title: Adequate hypoxia inducible factor 1α signaling is indispensable for bone regeneration.
abstract: 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.
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Steve
authors.initials: S
authors.lastname: Stegen
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sanne
authors.initials: S
authors.lastname: Deprez
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Torrekens
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Riet
authors.initials: R
authors.lastname: Van Looveren
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Jermaine
authors.initials: J
authors.lastname: Goveia
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.affiliation: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium; Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium. Electronic address: geert.carmeliet@med.kuleuven.be.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D015687:Cell Hypoxia; D002470:Cell Survival; D004734:Energy Metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006019:Glycolysis; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010521:Periosteum / Q000166:cytology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species
keywords: Bone repair; Cell metabolism; Energy homeostasis; Hypoxia inducible factor; Post-implantation survival; Redox balance; Regenerative medicine