Tanosaki Sho, Tohyama Shugo, Fujita Jun, Someya Shota, Hishiki Takako, Matsuura Tomomi, Nakanishi Hiroki, Ohto-Nakanishi Takayo, Akiyama Tomohiko, Morita Yuika, Kishino Yoshikazu, Okada Marina, Tani Hidenori, Soma Yusuke, Nakajima Kazuaki, Kanazawa Hideaki, Sugimoto Masahiro, Ko Minoru S H, Suematsu Makoto, Fukuda Keiichi
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
iScience. 2020 Sep 6;23(9):101535. doi: 10.1016/j.isci.2020.101535. eCollection 2020 Sep 25.
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 FA synthesis in the survival of undifferentiated hPSCs and suggest applications for FASN inhibition in regenerative medicine.
脂质代谢在人类多能干细胞（hPSCs）中的作用尚不清楚。我们利用大规模靶向蛋白质组学证明，未分化的hPSCs表达的与脂肪酸（FA）生物合成相关的酶，包括ATP柠檬酸裂解酶和脂肪酸合酶（FASN），与hPSC衍生的心肌细胞（hPSC-CMs）中表达的不同。详细的脂质分析表明，抑制FASN会导致鞘脂和磷脂酰胆碱（PC）显著减少；此外，我们发现PC是hPSCs细胞存活的关键代谢物。抑制FASN通过线粒体介导的凋亡诱导未分化hPSCs细胞死亡；然而，它并不影响hPSC-CMs、神经元或肝细胞的细胞存活，因为PC没有显著减少。此外，我们没有观察到经FASN抑制剂处理的细胞移植后形成肿瘤。我们的研究结果证明了FA合成在未分化hPSCs存活中的重要性，并提出了FASN抑制在再生医学中的应用。
