P.O. Box 3660, Riyadh 11481, Mail Code 1515 (KAIMRC)
+966 (11) 429-4444
+966 (11) 429-4440

Publication Details

Title :

Dinaciclib potently suppresses MCL-1 and selectively induces the cell death in human iPS cells without affecting the viability of cardiac tissue

Journal:

Nature Scientific Reports

Impact Factor:

5.228

Authors:

Khaled Alsayegh, Katsuhisa Matsuura, Hidekazu Sekine & Tatsuya Shimizu

Affiliations:

·    Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan

Khaled Alsayegh

Katsuhisa Matsuura

Hidekazu Sekine

& Tatsuya Shimizu

·   King Abdullah International Medical Research Center (KAIMRC), King Saudi bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia

Khaled Alsayegh

·   Department of Cardiology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku, Tokyo, 162-8666, Japan

Katsuhisa Matsuura

Year of Publication:

2017

DOI:

10.1038/srep45577

Abstract:

Induced pluripotent stem (iPS) cells hold great potential for being a major source of cells for regenerative medicine. One major issue that hinders their advancement to clinic is the persistence of undifferentiated iPS cells in iPS-derived tissue. In this report, we show that the CDKs inhibitor, Dinaciclib, selectively eliminates iPS cells without affecting the viability of cardiac cells. We found that low nanomolar concentration of dinaciclib increased DNA damage and p53 protein levels in iPSCs. This was accompanied by negative regulation of the anti-apoptotic protein MCL-1. Gene knockdown experiments revealed that p53 downregulation only increased the threshold of dinaciclib induced apoptosis in iPS cells. Dinaciclib also inhibited the phosphorylation of Serine 2 of the C-terminal domain of RNA Polyemrase II through CDK9 inhibition. This resulted in the inhibition of transcription of MCL-1 and the pluripotency genes, NANOG and c-MYC. Even though dinaciclib caused a slight downregulation of MCL-1 in iPS-derived cardiac cells, the viability of the cells was not significantly affected, and beating iPS-derived cardiac cell sheet could still be fabricated. These findings suggest a difference in tolerance of MCL-1 downregulation between iPSCs and iPS-derived cardiac cells which could be exploited to eliminate remaining iPS cells in bioengineered cell sheet tissues.