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Significance Naive and primed pluripotent stem cells (PSCs) provide a potential source of cells for regenerative medicine. Although both cell types can contribute to all three germ layers, they differ in cell morphology, gene expression programs, and epigenetic modifications, such as the X chromosome inactivation status. Here, we report that lysophosphatidic acid (LPA) lipid signaling and the LPA-producing enzyme autotaxin are crucial in converting primed PSCs into naive PSCs. Our results reveal relationships between signaling pathways by cytokines and the lipids that, in conjunction with nutrients, synergistically induce a transcription factor circuit necessary for establishing naive pluripotency. Thus, our study provides insights into the extracellular stimuli and gene regulation to precisely control PSCs for regenerative medicine and cell biology.

Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program