scholarly journals Adipose mesenchymal stem cell-derived extracellular vesicles containing microRNA-26a-5p target TLR4 and protect against diabetic nephropathy

2020 ◽  
Vol 295 (37) ◽  
pp. 12868-12884 ◽  
Author(s):  
Yurui Duan ◽  
Qingyang Luo ◽  
Yun Wang ◽  
Yali Ma ◽  
Fang Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Diabetic Nephropathy ◽  
Extracellular Vesicles ◽  
Target Genes ◽  
Cell Counting ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor ◽  
The Impact

Diabetic nephropathy (DN) is a complication of diabetes that is increasing in prevalence in China. Extracellular vesicles (EVs) carrying microRNAs (miRs) may represent a useful tool in the development of therapies for DN. Here, we report that EVs released by adipose-derived mesenchymal stem cells (ADSCs) during DN contain a microRNA, miR-26a-5p, that suppresses DN. Using bioinformatic analyses, we identified differentially expressed miRs in EVs from ADSCs and in DN and predicted downstream regulatory target genes. We isolated mesenchymal stem cells (MSCs) from adipose tissues and collected EVs from the ADSCs. We exposed mouse glomerular podocytes and MP5 cells to high glucose (HG), ADSC-derived EVs, miR-26a-5p inhibitor/antagomir, Toll-like receptor 4 (TLR4) plasmids, or the NF-κB pathway activator (phorbol-12-myristate-13-acetate, or PMA). We used the cell counting kit-8 (CCK-8) assay and flow cytometry to investigate the impact of miR-26a-5p on cell viability and apoptosis and validated the results of these assays with in vivo experiments in nude mice. We found that in DN, miR-26a-5p is expressed at very low levels, whereas TLR4 is highly expressed. Of note, EVs from ADSCs ameliorated the pathological symptoms of DN in diabetic mice and transferred miR-26a-5p to HG-induced MP5 cells, improving viability while suppressing the apoptosis of MP5 cells. We also found that miR-26a-5p protects HG-induced MP5 cells from injury by targeting TLR4, inactivating the NF-κB pathway, and downregulating vascular endothelial growth factor A (VEGFA). Moreover, ADSC-derived EVs transferred miR-26a-5p to mouse glomerular podocytes, which ameliorated DN pathology. These findings suggest that miR-26a-5p from ADSC-derived EVs protects against DN.

scholarly journals Rejuvenation of mesenchymal stem cells by extracellular vesicles inhibits the elevation of reactive oxygen species

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vuong Cat Khanh ◽  
Toshiharu Yamashita ◽  
Kinuko Ohneda ◽  
Chiho Tokunaga ◽  
Hideyuki Kato ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Cellular Senescence ◽  
Skin Flap ◽  
Reactive Oxygen ◽  
Oxygen Species

Abstract Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs’ ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.

Vascular Endothelial Growth Factor Inhibits the Development of Dendritic Cells and Dramatically Affects the Differentiation of Multiple Hematopoietic Lineages In Vivo

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4150-4166 ◽  
Author(s):  
Dmitry Gabrilovich ◽  
Tadao Ishida ◽  
Tsunehiro Oyama ◽  
Sophia Ran ◽  
Vladimir Kravtsov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Vascular Endothelial Growth Factor ◽  
Dendritic Cells ◽  
Growth Factor ◽  
System Control ◽  
Vascular Endothelial ◽  
Almost All ◽  
Endothelial Growth Factor

Abstract Defective function of dendritic cells (DC) in cancer has been recently described and may represent one of the mechanisms of tumor evasion from immune system control. We have previously shown in vitro that vascular endothelial growth factor (VEGF), produced by almost all tumors, is one of the tumor-derived factors responsible for the defective function of these cells. In this study, we investigated whether in vivo infusion of recombinant VEGF could reproduce the observed DC dysfunction. Continuous VEGF infusion, at rates as low as 50 ng/h (resulting in serum VEGF concentrations of 120 to 160 pg/mL), resulted in a dramatic inhibition of dendritic cell development, associated with an increase in the production of B cells and immature Gr-1+ myeloid cells. Infusion of VEGF was associated with inhibition of the activity of the transcription factor NF-κB in bone marrow progenitor cells. Experiments in vitro showed that VEGF itself, and not factors released by VEGF-activated endothelial cells, affected polypotent stem cells resulting in the observed abnormal hematopoiesis. These data suggest that VEGF, at pathologically relevant concentrations in vivo, may exert effects on pluripotent stem cells that result in blocked DC development as well as affect many other hematopoietic lineages.

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