RRC ID 62290
Author Alsayegh K, Matsuura K, Sekine H, Shimizu T.
Title Dinaciclib potently suppresses MCL-1 and selectively induces the cell death in human iPS cells without affecting the viability of cardiac tissue.
Journal Sci Rep
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.
Volume 7
Pages 45577
Published 2017-3-31
DOI 10.1038/srep45577
PII srep45577
PMID 28361959
PMC PMC5374522
MeSH Animals Apoptosis / drug effects Bridged Bicyclo Compounds, Heterocyclic / pharmacology* Cell Death / drug effects* Cell Differentiation / drug effects Cell Line Cell Survival / drug effects* Cyclic N-Oxides Cyclin-Dependent Kinase 9 / metabolism Down-Regulation / drug effects Humans Indolizines Induced Pluripotent Stem Cells / drug effects Induced Pluripotent Stem Cells / metabolism Mice Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors* Myocytes, Cardiac / drug effects* Myocytes, Cardiac / metabolism Nanog Homeobox Protein / metabolism Proto-Oncogene Proteins c-myc / metabolism Pyridinium Compounds / pharmacology* Rats Rats, Nude Transcription, Genetic / drug effects
IF 3.998
Human and Animal Cells 253G1(HPS0002) 201B7(HPS0063)