Controlling the stem cell compartment and regeneration in vivo: the role of pluripotency pathways

Since the realization that embryonic stem cells are maintained in a pluripotent state through the interplay of a number of key signal transduction pathways, it is becoming increasingly clear that stemness and pluripotency are defined by the complex molecular convergence of these pathways. Perhaps this has most clearly been demonstrated by the capacity to induce pluripotency in differentiated cell types, so termed iPS cells. We are therefore building an understanding of how cells may be maintained in a pluripotent state, and how we may manipulate cells to drive them between committed and pluripotent compartments. However, it is less clear how cells normally pass in and out of the stem cell compartment under normal and diseased physiological states in vivo, and indeed, how important these pathways are in these settings. It is also clear that there is a potential "dark side" to manipulating the stem cell compartment, as deregulation of somatic stem cells is being increasingly implicated in carcinogenesis and the generation of "cancer stem cells." This review explores these relationships, with a particular focus on the role played by key molecular regulators of stemness in tissue repair, and the possibility that a better understanding of this control may open the door to novel repair strategies in vivo. The successful development of such strategies has the potential to replace or augment intervention-based strategies (cell replacement therapies), although it is clear they must be developed with a full understanding of how such approaches might also influence tumorigenesis.