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

doi:10.1016/j.stem.2012.11.015

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

Department of Genetics

Research output: Contribution to journal › Article › peer-review

267 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 language	English
Pages (from-to)	167-179
Number of pages	13
Journal	Cell Stem Cell
Volume	12
Issue number	2
DOIs	https://doi.org/10.1016/j.stem.2012.11.015
State	Published - 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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10.1016/j.stem.2012.11.015

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Ben-David, U., Gan, Q. F., Golan-Lev, T., Arora, P., Yanuka, O., Oren, Y. S., Leikin-Frenkel, A., Graf, M., Garippa, R., Boehringer, M., Gromo, G., & Benvenisty, N. (2013). Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell, 12(2), 167-179. https://doi.org/10.1016/j.stem.2012.11.015

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title = "Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen",

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.",

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

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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Ben-David, U, Gan, QF, Golan-Lev, T, Arora, P, Yanuka, O, Oren, YS, Leikin-Frenkel, A, Graf, M, Garippa, R, Boehringer, M, Gromo, G & Benvenisty, N 2013, 'Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen', Cell Stem Cell, vol. 12, no. 2, pp. 167-179. https://doi.org/10.1016/j.stem.2012.11.015

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AU - Gan, Qing Fen

AU - Golan-Lev, Tamar

AU - Arora, Payal

AU - Yanuka, Ofra

AU - Oren, Yifat S.

AU - Leikin-Frenkel, Alicia

AU - Graf, Martin

AU - Garippa, Ralph

AU - Boehringer, Markus

AU - Gromo, Gianni

AU - Benvenisty, Nissim

N1 - 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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N2 - 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.

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Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen

Abstract

Bibliographical note

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