PUBLICATION
A new class of pluripotent stem cell cytotoxic small molecules
- Authors
- Richards, M., Phoon, C.W., Goh, G.T., Seng, E.K., Guo, X.M., Tan, C.M., Chan, W.K., Lee, J.M.
- ID
- ZDB-PUB-140513-314
- Date
- 2014
- Source
- PLoS One 9: e85039 (Journal)
- Registered Authors
- Chan, Woon-Khiong
- Keywords
- none
- MeSH Terms
-
- Activating Transcription Factor 4/antagonists & inhibitors
- Activating Transcription Factor 4/genetics
- Activating Transcription Factor 4/metabolism
- Animals
- Cell Differentiation
- Cell Survival/drug effects
- Cells, Cultured
- Cytotoxins/chemical synthesis
- Cytotoxins/pharmacology*
- Embryo, Nonmammalian/drug effects
- Embryo, Nonmammalian/physiology
- Endoplasmic Reticulum Stress/drug effects
- Endoplasmic Reticulum Stress/genetics
- Gene Expression Regulation
- Humans
- Mice
- Mice, SCID
- Myocytes, Cardiac/cytology
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/metabolism
- Neurons/cytology
- Neurons/drug effects
- Neurons/metabolism
- Organ Specificity
- Pluripotent Stem Cells/cytology
- Pluripotent Stem Cells/drug effects*
- Pluripotent Stem Cells/metabolism
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Reactive Oxygen Species/antagonists & inhibitors
- Reactive Oxygen Species/metabolism
- Signal Transduction
- Small Molecule Libraries/chemical synthesis
- Small Molecule Libraries/pharmacology*
- Stem Cell Transplantation
- Structure-Activity Relationship
- Teratoma/prevention & control*
- Transcription Factor CHOP/antagonists & inhibitors
- Transcription Factor CHOP/genetics
- Transcription Factor CHOP/metabolism
- Zebrafish
- eIF-2 Kinase/antagonists & inhibitors
- eIF-2 Kinase/genetics
- eIF-2 Kinase/metabolism
- PubMed
- 24647085 Full text @ PLoS One
Citation
Richards, M., Phoon, C.W., Goh, G.T., Seng, E.K., Guo, X.M., Tan, C.M., Chan, W.K., Lee, J.M. (2014) A new class of pluripotent stem cell cytotoxic small molecules. PLoS One. 9:e85039.
Abstract
A major concern in Pluripotent Stem Cell (PSC)-derived cell replacement therapy is the risk of teratoma formation from contaminating undifferentiated cells. Removal of undifferentiated cells from differentiated cultures is an essential step before PSC-based cell therapies can be safely deployed in a clinical setting. We report a group of novel small molecules that are cytotoxic to PSCs. Our data indicates that these molecules are specific and potent in their activity allowing rapid eradication of undifferentiated cells. Experiments utilizing mixed PSC and primary human neuronal and cardiomyocyte cultures demonstrate that up to a 6-fold enrichment for specialized cells can be obtained without adversely affecting cell viability and function. Several structural variants were synthesized to identify key functional groups and to improve specificity and efficacy. Comparative microarray analysis and ensuing RNA knockdown studies revealed involvement of the PERK/ATF4/DDIT3 ER stress pathway. Surprisingly, cell death following ER stress induction was associated with a concomitant decrease in endogenous ROS levels in PSCs. Undifferentiated cells treated with these molecules preceding transplantation fail to form teratomas in SCID mice. Furthermore, these molecules remain non-toxic and non-teratogenic to zebrafish embryos suggesting that they may be safely used in vivo.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping