幹細胞胞外體(stem cell-derived exosomes) 促 乳腺上皮細胞 重獲幹細胞特性

幹細胞突破 國衛院成功重建動物乳腺 國衛院細胞及系統醫學研究所助研究員李華容與博士後研究員林孟杰等人發現，利用誘發的幹細胞胞外體，成功地轉化已分化的乳腺管腔細胞為乳腺幹細胞，並能用於動物體內，重建乳腺組織，再生醫學再現曙光。 幹細胞研究及應用成為科學上眾所矚目焦點之一，幹細胞臨床應用也為再生醫學帶來了一線曙光，但現今幹細胞分化功能尚未完全釐清，加上幹細胞取得不易、數量稀少及培養困難，使得現今幹細胞治療上，存在許多風險及困難度。 國衛院電子報報導指出，前列腺素E2（prostaglandin E2）訊號傳遞，對於維持體內幹細胞恆定扮演非常重要的角色，在幹細胞自我更新及再生上也不可或缺，其中重要的分子機制至今仍然尚未釐清。李華容、林孟杰等人發現，阻斷乳腺幹細胞的前列腺素E2訊號傳遞，可促使維持幹細胞特性的分子聚集於細胞膜脂筏（lipid-raft）內，這些含幹細胞特性分子的脂筏，更進一步地經由胞外體（exosomes），大量被釋放到細胞外，進而導致乳腺幹細胞失去幹細胞特性，分化形成乳腺上皮細胞。 研究團隊發現，這些被誘發的幹細胞胞外體（stem cell-derived exosomes, SC-exosomes），可被已分化的乳腺上皮細胞吞噬，促使已分化的細胞重獲幹細胞特性；團隊利用此誘發的幹細胞胞外體，成功地轉化已分化的乳腺管腔細胞為乳腺幹細胞，並能用於動物體內，重建乳腺組織。此項研究有助於了解前列腺素E2訊號傳遞於幹細胞分化上的分子機制，並且證實幹細胞特性可藉由胞外體於細胞之間進行轉移。該研究成果對於發展非細胞性幹細胞胞外體的治療與應用，具有極大潛力，是再生醫學上的重大突破。研究團隊以此研究結果為方向，積極尋求多種幹細胞胞外體於組織再生上的應用，相關研究成果已申請專利，並於8月發表在Stem Cells期刊（in press; DOI: 10.1002/stem.2476）。 前列腺素E2訊號傳遞路徑被阻斷的情況之下，幹細胞大量釋放胞外體，此胞外體可被已分化的細胞吞噬，促使其重獲幹細胞特性。團隊成功利用產生的胞外體誘發幹細胞，並於動物體內重建乳腺組織。

Stem Cells. 2016 Aug 10. doi: 10.1002/stem.2476. PGE2 /EP4 Signaling Controls the Transfer of the Mammary Stem Cell State by Lipid Rafts in Extracellular Vesicles. 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 2016.