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

doi:10.1016/j.isci.2020.101535

Fatty Acid Synthesis Is Indispensable for Survival of Human Pluripotent Stem Cells

iScience. 2020 Sep 6;23(9):101535. doi: 10.1016/j.isci.2020.101535. eCollection 2020 Sep 25.

Authors

Sho Tanosaki^{1

2}, Shugo Tohyama^{1

3}, Jun Fujita^{1

4}, Shota Someya^{1

2}, Takako Hishiki^{5

6}, Tomomi Matsuura⁶, Hiroki Nakanishi⁷, Takayo Ohto-Nakanishi⁷, Tomohiko Akiyama⁸, Yuika Morita¹, Yoshikazu Kishino¹, Marina Okada¹, Hidenori Tani¹, Yusuke Soma¹, Kazuaki Nakajima¹, Hideaki Kanazawa¹, Masahiro Sugimoto^{9

10}, Minoru S H Ko⁸, Makoto Suematsu⁵, Keiichi Fukuda¹

Affiliations

¹ Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
² Department of Emergency and Critical Care Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
³ Department of Organ Fabrication, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
⁴ Endowed Course for Severe Heart Failure Treatment II, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
⁵ Department of Biochemistry, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
⁶ Clinical and Translational Research Center, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
⁷ Lipidome Lab Co., Ltd., Akita 010-0825, Japan.
⁸ Department of Systems Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
⁹ Research and Development Center for Minimally Invasive Therapies Health Promotion and Preemptive Medicine, Tokyo Medical University, Shinjuku, Tokyo 160-8402, Japan.
¹⁰ Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.

Abstract

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.

Keywords: Biological Sciences; Cell Biology; Metabolic Flux Analysis; Metabolomics; Proteomics; Stem Cells Research.