海棲熱袍菌(Thermotoga maritima)S-腺苷蛋氨酸脫羧酶晶體結(jié)構(gòu),，圖片來自維基共享資源,。
新加坡科技研究局(Agency for Science, Technology and Reseach, A*STAR)科學(xué)家第一次鑒定出精確地調(diào)控多胺水平在胚胎干細胞(embryonic stem cell, ESC)自我更新和定向分化中發(fā)揮著關(guān)鍵性作用。這篇論文于2012年3月1日發(fā)表在Genes & Development期刊上,，有助于人們更好地理解胚胎干細胞調(diào)控機制,。
胚胎干細胞很有潛力被用來開發(fā)出細胞療法(cell therapy)，即利用干細胞修復(fù)因為疾病或創(chuàng)傷而受損的組織,。這是因為它們擁有一種獨特的自我更新和分化成體內(nèi)任何一種特定類型細胞的能力,。細胞療法面臨的眾多挑戰(zhàn)之一就是確保胚胎干細胞充分地和有效地分化為正確的細胞類型。這項研究有助于人們理解胚胎干細胞是如何受到調(diào)節(jié)的,，而且這也是人們戰(zhàn)勝這些挑戰(zhàn)并將細胞療法轉(zhuǎn)變?yōu)楝F(xiàn)實的關(guān)鍵,。
利用小鼠模式動物,，來自新加坡科技研究局醫(yī)學(xué)生物研究所的科學(xué)家領(lǐng)導(dǎo)的一個研究小組證實高水平的Amd1(Adenosyl methionine decarboxylase,，腺苷蛋氨酸脫羧酶)---多胺物質(zhì)精胺和亞精胺合成途徑的一種關(guān)鍵性酶---是維持胚胎干細胞狀態(tài)和自我更新所必需的。為了進一步證實Amd1在胚胎干細胞中發(fā)揮的關(guān)鍵性作用,，研究小組發(fā)現(xiàn)增加Amd1水平導(dǎo)致胚胎干細胞分化發(fā)生延遲,。這項研究還揭示下調(diào)Amd1是胚胎干細胞分化為神經(jīng)祖細胞(neural precursor cell)所必需的，而且還發(fā)現(xiàn)可以利用microRNA調(diào)控Amd1的翻譯,，這也是第一次證實microRNA介導(dǎo)多胺合成途徑的調(diào)控,。
盡管人們已經(jīng)完全理解多胺合成途徑而且也知道多胺在癌癥和細胞增殖中發(fā)揮重要作用，但是它們在胚胎干細胞調(diào)控中所起的作用人們一直未知,。當研究小組開始進行全基因組篩選來尋找翻譯受到控制的mRNA以便鑒定出胚胎干細胞分化為神經(jīng)祖細胞的新調(diào)節(jié)物時,，他們發(fā)現(xiàn)多胺調(diào)節(jié)胚胎干細胞。
論文通訊作者Leah Vardy博士說,，“Amd1調(diào)控的多胺有潛力調(diào)控干細胞自我更新和分化的許多不同方面,。下一步就是更加詳細地揭示這些多胺在胚胎干細胞和分化為不同細胞系的細胞中發(fā)揮重要作用的分子靶標?？茖W(xué)家有可能通過多胺合成途徑的抑制物或激活物操縱胚胎干細胞中的多胺水平從而有助于指導(dǎo)胚胎干細胞分化為臨床上更加有用的細胞系,。” (生物谷：towersimper編譯)
doi:10.1101/gad.182998.111
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AMD1 is essential for ESC self-renewal and is translationally down-regulated on differentiation to neural precursor cells
Dawei Zhang, Tianyun Zhao, Haw Siang Ang, Peini Chong, Ryotaro Saiki, Kazuei Igarashi, Henry Yang and Leah A. Vardy
The gene expression networks governing embryonic stem cell (ESC) pluripotency are complex and finely regulated during differentiation toward specific lineages. We describe a new role for Amd1 (adenosyl methionine decarboxylase), a key enzyme in the polyamine synthesis pathway, in regulating both ESC self-renewal and differentiation to the neural lineage. Amd1 is highly expressed in ESCs and is translationally down-regulated by the neural precursor cell (NPC)-enriched microRNA miR-762 during NPC differentiation. Overexpression of Amd1 or addition of the polyamine spermine blocks ESC-to-NPC conversion, suggesting Amd1 must be down-regulated to decrease the levels of inhibitory spermine during differentiation. In addition, we demonstrate that high levels of Amd1 are required for maintenance of the ESC state. We show that forced overexpression of Amd1 in ESCs results in maintenance of high Myc levels and a delay in differentiation on removal of LIF. We propose that Amd1 is a major regulator of ESC self-renewal and that its essential role lies in its regulation of Myc levels within the cell.
