title: Autotaxin-mediated lipid signaling intersects with LIF and BMP signaling to promote the naive pluripotency transcription factor program.
abstract: 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.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Cody
authors.initials: C
authors.lastname: Kime
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Programs in Cell Biology and Developmental and Stem Cell Biology, Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143.
authors.forename: Masayo
authors.initials: M
authors.lastname: Sakaki-Yumoto
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Leeanne
authors.initials: L
authors.lastname: Goodrich
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Hayashi
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158.
authors.forename: Salma
authors.initials: S
authors.lastname: Sami
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Programs in Cell Biology and Developmental and Stem Cell Biology, Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143.
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158.
authors.forename: Barbara
authors.initials: B
authors.lastname: Panning
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158; yamanaka@cira.kyoto-u.ac.jp kiichiro.tomoda@gladstone.ucsf.edu.|Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158; yamanaka@cira.kyoto-u.ac.jp kiichiro.tomoda@gladstone.ucsf.edu.|Department of Pharmacology, Faculty of Medicine, Osaka Medical College, Osaka 569-8686, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002460:Cell Line; D065150:Cellular Reprogramming / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D005786:Gene Expression Regulation / Q000187:drug effects; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor / Q000494:pharmacology*; D008246:Lysophospholipids / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014815:Vitamins / Q000494:pharmacology; D000099189:Lysophospholipase D
chemical_list: D001205:Ascorbic Acid; D055415:Bone Morphogenetic Protein 4; D000090062:Kruppel-Like Factor 4; D053605:Leukemia Inhibitory Factor; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D014157:Transcription Factors; D014815:Vitamins; D000099189:Lysophospholipase D; C000715468:Klf4 protein, mouse; C032881:lysophosphatidic acid
keywords: BMP4 signaling; KLF2-KLF4-PRDM14 circuit; LIF signaling; LPA lipid signaling; naive pluripotency