Brief Reports: Controlling the Survival of Human Pluripotent Stem Cells by Small Molecule-Based Targeting of Topoisomerase II Alpha. (17th February 2015)

• Record Type: Journal Article
• Authors: Ben-David, Uri; Cowell, Ian G.; Austin, Caroline A.; Benvenisty, Nissim
• Is Part Of: Stem cells. Volume 33:Number 3(2015:Mar.)
• Page Start: 1013
• Page End: 1019
• Publication Date: 2015-02-17
• Subjects: Pluripotent stem cells -- Embryonic stem cells -- Induced pluripotent stem cells -- Cell biology -- Cancer -- Tumorigenicity -- Cell death; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.1888
• Languages: English
• ISSNs: 1066-5099

Abstract

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. Stem Cells 2015;33:1013–1019