Abstract
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 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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Biomarkers
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Brain / cytology
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Brain / physiology
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Brain / surgery
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Lineage / drug effects
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Cell Lineage / physiology
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Cells, Cultured
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Ceramides / pharmacology*
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DNA-Binding Proteins / metabolism
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Hippocampus / cytology
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Hippocampus / metabolism
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Humans
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Intermediate Filament Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Nerve Tissue Proteins / metabolism
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Nestin
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Neurons / physiology
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Neurons / transplantation*
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Octamer Transcription Factor-3
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Oleic Acids / pharmacology
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / drug effects*
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Pluripotent Stem Cells / physiology
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Propylene Glycols / pharmacology
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Stem Cell Transplantation / adverse effects
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Stem Cell Transplantation / methods*
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Teratoma / prevention & control*
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Transcription Factors / metabolism
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Tubulin / drug effects
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Tubulin / metabolism
Substances
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Apoptosis Regulatory Proteins
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Biomarkers
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Ceramides
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DNA-Binding Proteins
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Intermediate Filament Proteins
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Intracellular Signaling Peptides and Proteins
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N-oleoylserinol
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NES protein, human
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Nerve Tissue Proteins
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Nes protein, mouse
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Nestin
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Octamer Transcription Factor-3
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Oleic Acids
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POU5F1 protein, human
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Pou5f1 protein, mouse
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Propylene Glycols
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Transcription Factors
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Tubulin
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prostate apoptosis response-4 protein