Journal
JOURNAL OF CELL BIOLOGY
Volume 167, Issue 4, Pages 723-734Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200405144
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Funding
- NIMH NIH HHS [R01MH064794, R01 MH064794] Funding Source: Medline
- NINDS NIH HHS [R01NS046835, R01 NS046835] Funding Source: Medline
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The formation of stem cell-derived tumors (teratomas) is observed when engraffing 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-A (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 beta-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.
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