Abstract
BackgroundMesenchymal 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.MethodsTo 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.ResultsDMOG-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.ConclusionsLow doses of DMOG trigger exosomes to exert enhanced proangiogenic activity in cell-free therapeutic applications.
Highlights
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
The sections were stained with van Gieson’s picrofuchsin to assess new Exosome isolation, characterization, and internalization The exosomal marker proteins CD9, CD63, GM130, and TSG101 were detected in exosomes derived from bone marrow-derived MSCs (BMSCs) culture supernatants as expected, and no significant differences were observed on the expression of these markers between the MSC-Exos and DMOG-MSC-Exos groups (Additional file 1: Figure S1a)
Transmission electron microscopy (TEM) analysis showed that exosomes were round, membrane-bound vesicles ranging from 30 to 100 nm in diameter, with no obvious differences in morphology and quantity between the MSC-Exos and DMOG-MSC-Exos groups (Additional file 1: Figure S1b). qNano analysis shows that the size of the exosomes mainly ranged from 80 to 182 nm, with a mean size of 130 nm, and the predicted proper concentration was 6.65 × 108 particles/mL, with no distinguishing differences between the two exosome groups (Additional file 1: Figure S1c)
Summary
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. Autologous and allogeneic bone grafting are commonly used to promote the healing of bone defects but the limited supply, high costs, and rejection risks prevent their widespread use [2]. Bone tissue engineering has emerged as a therapeutic strategy. This approach involves the use of various cells and biological factors in combination with bone substitutes to improve their osteogenic and angiogenic activities. Angiogenesis is a prerequisite to bone healing, and restoration of the blood supply to bone defects provides a rich source of growth factors and nutrients [3]. How to promote angiogenesis in tissue-engineered bone is a critical area of research
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