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

J Cell Biol. 2004 Nov 22;167(4):723-34. doi: 10.1083/jcb.200405144. Epub 2004 Nov 15.

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

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Brain / cytology
  • Brain / physiology
  • Brain / surgery
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cell Lineage / drug effects
  • Cell Lineage / physiology
  • Cells, Cultured
  • Ceramides / pharmacology*
  • DNA-Binding Proteins / metabolism
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Humans
  • Intermediate Filament Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Nerve Tissue Proteins / metabolism
  • Nestin
  • Neurons / physiology
  • Neurons / transplantation*
  • Octamer Transcription Factor-3
  • Oleic Acids / pharmacology
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / drug effects*
  • Pluripotent Stem Cells / physiology
  • Propylene Glycols / pharmacology
  • Stem Cell Transplantation / adverse effects
  • Stem Cell Transplantation / methods*
  • Teratoma / prevention & control*
  • Transcription Factors / metabolism
  • Tubulin / drug effects
  • Tubulin / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers
  • Ceramides
  • DNA-Binding Proteins
  • Intermediate Filament Proteins
  • Intracellular Signaling Peptides and Proteins
  • N-oleoylserinol
  • NES protein, human
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Octamer Transcription Factor-3
  • Oleic Acids
  • POU5F1 protein, human
  • Pou5f1 protein, mouse
  • Propylene Glycols
  • Transcription Factors
  • Tubulin
  • prostate apoptosis response-4 protein