MiR-27b augments bone marrow progenitor cell survival via suppressing the mitochondrial apoptotic pathway in Type 2 diabetes

Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogeno...

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Published in:American journal of physiology: endocrinology and metabolism 2017-10, Vol.313 (4), p.E391-E401
Main Authors: Li, Hainan, Liu, Jenny, Wang, Yihan, Fu, Zhiyao, Hüttemann, Maik, Monks, Terrence J, Chen, Alex F, Wang, Jie-Mei
Format: Article
Language:English
Subjects:
3' Untranslated regions
Advanced glycosylation end products
Aminoquinolines - pharmacology
Angiogenesis
Animals
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Autografts
BAX protein
Bcl-2 protein
bcl-2-Associated X Protein - metabolism
Blotting, Western
Bone marrow
Bone Marrow Cells - cytology
Bone Marrow Cells - drug effects
Bone Marrow Cells - metabolism
Case-Control Studies
Cell survival
Cell Survival - drug effects
Cell Survival - genetics
Cells
Cells (biology)
Core Binding Factor Alpha 2 Subunit - metabolism
Diabetes
Diabetes mellitus
Diabetes Mellitus, Type 2 - metabolism
Electron transport
Endothelial Progenitor Cells - cytology
Endothelial Progenitor Cells - drug effects
Endothelial Progenitor Cells - metabolism
Enzyme Inhibitors - pharmacology
Gene expression
Glycation End Products, Advanced - pharmacology
Glycosylation
Hydrogen peroxide
Hydrogen Peroxide - pharmacology
Lipoproteins, LDL - pharmacology
Male
Mice
MicroRNAs
MicroRNAs - drug effects
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Mitochondria
Mitochondria - drug effects
Mitochondria - metabolism
Osteoprogenitor cells
Oxidants - pharmacology
Oxygen consumption
p53 Protein
Post-transcription
Progenitor cells
Proto-Oncogene Proteins c-bcl-2 - metabolism
Pyruvaldehyde
Pyruvaldehyde - pharmacology
Reactive oxygen species
Real-Time Polymerase Chain Reaction
Regeneration
Runx1 protein
Stem Cells - cytology
Stem Cells - drug effects
Stem Cells - metabolism
Survival analysis
Therapy
Tumor Suppressor Protein p53 - metabolism
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Summary:Bone marrow-derived progenitor cells (BMPCs) are potential candidates for autologous cell therapy in tissue repair and regeneration because of their high angiogenic potential. However, increased progenitor cell apoptosis in diabetes directly limits their success in the clinic. MicroRNAs are endogenous noncoding RNAs that regulate gene expression at the posttranscriptional level, but their roles in BMPC-mediated angiogenesis are incompletely understood. In the present study, we tested the hypothesis that the proangiogenic miR-27b inhibits BMPC apoptosis in Type 2 diabetes. Bone marrow-derived EPCs from adult male Type 2 diabetic mice and their normal littermates /+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased after 24 h of exposure to methylglyoxal (MGO) or oxidized low-density lipoprotein but not high glucose, advanced glycation end products, the reactive oxygen species generator LY83583, or H O The increase in BMPC apoptosis in the diabetic mice was rescued following transfection with a miR-27b mimic, and the increased apoptosis induced by MGO was also rescued by the miR-27b mimic. p53 protein expression and the Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in mice, both of which were suppressed by miR-27b. Furthermore, mitochondrial respiration, as measured by oxygen consumption rate, was enhanced by miR-27b in diabetic BMPCs, with concomitant decrease of mitochondrial Bax/Bcl-2 ratio. The 3' UTR binding assays revealed that both Bax, and its activator RUNX1, were direct targets of miR-27b, suggesting that miR-27b inhibits Bax expression in both direct and indirect manners. miR-27b prevents EPC apoptosis in Type 2 diabetic mice, at least in part, by suppressing p53 and the Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing BMPC dysfunction in diabetes for successful autologous cell therapy.
ISSN:0193-1849
1522-1555
DOI:10.1152/ajpendo.00073.2017