title: 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: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine & Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Yi
authors: Y
authors: Wang
authors: Dehua
authors: D
authors: Yang
authors: Lin
authors: L
authors: Song
authors: Ting
authors: T
authors: Li
authors: Juan
authors: J
authors: Yang
authors: Xiaojie
authors: X
authors: Zhang
authors: Weidong
authors: W
authors: Le
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059290:Dopaminergic Neurons; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology* / Q000637:transplantation; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015735:Mifepristone / Q000494:pharmacology* / Q000627:therapeutic use; D009374:Neoplasms, Experimental / Q000473:pathology / Q000517:prevention & control; D010300:Parkinson Disease / Q000628:therapy; D044968:Regenerative Medicine; D013724:Teratoma / Q000473:pathology / Q000517:prevention & control; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D020536:Enzyme Activators; D049452:Green Fluorescent Proteins; D015735:Mifepristone; D020170:Caspase 1