title: Inducible metabolic adaptation promotes mesenchymal stem cell therapy for ischemia: a hypoxia-induced and glycogen-based energy prestorage strategy.
abstract: OBJECTIVE
  Ischemic tissue is an environment with limited oxygen and nutrition availability. The poor retention of mesenchymal stem cells (MSC) in ischemic tissues greatly limits their therapeutic potential. The aim of this study was to determine whether and how inducible metabolic adaptation enhances MSC survival and therapy under ischemia.
  
  
  RESULTS
  MSC were subjected to glycogen synthase 1-specific small interfering RNA or vehicle treatment, and then sublethal hypoxic preconditioning (HP) was applied to induce glycogenesis. The treated cells were subjected to ischemic challenge. The results exhibited that HP of MSC induced glycogen storage and stimulated glycogen catabolism and cellular ATP production, thereby preserving cell viability in long-term ischemia. In vivo study using the mouse limb ischemia model transplanted with HP or control MSC into the ischemic thigh muscles revealed a significant increased retention of MSC with glycogen storage associated with improved limb salvage, perfusion recovery and angiogenesis in the ischemic muscles. In contrast, glycogen synthesis inhibition significantly abolished these improvements. Further molecular analysis indicated that phosphoinositide 3-kinase/AKT, hypoxia-inducible factor-1, and glycogen synthase kinase-3β regulated expression of glycogenesis genes, including glucose transporter 1, hexokinase, phosphoglucomutase 1, glycogen synthase 1, and glycogen phosphorylase, thereby regulating glycogen metabolism of stem cell during HP.
  
  
  CONCLUSIONS
  HP-induced glycogen storage improves MSC survival and therapy in ischemic tissues. Thus, inducible metabolic adaptation in stem cells may be considered as a novel strategy for potentiating stem cell therapy for ischemia.
authors.affiliation: From the Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital (H.Z., A.S., Y.Z., J.G.) and The Institute of Biomedical Science (H.Z., A.S., Y.Z., J.G.), Fudan University, Shanghai, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Zhu
authors.forename: Aijun
authors.initials: A
authors.lastname: Sun
authors.forename: Yunzeng
authors.initials: Y
authors.lastname: Zou
authors.forename: Junbo
authors.initials: J
authors.lastname: Ge
mesh_terms: D000222:Adaptation, Physiological; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D006614:Hindlimb; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D020127:Recovery of Function; D012039:Regional Blood Flow; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
chemical_list: D000255:Adenosine Triphosphate; D006003:Glycogen; D006006:Glycogen Synthase
keywords: energy metabolism; hypoxia; hypoxia-inducible factor 1; limb ischemia; mesenchymal stromal cells