Expression of the transcription factors OCT3/4, SOX2, KLF4 and c-MYC induces reprogramming of differentiated cells to a pluripotent state (induced pluripotent stem cells (iPSCs)). To understand the mechanisms behind the reprogramming of human cells, Yamanaka and colleagues (Nat. Commun. http://dx.doi.org/10.1038/ncomms4678; 2014) isolated cells at an intermediate stage of reprogramming on the basis of the expression of the surface marker TRA-1-60 and examined how they reach pluripotency. They uncovered the transient activation of the expression of genes characteristic of the mesendoderm, a lineage in the primitive streak in developing embryos, with the upregulation of mesendodermal markers, such as BRACHYURY (T), MIXL1, CER1, LHX1 and EOMES. They observed the presence of active chromatin marks at these promoters as well as an increased level of the protein they encode. Transient activation of these genes happened regardless of the germ-layer origin of the differentiated cells.

The authors then examined the effect of transcription factors linked to primitive streak specification on reprogramming, and found that FOXH1 promotes the maturation of intermediately reprogrammed cells to the pluripotent state. Expression of FOXH1 in the TRA-1-60+ cells enhanced the induction of epithelial markers, consistent with the notion that a mesenchymal-to-epithelial transition state is involved in reprogramming.

Future studies will be required to understand how OCT3/4, SOX2, KLF4 and c-MYC induce the mesendodermal fate during this process.