Mifepristone-inducible caspase-1 expression in mouse embryonic stem cells eliminates tumor formation but spares differentiated cells in vitro and in vivo.

Abstract

Embryonic stem cell (ESC)-based therapy is a promising treatment for neurodegenerative diseases. But there is always a risk of tumor formation that is due to contamination of undifferentiated ESCs. To reduce the risk and improve ESC-based therapy, we have established a novel strategy by which we can selectively eliminate tumor cells derived from undifferentiated ESCs but spare differentiated cells. In this study, we generated a caspase-1-ESC line transfected with a mifepristone-regulated caspase-1 expression system. Mifepristone induced caspase-1 overexpression both in differentiated and undifferentiated caspase-1-ESCs. All the undifferentiated caspase-1-ESCs were induced to death after mifepristone treatment. Tumors derived from undifferentiated caspase-1-ESCs were eliminated following 3 weeks of mifepristone treatment in vivo. However, differentiated caspase-1-ESCs survived well under the condition of mifepristone-induced caspase-1 overexpression. To examine in vivo the impact of mifepristone-induced caspase-1 activation on grafted cells, we transplanted wild-type ESCs or caspase-1-ESCs into nude mice brains. After 8 weeks of mifepristone treatment, we could not detect any tumor cells in the caspase-1-ESC grafts in the brains of mice. However, we found that donor dopamine neurons survived in the recipient brains. These data demonstrate that mifepristone-induced caspase-1 overexpression in ESCs can eliminate the potential tumor formation meanwhile spares the differentiated cells in the host brains. These results suggest that this novel ESC-based therapy can be used in Parkinson's disease and other related disorders without the risk of tumor formation.

• Authors: Yi Wang, Dehua Yang, Lin Song, Ting Li, Juan Yang, Xiaojie Zhang, Weidong Le
• Journal: Stem cells (Dayton, Ohio) (Stem Cells) Vol. 30 Issue 2 Pg. 169-79 (Feb 2012) ISSN: 1549-4918 [Electronic] England
• PMID: 22131096 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 AlphaMed Press.

Chemical References

• Antineoplastic Agents
• Enzyme Activators
• Green Fluorescent Proteins
• Mifepristone
• Caspase 1

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Caspase 1 (genetics, metabolism)
• Cell Death (drug effects)
• Cell Survival (drug effects)
• Dopaminergic Neurons
• Embryonic Stem Cells (drug effects, enzymology, physiology, transplantation)
• Enzyme Activation
• Enzyme Activators (pharmacology, therapeutic use)
• Female
• Gene Expression Regulation
• Genes, Reporter (drug effects)
• Green Fluorescent Proteins (biosynthesis, genetics)
• Male
• Mice
• Mice, Nude
• Mifepristone (pharmacology, therapeutic use)
• Neoplasms, Experimental (pathology, prevention & control)
• Parkinson Disease (therapy)
• Regenerative Medicine
• Teratoma (pathology, prevention & control)
• Tumor Burden (drug effects)