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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

257 Scopus citations

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.

Original languageAmerican English
Pages (from-to)167-179
Number of pages13
JournalCell Stem Cell
Volume12
Issue number2
DOIs
StatePublished - 7 Feb 2013

Bibliographical note

Funding Information:
The authors would like to thank Hong Ma and Adva Maimon for their assistance with tissue culture; Dr. Eric Chiao, Dr. Josh Babiarz, Dr. Jenny Cohen, and Sei Kameoka for their assistance with assay development; Sean Walker for his assistance with the liquid handler; Dr. Ann Hoffman for her assistance with microscopy imaging; Dr. Rachel Eiges for her assistance with the in vitro embryonic development assay and for critically reading the manuscript; Dr. Sonia Steiner-Mordoch and Professor Oded Meyuhas for their assistance with the protein synthesis inhibition assay; Dr. Simona Ceccarelli for her assistance with the chemical analysis of compounds; Tamar Shiloach for her assistance with apoptosis assays; Dr. Eran Meshorer for the mouse ESCs and for critically reading the manuscript; Oded Kopper for the CSES2-SO2/3 cells; Professor Batsheva Kerem, Dr. Kyle Kolaja, Dr. Jacques Mizrahi, and Dr. David Mark for fruitful discussions and helpful suggestions. N.B. is the Herbert Cohn Chair in Cancer Research. U.B.-D. is a Clore Fellow. This work was supported by a grant from Hoffmann La Roche-Yissum collaboration. Q.F.G., M.G., M.B., and G.G. are employees of the company. R.G. and P.A. are former employees of the company.

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