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Brief Reports: Controlling the Survival of Human Pluripotent Stem Cells by Small Molecule-Based Targeting of Topoisomerase II Alpha

Lookup NU author(s): Dr Ian Cowell, Professor Caroline Austin

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Abstract

Pluripotent-specific inhibitors (PluriSIns) make a powerful tool to study the mechanisms controlling the survival of human pluripotent stem cells (hPSCs). Here, we characterize the mechanism of action of PluriSIn#2, a compound that selectively eliminates undifferentiated hPSCs, while sparing various other cell types derived from them. Toxicogenomic analysis predicts this compound to be a topoisomerase inhibitor. Gene expression analyses reveal that one of the human topoisomerase enzymes, topoisomerase II alpha (TOP2A), is uniquely expressed in hPSCs: TOP2A is highly expressed in undifferentiated cells, is downregulated during their differentiation, and its expression depends on the expression of core pluripotency transcription factors. Furthermore, siRNA-based knockdown of TOP2A in undifferentiated hPSCs results in their cell death, revealing that TOP2A expression is required for the survival of these cells. We find that PluriSIn#2 does not directly inhibit TOP2A enzymatic activity, but rather selectively represses its transcription, thereby significantly reducing TOP2A protein levels. As undifferentiated hPSCs require TOP2A activity for their survival, TOP2A inhibition by PluriSIn#2 thus causes their cell death. Therefore, TOP2A dependency can be harnessed for the selective elimination of tumorigenic hPSCs from culture.


Publication metadata

Author(s): Ben-David U, Cowell IG, Austin CA, Benvenisty N

Publication type: Article

Publication status: Published

Journal: Stem Cells

Year: 2015

Volume: 33

Issue: 3

Pages: 1013-1019

Print publication date: 01/03/2015

Online publication date: 17/02/2015

Acceptance date: 27/09/2014

ISSN (print): 1066-5099

ISSN (electronic): 1549-4918

Publisher: Wiley

URL: http://dx.doi.org/10.1002/stem.1888

DOI: 10.1002/stem.1888


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