PMID- 26863487
OWN - NLM
STAT- MEDLINE
DCOM- 20161031
LR  - 20210627
IS  - 1932-7420 (Electronic)
IS  - 1550-4131 (Print)
IS  - 1550-4131 (Linking)
VI  - 23
IP  - 2
DP  - 2016 Feb 9
TI  - HIF-1alpha Promotes Glutamine-Mediated Redox Homeostasis and Glycogen-Dependent 
      Bioenergetics to Support Postimplantation Bone Cell Survival.
PG  - 265-79
LID - S1550-4131(16)00036-X [pii]
LID - 10.1016/j.cmet.2016.01.002 [doi]
AB  - 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-1alpha) 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-1alpha stabilization stimulated glutaminase-mediated glutathione synthesis, 
      maintaining redox homeostasis at baseline and during oxidative or nutrient 
      stress. Simultaneously, HIF-1alpha 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.
CI  - Copyright (c) 2016 Elsevier Inc. All rights reserved.
FAU - Stegen, Steve
AU  - Stegen S
AD  - 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.
FAU - van Gastel, Nick
AU  - van Gastel N
AD  - 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.
FAU - Eelen, Guy
AU  - Eelen G
AD  - Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, 
      Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Ghesquiere, Bart
AU  - Ghesquiere B
AD  - Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, 
      Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - D'Anna, Flora
AU  - D'Anna F
AD  - Laboratory of Translational Genetics, Vesalius Research Center, Department of 
      Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Thienpont, Bernard
AU  - Thienpont B
AD  - Laboratory of Translational Genetics, Vesalius Research Center, Department of 
      Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Goveia, Jermaine
AU  - Goveia J
AD  - Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, 
      Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Torrekens, Sophie
AU  - Torrekens S
AD  - Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and 
      Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
FAU - Van Looveren, Riet
AU  - Van Looveren R
AD  - Laboratory of Clinical and Experimental Endocrinology, Department of Clinical and 
      Experimental Medicine, KU Leuven, 3000 Leuven, Belgium.
FAU - Luyten, Frank P
AU  - Luyten FP
AD  - 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.
FAU - Maxwell, Patrick H
AU  - Maxwell PH
AD  - Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 
      0XU, UK.
FAU - Wielockx, Ben
AU  - Wielockx B
AD  - Heisenberg Research Group, Department of Clinical Pathobiochemistry, Institute 
      for Clinical Chemistry and Laboratory Medicine, Technische Universitat Dresden, 
      01069 Dresden, Germany.
FAU - Lambrechts, Diether
AU  - Lambrechts D
AD  - Laboratory of Translational Genetics, Vesalius Research Center, Department of 
      Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Fendt, Sarah-Maria
AU  - Fendt SM
AD  - Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research 
      Center, Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Carmeliet, Peter
AU  - Carmeliet P
AD  - Laboratory of Angiogenesis & Vascular Metabolism, Vesalius Research Center, 
      Department of Oncology, KU Leuven/VIB, 3000 Leuven, Belgium.
FAU - Carmeliet, Geert
AU  - Carmeliet G
AD  - 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.
LA  - eng
GR  - 096956/WT_/Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cell Metab
JT  - Cell metabolism
JID - 101233170
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Reactive Oxygen Species)
RN  - 0RH81L854J (Glutamine)
RN  - 9005-79-2 (Glycogen)
RN  - EC 3.5.1.2 (GLS1 protein, mouse)
RN  - EC 3.5.1.2 (Glutaminase)
SB  - IM
MH  - Animals
MH  - Bone Regeneration
MH  - Cell Respiration
MH  - Cell Survival
MH  - *Energy Metabolism
MH  - Gene Deletion
MH  - Gene Knockdown Techniques
MH  - Gene Silencing
MH  - Glutaminase/metabolism
MH  - Glutamine/*metabolism
MH  - Glycogen/*metabolism
MH  - *Homeostasis
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism
MH  - Mice
MH  - Neovascularization, Physiologic
MH  - Osteocytes/metabolism/*transplantation
MH  - Oxidation-Reduction
MH  - Oxidative Stress
MH  - Periosteum/pathology
MH  - Reactive Oxygen Species/metabolism
PMC - PMC7611069
MID - EMS127989
EDAT- 2016/02/11 06:00
MHDA- 2016/11/01 06:00
PMCR- 2021/06/24
CRDT- 2016/02/11 06:00
PHST- 2015/04/28 00:00 [received]
PHST- 2015/10/19 00:00 [revised]
PHST- 2016/01/02 00:00 [accepted]
PHST- 2016/02/11 06:00 [entrez]
PHST- 2016/02/11 06:00 [pubmed]
PHST- 2016/11/01 06:00 [medline]
PHST- 2021/06/24 00:00 [pmc-release]
AID - S1550-4131(16)00036-X [pii]
AID - 10.1016/j.cmet.2016.01.002 [doi]
PST - ppublish
SO  - Cell Metab. 2016 Feb 9;23(2):265-79. doi: 10.1016/j.cmet.2016.01.002.