Inhibition of an NAD⁺ salvage pathway provides efficient and selective toxicity to human pluripotent stem cells

Area of Science:

• Stem Cell Biology
• Cancer Biology
• Biochemistry

Background:

• Tumorigenic potential of human pluripotent stem cells (hPSCs) hinders clinical applications.
• Existing methods for hPSC elimination have limitations.

Purpose of the Study:

• To identify effective methods for eliminating undifferentiated hPSCs.
• To investigate the role of NAD+ salvage pathways in hPSC biology.

Main Methods:

• Utilized the small molecule STF-31 to treat hPSCs.
• Investigated the mechanism of action of STF-31, including its effect on glucose transporter 1 and NAMPT.
• Assessed the efficacy of STF-31 in eliminating hPSCs across various culture conditions.

Main Results:

• STF-31 effectively eliminates undifferentiated hPSCs under diverse culture conditions.
• Data support reclassifying STF-31 as a specific inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in the NAD+ salvage pathway.
• STF-31 demonstrates advantages over previously described methods targeting metabolic processes.

Conclusions:

• The NAD+ salvage pathway is crucial for hPSC biology.
• Inhibition of NAMPT by STF-31 provides an effective strategy for eliminating hPSCs from cultures.
• These findings pave the way for developing safer, clinically applicable hPSC-derived cell therapies.