Dataset Information

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

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.

SUBMITTER: Liang B

PROVIDER: S-EPMC6869275 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

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

Liang Bo B Liang Jia-Ming JM Ding Jia-Ning JN Xu Jia J Xu Jian-Guang JG Chai Yi-Min YM

Stem cell research & therapy 20191120 1

<h4>Background</h4>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.<h4>Methods ...[more]

PMID: 31747933

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Project description:BackgroundCurrently, bone marrow mesenchymal stem cells (BMSCs) have been reported to promote endometrial regeneration in rat models of mechanically injury-induced uterine adhesions (IUAs), but the therapeutic effects and mechanisms of hypoxic BMSC-derived exosomes on IUAs have not been elucidated.ObjectiveTo investigate the potential mechanism by which the BMSCS-derived exosomal miR-424-5p regulates IUA angiogenesis through the DLL4/Notch signaling pathway under hypoxic conditions and promotes endometrial injury repair.MethodsThe morphology of the exosomes was observed via transmission electron microscopy, and the expression of exosome markers (CD9, CD63, CD81, and HSP70) was detected via flow cytometry and Western blotting. The expression of angiogenesis-related genes (Ang1, Flk1, Vash1, and TSP1) was detected via RT‒qPCR, and the expression of DLL4/Notch signaling pathway-related proteins (DLL4, Notch1, and Notch2) was detected via Western blotting. Cell proliferation was detected by a CCK-8 assay, and angiogenesis was assessed via an angiogenesis assay. The expression of CD3 was detected by immunofluorescence. The endometrial lesions of IUA rats were observed via HE staining, and the expression of CD3 and VEGFA was detected via immunohistochemistry.ResultsCompared with those in exosomes from normoxic conditions, miR-424-5p was more highly expressed in the exosomes from hypoxic BMSCs. Compared with those in normoxic BMSC-derived exosomes, the proliferation and angiogenesis of HUVECs were significantly enhanced after treatment with hypoxic BMSC-derived exosomes, and these effects were weakened after inhibition of miR-424-5p. miR-424-5p can target and negatively regulate the expression of DLL4, promote the expression of the proangiogenic genes Ang1 and Flk1, and inhibit the expression of the antiangiogenic genes Vash1 and TSP1. The effect of miR-424-5p can be reversed by overexpression of DLL4. In IUA rats, treatment with hypoxic BMSC exosomes and the miR-424-5p mimic promoted angiogenesis and improved endometrial damage.ConclusionThe hypoxic BMSC-derived exosomal miR-424-5p promoted angiogenesis and improved endometrial injury repair by regulating the DLL4/Notch signaling pathway, which provides a new idea for the treatment of IUAs.

Project description:Bone regeneration poses a significant challenge in the field of tissue engineering, prompting ongoing research to explore innovative strategies for effective bone healing. The integration of stem cells and nanomaterial scaffolds has emerged as a promising approach, offering the potential to enhance regenerative outcomes. This study focuses on the application of a stem cell-laden nanomaterial scaffold designed for bone regeneration in rabbits. The in vivo study was conducted on thirty-six healthy skeletally mature New Zealand white rabbits that were randomly allocated into six groups. Group A was considered the control, wherein a 15 mm critical-sized defect was created and left as such without any treatment. In group B, this defect was filled with a polycaprolactone-hydroxyapatite (PCL + HAP) scaffold, whereas in group C, a PCL + HAP-carboxylated multiwalled carbon nanotube (PCL + HAP + MWCNT-COOH) scaffold was used. In group D, a PCL + HAP + MWCNT-COOH scaffold was used with local injection of bone morphogenetic protein-2 (BMP-2) on postoperative days 30, 45, and 60. The rabbit bone marrow-derived mesenchymal stem cells (rBMSCs) were seeded onto the PCL + HAP + MWCNT-COOH scaffold by the centrifugal method. In group E, an rBMSC-seeded PCL + HAP + MWCNT-COOH scaffold was used along with the local injection of rBMSC on postoperative days 7, 14, and 21. For group F, in addition to the treatment given to group E, BMP-2 was administered locally on postoperative days 30, 45, and 60. Gross observations, radiological observation, scanning electron microscopic assessment, and histological evaluation study showed that group F displayed the best healing properties, followed by group E, group D, group C, and B. Group A showed no healing with ends blunting minimal fibrous tissue. Incorporating growth factor BMP-2 in tissue-engineered rBMSC-loaded nanocomposite PCL + HAP + MWCNT-COOH construct can augment the osteoinductive and osteoconductive properties, thereby enhancing the healing in a critical-sized bone defect. This novel stem cell composite could prove worthy in the treatment of non-union and delayed union fractures in the near future.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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