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

Seung Ju Cho, Keun Tae Kim, Ho Chang Jeong, Ju Chan Park, Ok Seon Kwon, Yun Ho Song, Joong Gon Shin, Seungmin Kang, Wankyu Kim, Hyoung Doo Shin, Mi Ok Lee, Sung Hwan Moon, Hyuk Jin Cha

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

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. In this article, Cha and colleagues demonstrate that in culture-adapted hESCs, survival advantage toward several genotoxic stresses as well as YM155, a stemtoxic chemical, results from increased Bcl-xL expression. BH3 mimetics, predicted by a bioinformatics tool based on the gene expression signature of culture-adapted hESCs, induces selective cell death while normal hESCs remain functionally intact even after BH3 mimetics exposure.

Original languageEnglish
Pages (from-to)1244-1256
Number of pages13
JournalStem Cell Reports
Volume11
Issue number5
DOIs
StatePublished - 13 Nov 2018

Bibliographical note

Funding Information:
This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare (grant number HI14C3365 ), and by a grant from the National Research Foundation of Korea (NRF) ( 2017M3A9B3061843 and 2017R1A2A2A05000766 ).

Publisher Copyright:
© 2018 The Author(s)

Keywords

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

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