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Stem Cell Reports. 2018 Nov 13;11(5):1244-1256. doi: 10.1016/j.stemcr.2018.09.002. Epub 2018 Oct 4.

Selective Elimination of Culture-Adapted Human Embryonic Stem Cells with BH3 Mimetics.

Author information

1
Department of Life Sciences, Sogang University, Seoul 04107, Republic of Korea.
2
School of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
3
Department of Medicine, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
4
Ewha Research Center for Systems Biology, Division of Molecular & Life Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
5
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Republic of Korea.
6
Department of Medicine, School of Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea. Electronic address: sunghwanmoon@kku.ac.kr.
7
School of Pharmacy, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea. Electronic address: hjcha93@snu.ac.kr.

Abstract

The selective survival advantage of culture-adapted human embryonic stem cells (hESCs) is a serious safety concern for their clinical application. With a set of hESCs with various passage numbers, we observed that a subpopulation of hESCs at late passage numbers was highly resistant to various cell death stimuli, such as YM155, a survivin inhibitor. Transcriptome analysis from YM155-sensitive (YM155S) and YM155-resistant (YM155R) hESCs demonstrated that BCL2L1 was highly expressed in YM155R hESCs. By matching the gene signature of YM155R hESCs with the Cancer Therapeutics Response Portal dataset, BH3 mimetics were predicted to selectively ablate these cells. Indeed, short-course treatment with a sub-optimal dose of BH3 mimetics induced the spontaneous death of YM155R, but not YM155S hESCs by disrupting the mitochondrial membrane potential. YM155S hESCs remained pluripotent following BH3 mimetics treatment. Therefore, the use of BH3 mimetics is a promising strategy to specifically eliminate hESCs with a selective survival advantage.

KEYWORDS:

BCL-xL; BCL2L1; BH3 mimetics; CTRP; YM155; culture adaptation; survival advantage

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