TY - JOUR
T1 - Selective apoptosis of pluripotent mouse and human stem cell by novel ceramide analogues prevents teratoma formation and enriches for neural precursors in ES cell-derived neural transplants
AU - Bieberich, Erhard
AU - Silva, Jeane
AU - Wang, Guanghu
AU - Krishnamurthy, Kannan
AU - Condie, Brian G.
PY - 2004/11/22
Y1 - 2004/11/22
N2 - 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 β-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.
AB - 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 β-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.
UR - http://www.scopus.com/inward/record.url?scp=9444265273&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=9444265273&partnerID=8YFLogxK
U2 - 10.1083/jcb.200405144
DO - 10.1083/jcb.200405144
M3 - Article
C2 - 15545317
AN - SCOPUS:9444265273
SN - 0021-9525
VL - 167
SP - 723
EP - 734
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 4
ER -