Adequate hypoxia inducible factor 1α signaling is indispensable for bone regeneration

Engineered cell-based constructs are an appealing strategy to treat large skeletal defects. However, transplanted cells are often confronted with an environment that is deprived of oxygen and nutrients. Upon hypoxia, most cell types activate hypoxia-inducible factor 1α (HIF-1α) signaling, but its importance for implanted osteoprogenitor cells during bone regeneration is not elucidated. To this end, we specifically deleted the HIF--1α isoform in periosteal progenitor cells and show that activation of HIF-1α signaling in these cells is critical for bone repair by modulating angiogenic and metabolic processes. Activation of HIF-1α is not only crucial for blood vessel invasion, by enhancing angiogenic growth factor production, but also for periosteal cell survival early after implantation, when blood vessels have not yet invaded the construct. HIF-1α signaling limits oxygen consumption to avoid accumulation of harmful ROS and preserve redox balance, and additionally induces a switch to glycolysis to prevent energetic distress. Altogether, our results indicate that the proangiogenic capacity of implanted periosteal cells is HIF-1α regulated and that metabolic adaptations mediate post-implantation cell survival.