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Published online 15 November 2004. doi:10.1083/jcb.200405144
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 4, 723-734
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Article

Selective apoptosis of pluripotent mouse and human stem cells by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell–derived neural transplants



Erhard Bieberich1, Jeane Silva1, Guanghu Wang1, Kannan Krishnamurthy1, and Brian G. Condie1,2

1 Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, GA 30912
2 University of Georgia, Department of Genetics, University of Georgia, Athens, GA 30602

Correspondence to Erhard Bieberich: ebieberich{at}mail.mcg.edu; or Brian G. Condie: bcondie{at}mail.mcg.edu

The formation of stem cell–derived tumors (teratomas) is observed when engrafting undifferentiated embryonic stem (ES) cells, embryoid body–derived cells (EBCs), or mammalian embryos and is a significant obstacle to stem cell therapy. We show that in tumors formed after engraftment of EBCs into mouse brain, expression of the pluripotency marker Oct-4 colocalized with that of prostate apoptosis response-4 (PAR-4), a protein mediating ceramide-induced apoptosis during neural differentiation of ES cells. We tested the ability of the novel ceramide analogue N-oleoyl serinol (S18) to eliminate mouse and human Oct-4(+)/PAR-4(+) cells and to increase the proportion of nestin(+) neuroprogenitors in EBC-derived cell cultures and grafts. S18-treated EBCs persisted in the hippocampal area and showed neuronal lineage differentiation as indicated by the expression of ß-tubulin III. However, untreated cells formed numerous teratomas that contained derivatives of endoderm, mesoderm, and ectoderm. Our results show for the first time that ceramide-induced apoptosis eliminates residual, pluripotent EBCs, prevents teratoma formation, and enriches the EBCs for cells that undergo neural differentiation after transplantation.

Abbreviations used in this paper: EB, embryoid body; EBC, EB-derived cell; ES; embryonic stem; FLICA, fluorochrome inhibitor of caspase; MACS, magnetic-activated cell sorting; NP, neuroprogenitor; PAR-4, prostate apoptosis response-4.


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