PAR-4 in the Regulation of Stem Cell Death and Embryo Development

Prostate apoptosis response-4 (PAR-4) is widely known to induce apoptosis in cancer cells, suggesting that it may also regulate cell death in other rapidly dividing cell types, particularly stem cells. In fact, the stem cell niche was one of the first tissues that were found to express high levels of PAR-4, suggesting that PAR-4 regulates cell death during stem cell differentiation and embryo morphogenesis. In the last two decades, embryonic stem (ES) cells or induced pluripotent stem (iPS) cells emerged as a source for tissue regeneration or repair, using stem cell therapy. However, stem cell therapy is hampered by unwanted transformation of ES or iPS cells into tumorigenic tissue. Currently, there are only limited intervention strategies available to prevent tumor growth from pluripotent stem cells, which is a major obstacle in stem cell therapy using ES or iPS cell-derived progenitor cell transplants. Research from our laboratory demonstrated that PAR-4 mediated apoptosis regulates differentiation of neural progenitor cells (NPCs) during brain development and activation of PAR-4 is a viable strategy to eliminate tumorigenic stem cells from NPC transplants. We discovered that activation of PAR-4 in these cells is achieved by upregulation of a sphingolipid, ceramide, that partners with PAR-4 to induce apoptosis. Simultaneous increase of ceramide and PAR-4 levels eliminates tumorigenic stem cells and regulates stem cell survival during normal development. This chapter discusses mechanisms underlying apoptosis induction by ceramide and PAR-4 during stem cell differentiation and tissue development, as well as novel strategies to utilize these mechanisms as a means to make stem cell therapy safer.