期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 44, 页码 12478-12483出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1608564113
关键词
naive pluripotency; LPA lipid signaling; LIF signaling; BMP4 signaling; KLF2-KLF4-PRDM14 circuit
资金
- NIH [R01 GM088506, P30 AI027763, S10 RR028962-01]
- Kyoto University grants
- Gladstone Institutes
- L.K. Whittier Foundation
- Roddenberry Foundation
- National Heart, Lung, and Blood Institute/NIH [U01-HL100406, U01-HL098179]
- University of California San Francisco-Gladstone Institute of Virology & Immunology Center for AIDS Research, NIH [P30 AI027763, S10 RR028962-01]
- California Institute for Regenerative Medicine (CIRM)
- National Center for Research Resources [RR18928-01]
Developmental signaling molecules are used for cell fate determination, and understanding how their combinatorial effects produce the variety of cell types in multicellular organisms is a key problem in biology. Here, we demonstrate that the combination of leukemia inhibitory factor (LIF), bone morphogenetic protein 4 (BMP4), lysophosphatidic acid (LPA), and ascorbic acid (AA) efficiently converts mouse primed pluripotent stem cells (PSCs) into naive PSCs. Signaling by the lipid LPA through its receptor LPAR1 and downstream effector Rho-associated protein kinase (ROCK) cooperated with LIF signaling to promote this conversion. BMP4, which also stimulates conversion to naive pluripotency, bypassed the need for exogenous LPA by increasing the activity of the extracellular LPA-producing enzyme autotaxin (ATX). We found that LIF and LPA-LPAR1 signaling affect the abundance of signal transducer and activator of transcription 3 (STAT3), which induces a previously unappreciated Kruppel-like factor (KLF) 2-KLF4-PR domain 14 (PRDM14) transcription factor circuit key to establish naive pluripotency. AA also affects this transcription factor circuit by controlling PRDM14 expression. Thus, our study reveals that ATX-mediated autocrine lipid signaling promotes naive pluripotency by intersecting with LIF and BMP4 signaling.
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