HIF-1α Promotes Glutamine-Mediated Redox Homeostasis and Glycogen-Dependent Bioenergetics to Support Post-Implantation Cell Survival

• Published in: Cell metabolism Vol. 23; no. 2; pp. 265 - 79
• Main Authors: Stegen, Steve, van Gastel, Nick, Eelen, Guy, Ghesquière, Bart, D’Anna, Flora, Thienpont, Bernard, Goveia, Jermaine, Torrekens, Sophie, Van Looveren, Riet, Luyten, Frank P., Maxwell, Patrick H., Wielockx, Ben, Lambrechts, Diether, Fendt, Sarah-Maria, Carmeliet, Peter, Carmeliet, Geert
• Format: Journal Article
• Language: English
• Published: 09.02.2016
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2016.01.002

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 post-implantation 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. Graphical Abstract