Hongming Zhu1, Aijun Sun, Yunzeng Zou, Junbo Ge. 1. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Steve Stegen; Nick van Gastel; Guy Eelen; Bart Ghesquière; Flora D'Anna; Bernard Thienpont; Jermaine Goveia; Sophie Torrekens; Riet Van Looveren; Frank P Luyten; Patrick H Maxwell; Ben Wielockx; Diether Lambrechts; Sarah-Maria Fendt; Peter Carmeliet; Geert Carmeliet Journal: Cell Metab Date: 2016-02-09 Impact factor: 27.287
Authors: Simen W Schive; Mohammad Reza Mirlashari; Grete Hasvold; Mengyu Wang; Dag Josefsen; Hans Petter Gullestad; Olle Korsgren; Aksel Foss; Gunnar Kvalheim; Hanne Scholz Journal: Cell Med Date: 2017-04-14