title: HIF-1α Promotes Glutamine-Mediated Redox Homeostasis and Glycogen-Dependent Bioenergetics to Support Postimplantation Bone Cell Survival.
abstract: Cell-based therapy is a promising strategy in regenerative medicine, but the poor survival rate of the implanted cells remains a major challenge and limits clinical translation. We preconditioned periosteal cells to the hypoxic and ischemic environment of the bone defect site by deleting prolyl hydroxylase domain-containing protein 2 (PHD2), resulting in hypoxia-inducible factor 1 alpha (HIF-1α) stabilization. This strategy increased postimplantation cell survival and improved bone regeneration. The enhanced cell viability was angiogenesis independent but relied on combined changes in glutamine and glycogen metabolism. HIF-1α stabilization stimulated glutaminase-mediated glutathione synthesis, maintaining redox homeostasis at baseline and during oxidative or nutrient stress. Simultaneously, HIF-1α signaling increased glycogen storage, preventing an energy deficit during nutrient or oxygen deprivation. Pharmacological inhibition of PHD2 recapitulated the adaptations in glutamine and glycogen metabolism and, consequently, the beneficial effects on cell survival. Thus, targeting cellular metabolism is an appealing strategy for bone regeneration and cell-based therapy in general.
authors: 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: Steve
authors: S
authors: Stegen
authors: 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: Nick
authors: N
authors: van Gastel
authors: Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Guy
authors: G
authors: Eelen
authors: Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Bart
authors: B
authors: Ghesquière
authors: Laboratory of Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Flora
authors: F
authors: D'Anna
authors: Laboratory of Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Bernard
authors: B
authors: Thienpont
authors: Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Jermaine
authors: J
authors: Goveia
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
authors: Sophie
authors: S
authors: Torrekens
authors: Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
authors: Riet
authors: R
authors: Van Looveren
authors: Prometheus, Division of Skeletal Tissue Engineering, KU Leuven, 3000 Leuven, Belgium; Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium.
authors: Frank P
authors: FP
authors: Luyten
authors: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XU, UK.
authors: Patrick H
authors: PH
authors: Maxwell
authors: Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01069 Dresden, Germany.
authors: Ben
authors: B
authors: Wielockx
authors: Laboratory of Translational Genetics, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Diether
authors: D
authors: Lambrechts
authors: Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Sarah-Maria
authors: SM
authors: Fendt
authors: Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
authors: Peter
authors: P
authors: Carmeliet
authors: 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: Geert
authors: G
authors: Carmeliet
mesh_terms: D000818:Animals; D001861:Bone Regeneration; D019069:Cell Respiration; D002470:Cell Survival; D004734:Energy Metabolism; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005972:Glutaminase / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism*; D006003:Glycogen / Q000378:metabolism*; D006706:Homeostasis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D018919:Neovascularization, Physiologic; D010011:Osteocytes / Q000378:metabolism / Q000637:transplantation*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010521:Periosteum / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; D005973:Glutamine; D006003:Glycogen; C574238:GLS1 protein, mouse; D005972:Glutaminase