Inhibition of an NAD+ Salvage Pathway Provides Efficient and Selective Toxicity to Human Pluripotent Stem Cells

• Published in: Stem cells translational medicine Vol. 4; no. 5; pp. 483 - 493
• Main Authors: Kropp, Erin M., Oleson, Bryndon J., Broniowska, Katarzyna A., Bhattacharya, Subarna, Chadwick, Alexandra C., Diers, Anne R., Hu, Qinghui, Sahoo, Daisy, Hogg, Neil, Boheler, Kenneth R., Corbett, John A., Gundry, Rebekah L.
• Format: Journal Article
• Language: English
• Published: Durham, NC, USA AlphaMed Press 01.05.2015; Oxford University Press
• Subjects: Cell culture; Cell Culture Techniques; Cell Differentiation - drug effects; Cytokines - antagonists & inhibitors; Cytotoxicity; Data analysis; Data collection; Enabling Technologies for Cell-Based Clinical Translation; Glucose; Glucose transporter; Grants; Human pluripotent stem cells; Humans; Metabolism; Metabolites; NAD; NAD - antagonists & inhibitors; NAD - metabolism; Nicotinamide; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Phosphoribosyltransferase; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pyridines - pharmacology; Reclassification; Salvage pathway; Selective toxicity; Signal Transduction - drug effects; Small Molecule Libraries - pharmacology; Stem cells; Studies; Toxicity; Writing; NAD; Salvage pathway; Human pluripotent stem cells; Metabolism; Selective toxicity
• ISSN: 2157-6564; 2157-6580
• DOI: 10.5966/sctm.2014-0163

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. This study demonstrates that small molecule STF‐31 effectively eliminates undifferentiated human pluripotent stem cells (hPSCs) across a broad range of cell culture conditions with important advantages over previously described methods that target metabolic processes. The results demonstrate the importance of an NAD+ salvage pathway in hPSC biology and describe how inhibition of nicotinamide phosphoribosyltransferase can eliminate hPSCs from culture, advancing development of safe, clinically relevant hPSC‐derived cell‐based therapies.