Pluripotency in Mouse Somatic Cells with Lineage Specifiers

The reprogramming factors that induce pluripotency have been identified primarily from embryonic stem cell (ESC)-enriched, pluripotency-associated factors. Here, we report that, during mouse somatic cell reprogramming, pluripotency can be induced with lineage specifiers that are pluripotency rivals to suppress ESC identity, most of which are not enriched in ESCs. We found that OCT4 and SOX2, the core regulators of pluripotency, can be replaced by lineage specifiers that are involved in mesendodermal (ME) specification and in ectodermal (ECT) specification, respectively. OCT4 and its substitutes attenuated the elevated expression of a group of ECT genes, whereas SOX2 and its substitutes curtailed a group of ME genes during reprogramming. Surprisingly, the two counteracting lineage specifiers can synergistically induce pluripotency in the absence of both OCT4 and SOX2. Our study suggests a “seesaw model” in which a balance that is established using pluripotency factors and/or counteracting lineage specifiers can facilitate reprogramming. [Display omitted] •OCT4 and SOX2 can be replaced by lineage specifiers during reprogramming•OCT4 substitutes and SOX2 substitutes inhibit some ECT and ME genes, respectively•A seesaw model suggests that balancing counteracting forces facilitates reprogramming Competing lineage specifiers each inducing a different cell fate can be used to generate iPSCs without pluripotency factors.