Cell Biology Select

The unique characteristics of stem cells—their ability to self-renew and to differentiate into many different cell types—has prompted hopes that they can be exploited to boost regeneration of damaged tissues. A first step in commandeering these cells for therapeutic benefit is to elucidate the key molecules and pathways that govern stem cell self-renewal and differentiation. Using embryonic, neural, and germ stem cells, a cluster of recent studies take on this task. Their results reveal the daunting complexity of stem cell biology with different types of stem cells relying on different molecules to direct self-renewal and differentiation decisions. There is much interest in delineating the molecules that imbue the most primitive stem cells, embryonic stem (ES) cells, with their remarkable pluripotency. Three core transcription factors have so far been identified—Nanog, Sox2, and Oct4— with at least two other key factors rumored to exist. An elegant series of experiments by Austin Smith and colleagues (Silva et al., 2006) reveal that Nanog has the ability to reprogram a mouse neural stem cell so that it acquires the characteristics of a plu-ripotent ES cell. First, the investigators fused mouse ES cells overexpressing Nanog with mouse neural stem cells to form hybrids, each containing a tetraploid nucleus. Overexpression of Nanog enabled recovery of dramatically increased numbers of hybrids. Critically, the hybrids expressed embryonic genes (such as Oct4 and XIST) from the neural genome, whereas expression of neural genes (such as Olig2 and Blbp) was repressed. In addition, the hybrid nucleus lacked certain repressive histone marks, suggesting that the neural stem cell epigenome had been reprogrammed to a more primitive state. Next came a key experiment: hybrids were released from Nanog's control (by excising the Nanog overexpression cassette) and were allowed to form embryoid bodies. The embryoid bodies expressed markers for endoderm and mesoderm, which are not expressed by either ES cells or neural stem cells, indicating that the hybrid-derived embryoid bodies have the capacity for differentiation into multiple cell lineages. Nanog does not act alone, however, because enforced expression of Nanog in neural stem cells is insufficient to alter their phenotype. Therefore, Nanog must cooperate with other ES cell factors to deprogram the neural stem cell genome and reset pluripotency. Elucidating how to deprogram differentiated cells may increase the feasibility of ES cell-based therapies by circumventing the need for a nuclear transfer step. For ES cells to be of value for regenerating damaged tissues, they …