期刊
CELL METABOLISM
卷 23, 期 2, 页码 265-279出版社
CELL PRESS
DOI: 10.1016/j.cmet.2016.01.002
关键词
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资金
- Fund for Scientific Research-Flanders [FWO: G.0835.11, G.0A72.13, G.096414]
- Flemish Government
- Marie Curie-CIG
- FWO-Odysseus
- Concern Foundation
- FWO-Research Grants
- Bayer Health Care
- KUL-GOA [3M120209]
- National Institute for Health Research [NF-SI-0514-10122, NF-SI-0507-10315] Funding Source: researchfish
- Wellcome Trust [096956/Z/11/Z] Funding Source: researchfish
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-1 alpha) 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-1 alpha stabilization stimulated glutaminase-mediated glutathione synthesis, maintaining redox homeostasis at baseline and during oxidative or nutrient stress. Simultaneously, HIF-1 alpha 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.
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