title: Quiescence Preconditioned Human Multipotent Stromal Cells Adopt a Metabolic Profile Favorable for Enhanced Survival under Ischemia.
abstract: A major impediment to the development of therapies with mesenchymal stem cells/multipotent stromal cells (MSC) is the poor survival and engraftment of MSCs at the site of injury. We hypothesized that lowering the energetic demand of MSCs by driving them into a quiescent state would enhance their survival under ischemic conditions. Human MSCs (hMSCs) were induced into quiescence by serum deprivation (SD) for 48 hours. Such preconditioned cells (SD-hMSCs) exhibited reduced nucleotide and protein syntheses compared to unpreconditioned hMSCs. SD-hMSCs sustained their viability and their ATP levels upon exposure to severe, continuous, near-anoxia (0.1% O2) and total glucose depletion for up to 14 consecutive days in vitro, as they maintained their hMSC multipotential capabilities upon reperfusion. Most importantly, SD-hMSCs showed enhanced viability in vivo for the first week postimplantation in mice. Quiescence preconditioning modified the energy-metabolic profile of hMSCs: it suppressed energy-sensing mTOR signaling, stimulated autophagy, promoted a shift in bioenergetic metabolism from oxidative phosphorylation to glycolysis and upregulated the expression of gluconeogenic enzymes, such as PEPCK. Since the presence of pyruvate in cell culture media was critical for SD-hMSC survival under ischemic conditions, we speculate that these cells may utilize some steps of gluconeogenesis to overcome metabolic stress. These findings support that SD preconditioning causes a protective metabolic adaptation that might be taken advantage of to improve hMSC survival in ischemic environments. Stem Cells 2017;35:181-196.
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Adrien
authors: A
authors: Moya
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Nathanaël
authors: N
authors: Larochette
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Joseph
authors: J
authors: Paquet
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Mickael
authors: M
authors: Deschepper
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Morad
authors: M
authors: Bensidhoum
authors: Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Valentina
authors: V
authors: Izzo
authors: Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, France.|Cell Biology and Metabolomics platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France.|INSERM, U1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.|Université Pierre et Marie Curie, Paris, France.|Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.|Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital Q2:07, Stockholm, Sweden.
authors: Guido
authors: G
authors: Kroemer
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Hervé
authors: H
authors: Petite
authors: Laboratory of Bioengineering and Bioimaging for Osteo-Articular tissues, UMR 7052, CNRS, Paris Diderot University, Sorbonne Paris Cité, Paris, France.
authors: Delphine
authors: D
authors: Logeart-Avramoglou
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001343:Autophagy; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D002470:Cell Survival; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D006801:Humans; D007511:Ischemia / Q000473:pathology*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D055442:Metabolome; D015424:Reperfusion; D013312:Stress, Physiological
chemical_list: D016895:Culture Media, Serum-Free; D000255:Adenosine Triphosphate
keywords: Autophagy; Cell metabolism; Cell survival; Human mesenchymal stromal cells; Ischemia; Quiescence