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.
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.
Bieberich
Erhard
E
Institute of Molecular Medicine and Genetics, School of Medicine, Medical College of Georgia, Augusta, GA 30912, USA. ebieberich@mail.mcg.edu
Silva
Jeane
J
Wang
Guanghu
G
Krishnamurthy
Kannan
K
Condie
Brian G
BG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D001921:Brain / Q000166:cytology / Q000502:physiology / Q000601:surgery; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009474:Neurons / Q000502:physiology / Q000637:transplantation*; D050814:Octamer Transcription Factor-3; D009829:Oleic Acids / Q000494:pharmacology; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D011409:Propylene Glycols / Q000494:pharmacology; D033581:Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D013724:Teratoma / Q000517:prevention & control*; D014157:Transcription Factors / Q000378:metabolism; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; D002518:Ceramides; D004268:DNA-Binding Proteins; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; C495214:N-oleoylserinol; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D050814:Octamer Transcription Factor-3; D009829:Oleic Acids; C494173:POU5F1 protein, human; C494174:Pou5f1 protein, mouse; D011409:Propylene Glycols; D014157:Transcription Factors; D014404:Tubulin; C101296:prostate apoptosis response-4 protein