Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells
Sho Tanosaki,
Shugo Tohyama,
Jun Fujita,
Shota Someya,
Takako Hishiki,
Tomomi Matsuura,
Hiroki Nakanishi,
Takayo Ohto-Nakanishi,
Tomohiko Akiyama,
Yuika Morita,
Yoshikazu Kishino,
Marina Okada,
Hidenori Tani,
Yusuke Soma,
Kazuaki Nakajima,
Hideaki Kanazawa,
Masahiro Sugimoto,
Minoru S.H. Ko,
Makoto Suematsu,
Keiichi Fukuda
Affiliations
Sho Tanosaki
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
Shugo Tohyama
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan; Department of Organ Fabrication, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan; Corresponding author
Jun Fujita
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan; Endowed Course for Severe Heart Failure Treatment II, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan; Corresponding author
Shota Someya
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
Takako Hishiki
Department of Biochemistry, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan; Clinical and Translational Research Center, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Tomomi Matsuura
Clinical and Translational Research Center, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Hiroki Nakanishi
Lipidome Lab Co., Ltd., Akita 010-0825, Japan
Takayo Ohto-Nakanishi
Lipidome Lab Co., Ltd., Akita 010-0825, Japan
Tomohiko Akiyama
Department of Systems Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Yuika Morita
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Yoshikazu Kishino
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Marina Okada
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Hidenori Tani
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Yusuke Soma
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Kazuaki Nakajima
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Hideaki Kanazawa
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Masahiro Sugimoto
Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University, Shinjuku, Tokyo 160-8402, Japan; Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
Minoru S.H. Ko
Department of Systems Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Makoto Suematsu
Department of Biochemistry, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Keiichi Fukuda
Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan
Summary: 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.
