Ceramide leaves stem cells free to form neurons.

Therapeutic use of embryonic stem cells may be hampered by their proclivity to form pluripotent tumors called teratomas. On page 723, Bieberich et al. describe the use of a ceramide analogue, S18, to induce apoptosis in a subpopulation of embryoid body–derived stem cells (EBCs). Cells that survive the treatment express the neural marker nestin and differentiate into neural progenitors when injected into the brains of young mice. They do not form teratomas.

The S18 selectively affects those EBCs that express prostate apoptosis response-4 (PAR-4) protein, an endogenous inhibitor of atypical PKCζ. Significantly, the majority of the PAR-4–expressing cells also express Oct-4, a marker for pluripotency. Almost all Oct-4+ cells were positive for PAR-4, suggesting that teratoma formation might be prevented via elimination of PAR-4-expressing cells with ceramide-induced apoptosis before injection into animals. Sure enough, after injection into the brains of mice, treated cells differentiated into neural cells and some benign tumors, but no invasive tumors. Untreated cells gave rise to a significant number of teratomas in the same animals.

Bieberich et al. hypothesize that coexpression of Oct-4 and PAR-4 may indicate that the expression of PAR-4 is specifically up-regulated at particular stages during ES cell differentiation. Discovering the function and mechanism behind this up-regulation is the next task the team plans to tackle.