Selective Elimination of Human Pluripotent Stem Cells by an Oleate Synthesis Inhibitor Discovered in a High-Throughput Screen

Uri Ben-David, Qing-Fen Gan, Tamar Golan-Lev, Payal Arora, Ofra Yanuka, Yifat S Oren, Alicia Leikin-Frenkel, Martin Graf, Ralph Garippa, Markus Boehringer, Gianni Gromo, Nissim Benvenisty

Cell Stem Cell. 2013 Feb 7;12(2):167-79.

PMID: 23318055

Abstract:

The use of human pluripotent stem cells (hPSCs) in cell therapy is hindered by the tumorigenic risk from residual undifferentiated cells. Here we performed a high-throughput screen of over 52,000 small molecules and identified 15 pluripotent cell-specific inhibitors (PluriSIns), nine of which share a common structural moiety. The PluriSIns selectively eliminated hPSCs while sparing a large array of progenitor and differentiated cells. Cellular and molecular analyses demonstrated that the most selective compound, PluriSIn #1, induces ER stress, protein synthesis attenuation, and apoptosis in hPSCs. Close examination identified this molecule as an inhibitor of stearoyl-coA desaturase (SCD1), the key enzyme in oleic acid biosynthesis, revealing a unique role for lipid metabolism in hPSCs. PluriSIn #1 was also cytotoxic to mouse blastocysts, indicating that the dependence on oleate is inherent to the pluripotent state. Finally, application of PluriSIn #1 prevented teratoma formation from tumorigenic undifferentiated cells. These findings should increase the safety of hPSC-based treatments.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP91396882	PluriSIn #1		91396-88-2	Price