O2 regulates stem cells through Wnt/β-catenin signalling

Stem cells reside in specialized microenvironments or 'niches' that regulate their function. In vitro studies using hypoxic culture conditions (< 5% O-2) have revealed strong regulatory links between O-2 availability and functions of stem and precursor cells(1-6). Although some stem cells are perivascular, others may occupy hypoxic niches and be regulated by O-2 gradients. However, the underlying mechanisms remain unclear. Here, we show that hypoxia inducible factor-1 alpha (HIF-1 alpha), a principal mediator of hypoxic adaptations, modulates Wnt/beta-catenin signalling in hypoxic embryonic stem (ES) cells by enhancing beta-catenin activation and expression of the downstream effectors LEF-1 and TCF-1. This regulation extends to primary cells, including isolated neural stem cells (NSCs), and is not observed in differentiated cells. In vivo, Wnt/beta-catenin activity is closely associated with low O-2 regions in the subgranular zone of the hippocampus, a key NSC niche(7). Hif-1 alpha deletion impairs hippocampal Wnt-dependent processes, including NSC proliferation, differentiation and neuronal maturation. This decline correlates with reduced Wnt/beta-catenin signalling in the subgranular zone. O-2 availability, therefore, may have a direct role in stem cell regulation through HIF-1 alpha modulation of Wnt/beta-catenin signalling.