Chang Chen1,2,3, Qi Tang1,2,3, Yan Zhang1,2,3, Minjia Dai1,2,3, Yichen Jiang1,2,3, Hang Wang1,2,3, Mei Yu1,2, Wei Jing1,2,3, Weidong Tian1,2,3. 1. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China. 2. National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu, China. 3. Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Abstract
OBJECTIVES: Poor cell survival severely limits the beneficial effect of adipose-derived stem cell (ADSC)-based therapy for disease treatment and tissue regeneration, which might be caused by the attenuated level of hypoxia-inducible factor-1 (HIF-1) in these cells after having been cultured in 21% ambient oxygen in vitro for weeks. In this study, we explored the role of pre-incubation in dimethyloxalylglycine (DMOG, HIF-1 activator) in the survivability of human ADSCs in a simulated ischaemic microenvironment in vitro and in vivo. The underlying mechanism and angiogenesis were also studied. MATERIALS AND METHODS: Survivability of ADSCs was determined in a simulated ischaemic model in vitro and a nude mouse model in vivo. Cell metabolism and angiogenesis were investigated by tube formation assay, flow cytometry, fluorescence staining and real-time polymerase chain reaction (RT-PCR) after DMOG treatment. RESULTS: The results of the experimental groups showed significant enhancement of ADSC survivability in a simulated ischaemic microenvironment in vitro and transplanted model in vivo. Study of the underlying mechanisms suggested that the improved cell survival was regulated by HIF-1-induced metabolic reprogramming including decreased reactive oxygen species, increased intracellular pH, enhanced glucose uptake and increased glycogen synthesis. Tube formation assay revealed higher angiogenic ability in the DMOG-treated group than that in control group. CONCLUSIONS: The promotion of HIF-1 level in ADSCs induced by DMOG preconditioning suggests a potential strategy for improving the outcome of cell therapy due to increased survival and angiogenic ability.
OBJECTIVES: Poor cell survival severely limits the beneficial effect of adipose-derived stem cell (ADSC)-based therapy for disease treatment and tissue regeneration, which might be caused by the attenuated level of hypoxia-inducible factor-1 (HIF-1) in these cells after having been cultured in 21% ambient oxygen in vitro for weeks. In this study, we explored the role of pre-incubation in dimethyloxalylglycine (DMOG, HIF-1 activator) in the survivability of human ADSCs in a simulated ischaemic microenvironment in vitro and in vivo. The underlying mechanism and angiogenesis were also studied. MATERIALS AND METHODS: Survivability of ADSCs was determined in a simulated ischaemic model in vitro and a nude mouse model in vivo. Cell metabolism and angiogenesis were investigated by tube formation assay, flow cytometry, fluorescence staining and real-time polymerase chain reaction (RT-PCR) after DMOG treatment. RESULTS: The results of the experimental groups showed significant enhancement of ADSC survivability in a simulated ischaemic microenvironment in vitro and transplanted model in vivo. Study of the underlying mechanisms suggested that the improved cell survival was regulated by HIF-1-induced metabolic reprogramming including decreased reactive oxygen species, increased intracellular pH, enhanced glucose uptake and increased glycogen synthesis. Tube formation assay revealed higher angiogenic ability in the DMOG-treated group than that in control group. CONCLUSIONS: The promotion of HIF-1 level in ADSCs induced by DMOG preconditioning suggests a potential strategy for improving the outcome of cell therapy due to increased survival and angiogenic ability.
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: Jane Ru Choi; Belinda Pingguan-Murphy; Wan Abu Bakar Wan Abas; Kar Wey Yong; Chi Tat Poon; Mat Adenan Noor Azmi; Siti Zawiah Omar; Kien Hui Chua; Feng Xu; Wan Kamarul Zaman Wan Safwani Journal: PLoS One Date: 2015-01-23 Impact factor: 3.240