PGE₂/EP₄ Signaling Controls the Transfer of the Mammary Stem Cell State by Lipid Rafts in Extracellular Vesicles

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• 作者：Meng‐Chieh Lin ; Shih‐Yin Chen ; Ho‐Min Tsai ; Pei‐Lin He ; Yen‐Chun Lin ; Harvey Herschman ; Hua‐Jung Li
• 刊名：STEM CELLS
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：35
• 期：2
• 页码：425-444
• 全文大小：1.5MB
• ISSN：1549-4918

文摘

Prostaglandin E₂ (PGE₂)-initiated signaling contributes to stem cell homeostasis and regeneration. However, it is unclear how PGE₂ signaling 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. EP₄ antagonists elicit release of signaling components, by controlling their trafficking into extracellular vesicles/exosomes in a lipid raft/caveolae-dependent manner. Consequently, EP₄ antagonism 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. EP₄ antagonism causes signaling receptors and signaling components to shift from non-lipid raft fractions to lipid raft fractions, and to then be released in EP₄ antagonist-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 EP₄ antagonist-induced stem cell extracellular vesicles/exosomes, and can then form mammary glands. These findings demonstrate that PGE₂/EP₄ signaling 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