Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway

Liang, Bo, Jia-Ming Liang, Jia-Ning Ding, Jia Xu, Jian-Guang Xu, and Yi-Min Chai. "Dimethyloxaloylglycine-stimulated human bone marrow mesenchymal stem cell-derived exosomes enhance bone regeneration through angiogenesis by targeting the AKT/mTOR pathway." Stem cell research & therapy 10, no. 1 (2019): 335.

Abstract
Background
Mesenchymal stem cell (MSC)-derived exosomes have been recognized as new candidate agents for treating critical-sized bone defects; they promote angiogenesis and may be an alternative to cell therapy. In this study, we evaluated whether exosomes derived from bone marrow-derived MSCs (BMSCs) preconditioned with a low dose of dimethyloxaloylglycine (DMOG), DMOG-MSC-Exos, exert superior proangiogenic activity in bone regeneration and the underlying mechanisms involved.

Methods
To investigate the effects of these exosomes, scratch wound healing, cell proliferation, and tube formation assays were performed in human umbilical vein endothelial cells (HUVECs). To test the effects in vivo, a critical-sized calvarial defect rat model was established. Eight weeks after the procedure, histological/histomorphometrical analysis was performed to measure bone regeneration, and micro-computerized tomography was used to measure bone regeneration and neovascularization.

Results
DMOG-MSC-Exos activated the AKT/mTOR pathway to stimulate angiogenesis in HUVECs. This contributed to bone regeneration and angiogenesis in the critical-sized calvarial defect rat model in vivo.

Conclusions
Low doses of DMOG trigger exosomes to exert enhanced proangiogenic activity in cell-free therapeutic applications.

Keywords
Exosome Mesenchymal stem cell Bone regeneration Angiogenesis Dimethyloxaloylglycine Tissue engineering
Abbreviations
BMSCs
Bone marrow-derived MSCs

DMOG
Dimethyloxaloylglycine

EVs
Extracellular vesicles

HIF
Hypoxia-inducible factor

HUVECs
Human umbilical vein endothelial cells

MSC
Mesenchymal stem cell

MVBs
Multivesicular bodies

MVs
Microvesicles

OD
Optical density

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