title: Inhibition of an NAD⁺ salvage pathway provides efficient and selective toxicity to human pluripotent stem cells.
abstract: The tumorigenic potential of human pluripotent stem cells (hPSCs) is a major limitation to the widespread use of hPSC derivatives in the clinic. Here, we demonstrate that the small molecule STF-31 is effective at eliminating undifferentiated hPSCs across a broad range of cell culture conditions with important advantages over previously described methods that target metabolic processes. Although STF-31 was originally described as an inhibitor of glucose transporter 1, these data support the reclassification of STF-31 as a specific NAD⁺ salvage pathway inhibitor through the inhibition of nicotinamide phosphoribosyltransferase (NAMPT). These findings demonstrate the importance of an NAD⁺ salvage pathway in hPSC biology and describe how inhibition of NAMPT can effectively eliminate hPSCs from culture. These results will advance and accelerate the development of safe, clinically relevant hPSC-derived cell-based therapies.
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Kropp
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Bryndon J
authors.initials: BJ
authors.lastname: Oleson
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Broniowska
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Subarna
authors.initials: S
authors.lastname: Bhattacharya
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Chadwick
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Diers
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Qinghui
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Hogg
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Boheler
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Corbett
authors.affiliation: Department of Biochemistry, Department of Biophysics, Redox Biology Program, and Department of Medicine, Division of Endocrinology, Metabolism and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; Department of Physiology, Stem Cell and Regenerative Medicine Consortium, Li Ka Shing Faculty of Medicine, Hong Kong University, Hong Kong, Special Administrative Region of the People's Republic of China; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA rgundry@mcw.edu.
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Gundry
mesh_terms: D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects*; D016207:Cytokines / Q000037:antagonists & inhibitors; D006801:Humans; D009243:NAD / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D016207:Cytokines; D011725:Pyridines; C000599307:STF-31; D054852:Small Molecule Libraries; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human
keywords: Human pluripotent stem cells; Metabolism; NAD; Salvage pathway; Selective toxicity
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