Non-cell-autonomous promotion of pluripotency induction mediated by YAP

While Yes-associated protein (YAP) antagonizes pluripotency during early embryogenesis, it has also been shown to promote stemness of multiple stem cell types, including pluripotent stem cells. Whether cellular context underlies these distinct functions of YAP in pluripotency remains unclear. Here, we establish that depending on the specific cells in which it is expressed, YAP exhibits opposing effects on pluripotency induction from somatic cells. Specifically, YAP inhibits pluripotency induction cell-autonomously but promotes it non-cell-autonomously. For its non-cell-autonomous role, YAP alters the expression of many secreted and matricellular proteins including CYR61, which recapitulates the promotional effect when added as a recombinant protein. Thus, we define a unique YAP-driven non-cell-autonomous process that enhances pluripotency induction. Our work highlights the importance of considering the distinct contributions from heterologous cell types in deciphering the mechanism of cell fate control and calls for careful re-examination of the co-existing bystander cells in complex cultures or tissues.