Wnt of the two horizons: putting stem cell self-renewal and cell fate determination into context

The canonical Wnt/β-catenin pathway has long been associated with self-renewal and expansion of embryonic stem cells (ESCs). Recent studies have brought into question some earlier assumptions concerning the functional role that canonical Wnt signaling plays in self-renewal mechanisms by demonstrating clear effects on differentiation. In addition, Wnt is crucial for cell fate determination during embryogenesis. The seemingly contradictory data compiled over several years now point to a more complex system of organismal development by which the downstream effects of Wnt activity are largely determined by the context in which signaling occurs. This review will assess seemingly contradictory findings regarding Wnt signaling in either self-renewal or differentiation in ESCs and then explicate cellular scenarios that determine the context by which Wnt ligands exert their differential effects. Both physiological embryonic development and pathogenic adult carcinogenesis provide opportunities to gleam illuminating insights from stem or stem-like progenitor cells that place Wnt signaling at the center of important cellular decisions to expand or differentiate. The impact of heterogeneity, concentration, metabolic state, and the array of accessible interacting cofactors from various signaling pathways that regulate these functions in ESCs will be critically examined, and implications for early embryonic development and cancer biology will be explored.