Reprogramming of Human Fibroblasts to Pluripotency with Lineage Specifiers

Since the initial discovery that OCT4, SOX2, KLF4, and c-MYC overexpression sufficed for the induction of pluripotency in somatic cells, methodologies replacing the original factors have enhanced our understanding of the reprogramming process. However, unlike in mouse, OCT4 has not been replaced successfully during reprogramming of human cells. Here we report on a strategy to accomplish this replacement. Through a combination of transcriptome and bioinformatic analysis we have identified factors previously characterized as being lineage specifiers that are able to replace OCT4 and SOX2 in the reprogramming of human fibroblasts. Our results show that it is possible to replace OCT4 and SOX2 simultaneously with alternative lineage specifiers in the reprogramming of human cells. At a broader level, they also support a model in which counteracting lineage specification networks underlies the induction of pluripotency. •Mesendodermal lineage specifiers replace OCT4 in hiPSC generation•Ectodermal lineage specifiers are able to replace SOX2 in hiPSC generation•Simultaneous replacement of OCT4 and SOX2 allows human cell reprogramming to iPSCs Successful reprogramming of human cells with OCT4 and SOX2 replaced with lineage specifiers, supporting the idea that pluripotency is achieved through an equilibrium between counteracting differentiation networks.