title: PGE2/EP4Signaling Controls the Transfer of the Mammary Stem Cell State by Lipid Rafts in Extracellular Vesicles.
abstract: Prostaglandin E2(PGE2)-initiated signaling contributes to stem cell homeostasis and regeneration. However, it is unclear how PGE2signaling controls cell stemness. This study identifies a previously unknown mechanism by which PGE2/prostaglandin E receptor 4 (EP4) signaling regulates multiple signaling pathways (e.g., PI3K/Akt signaling, TGFβ signaling, Wnt signaling, EGFR signaling) which maintain the basal mammary stem cell phenotype. A shift of basal mammary epithelial stem cells (MaSCs) from a mesenchymal/stem cell state to a non-basal-MaSC state occurs in response to prostaglandin E receptor 4 (EP4) antagonism. EP4antagonists elicit release of signaling components, by controlling their trafficking into extracellular vesicles/exosomes in a lipid raft/caveolae-dependent manner. Consequently, EP4antagonism indirectly inactivates, through induced extracellular vesicle/exosome release, pathways required for mammary epithelial stem cell homeostasis, e.g. canonical/noncanonical Wnt, TGFβ and PI3K/Akt pathways. EP4antagonism causes signaling receptors and signaling components to shift from non-lipid raft fractions to lipid raft fractions, and to then be released in EP4antagonist-induced extracellular vesicles/exosomes, resulting in the loss of the stem cell state by mammary epithelial stem cells. In contrast, luminal mammary epithelial cells can acquire basal stem cell properties following ingestion of EP4antagonist-induced stem cell extracellular vesicles/exosomes, and can then form mammary glands. These findings demonstrate that PGE2/EP4signaling controls homeostasis of mammary epithelial stem cells through regulating extracellular vesicle/exosome release. Reprogramming of mammary epithelial cells can result from EP4-mediated stem cell property transfer by extracellular vesicles/exosomes containing caveolae-associated proteins, between mammary basal and luminal epithelial cells. Stem Cells 2017;35:425-444.
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Meng-Chieh
authors: MC
authors: Lin
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Shih-Yin
authors: SY
authors: Chen
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Ho-Min
authors: HM
authors: Tsai
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Pei-Lin
authors: PL
authors: He
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.|Department of Biochemistry, University of Washington, Seattle, Washington, USA.
authors: Yen-Chun
authors: YC
authors: Lin
authors: Department of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California, USA.|Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, USA.
authors: Harvey
authors: H
authors: Herschman
authors: Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
authors: Hua-Jung
authors: HJ
authors: Li
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D021941:Caveolae / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D048430:Cell Shape; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D000067128:Extracellular Vesicles / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D006801:Humans; D016023:Integrins / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology*; D021962:Membrane Microdomains / Q000378:metabolism* / Q000648:ultrastructure; D008810:Mice, Inbred C57BL; D000071876:Prostaglandin-E Synthases / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000166:cytology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D016023:Integrins; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051546:Cyclooxygenase 2; D020691:rab GTP-Binding Proteins; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
keywords: EP4 receptor; Exosome; Extracellular vesicle; Lipid raft; PGE2; Stem cell homeostasis