Selective Elimination of Human Pluripotent Stem Cells by an Oleate Synthesis Inhibitor Discovered in a High-Throughput Screen
Selective Elimination of Human Pluripotent Stem Cells by an Oleate Synthesis Inhibitor Discovered in a High-Throughput Screen
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DOI：
10.1016/j.stem.2012.11.015
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发表时间：
2013-02-07
期刊：
影响因子：
23.9
通讯作者：
Benvenisty, Nissim
中科院分区：
文献类型：
--
作者：
Ben-David, Uri;Gan, Qing-Fen;Benvenisty, Nissim
残留未分化细胞的致瘤风险阻碍了人类多能干细胞（hPSC）在细胞治疗中的使用。在这里，我们对超过 52,000 个小分子进行了高通量筛选，并鉴定了 15 种多能细胞特异性抑制剂 (PluriSIns)，其中 9 种具有共同的结构部分。 PluriSIn 选择性消除 hPSC，同时保留大量祖细胞和分化细胞。细胞和分子分析表明，最具选择性的化合物 PluriSIn #1 可诱导 hPSC 内质网应激、蛋白质合成减弱和细胞凋亡。仔细检查发现该分子是硬脂酰辅酶A去饱和酶 (SCD1) 的抑制剂，而 SCD1 是油酸生物合成的关键酶，揭示了 hPSC 脂质代谢的独特作用。 PluriSIn #1 对小鼠囊胚也具有细胞毒性，表明对油酸盐的依赖性是多能状态所固有的。最后，PluriSIn #1 的应用阻止了致瘤未分化细胞形成畸胎瘤。这些发现应该会提高基于 hPSC 的治疗的安全性。
The use of human pluripotent stem cells (hPSCs) in cell therapy is hindered by the tumorigenic risk from residual undifferentiated cells. Here we performed a high-throughput screen of over 52,000 small molecules and identified 15 pluripotent cell-specific inhibitors (PluriSIns), nine of which share a common structural moiety. The PluriSIns selectively eliminated hPSCs while sparing a large array of progenitor and differentiated cells. Cellular and molecular analyses demonstrated that the most selective compound, PluriSIn #1, induces ER stress, protein synthesis attenuation, and apoptosis in hPSCs. Close examination identified this molecule as an inhibitor of stearoyl-coA desaturase (SCD1), the key enzyme in oleic acid biosynthesis, revealing a unique role for lipid metabolism in hPSCs. PluriSIn #1 was also cytotoxic to mouse blastocysts, indicating that the dependence on oleate is inherent to the pluripotent state. Finally, application of PluriSIn #1 prevented teratoma formation from tumorigenic undifferentiated cells. These findings should increase the safety of hPSC-based treatments.