Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells.
Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells.
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DOI：
10.1016/j.isci.2020.101535
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发表时间：
2020-09-25
期刊：
影响因子：
5.8
通讯作者：
Fukuda K
中科院分区：
文献类型：
--
作者：
Tanosaki S;Tohyama S;Fujita J;Someya S;Hishiki T;Matsuura T;Nakanishi H;Ohto-Nakanishi T;Akiyama T;Morita Y;Kishino Y;Okada M;Tani H;Soma Y;Nakajima K;Kanazawa H;Sugimoto M;Ko MSH;Suematsu M;Fukuda K
人类多能干细胞(HPSCs)中脂代谢的作用还知之甚少。我们利用大规模的靶向蛋白质组学方法证明，未分化的hPSC表达不同于hPSC来源的心肌细胞(hPSC-CMS)的脂肪酸(FA)生物合成相关酶，包括ATP柠檬酸裂解酶和FA合成酶(FASN)。详细的脂谱分析显示，抑制FASN导致神经鞘脂和磷脂酰胆碱(PC)显著减少；此外，我们发现PC是hPSCs存活的关键代谢物。抑制FASN通过线粒体途径诱导未分化的hPSCs细胞死亡，但不影响hPSC-CMS、神经元或肝细胞的存活，因为PC没有明显减少。此外，我们没有观察到FASN抑制剂处理的细胞移植后的肿瘤形成。我们的发现证明了从头合成FA在未分化的hPSCs存活中的重要性，并建议将FASN抑制应用于再生医学。未分化hPSCs上调新生FA合成相关酶抑制新生FA合成诱导未分化hPSC细胞死亡磷脂酰胆碱是hPSC存活所需的关键代谢物FASN抑制消除hPSC衍生物中未分化的hPSC生物科学；细胞生物学；干细胞研究；蛋白质组学；代谢组学；代谢流量分析
The role of lipid metabolism in human pluripotent stem cells (hPSCs) is poorly understood. We have used large-scale targeted proteomics to demonstrate that undifferentiated hPSCs express different fatty acid (FA) biosynthesis-related enzymes, including ATP citrate lyase and FA synthase (FASN), than those expressed in hPSC-derived cardiomyocytes (hPSC-CMs). Detailed lipid profiling revealed that inhibition of FASN resulted in significant reduction of sphingolipids and phosphatidylcholine (PC); moreover, we found that PC was the key metabolite for cell survival in hPSCs. Inhibition of FASN induced cell death in undifferentiated hPSCs via mitochondria-mediated apoptosis; however, it did not affect cell survival in hPSC-CMs, neurons, or hepatocytes as there was no significant reduction of PC. Furthermore, we did not observe tumor formation following transplantation of FASN inhibitor-treated cells. Our findings demonstrate the importance of de novo FA synthesis in the survival of undifferentiated hPSCs and suggest applications for FASN inhibition in regenerative medicine. Undifferentiated hPSCs upregulate de novo FA synthesis-related enzymes Inhibition of de novo FA synthesis induces cell death in undifferentiated hPSCs Phosphatidylcholine is the key metabolite required for hPSC survival FASN inhibition eliminates undifferentiated hPSCs from hPSC derivatives Biological Sciences; Cell Biology; Stem Cells Research; Proteomics; Metabolomics; Metabolic Flux Analysis
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影响因子：
64.8
作者：
Jiang L;Shestov AA;Swain P;Yang C;Parker SJ;Wang QA;Terada LS;Adams ND;McCabe MT;Pietrak B;Schmidt S;Metallo CM;Dranka BP;Schwartz B;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
48
作者：
Burridge, Paul W.;Matsa, Elena;Shukla, Praveen;Lin, Ziliang C.;Churko, Jared M.;Ebert, Antje D.;Lan, Feng;Diecke, Sebastian;Huber, Bruno;Mordwinkin, Nicholas M.;Plews, Jordan R.;Abilez, Oscar J.;Cui, Bianxiao;Gold, Joseph D.;Wu, Joseph C.
通讯作者：
Wu, Joseph C.
影响因子：
4.8
作者：
Hannah, VC;Ou, JF;Brown, MS
通讯作者：
Brown, MS
影响因子：
64.8
作者：
Metallo, Christian M.;Gameiro, Paulo A.;Bell, Eric L.;Mattaini, Katherine R.;Yang, Juanjuan;Hiller, Karsten;Jewell, Christopher M.;Johnson, Zachary R.;Irvine, Darrell J.;Guarente, Leonard;Kelleher, Joanne K.;Vander Heiden, Matthew G.;Iliopoulos, Othon;Stephanopoulos, Gregory
通讯作者：
Stephanopoulos, Gregory
影响因子：
29
作者：
Folmes CD;Nelson TJ;Martinez-Fernandez A;Arrell DK;Lindor JZ;Dzeja PP;Ikeda Y;Perez-Terzic C;Terzic A
通讯作者：
Terzic A