Abstract
Introduction: Endothelial progenitor cells (EPCs) are promising candidates for autologous cell therapy of diabetic wound repair because of their high angiogenic potentials. However, increased EPC apoptosis in diabetes directly limits its clinical success. MicroRNAs are endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level, but their roles in EPC-mediated angiogenesis in diabetes are incompletely understood. We hypothesized that the pro-angiogenic miR-27b inhibits EPC apoptosis and improves wound healing in type 2 diabetes. Methods and Results: Bone marrow-derived EPCs from adult male type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased by >66% in db/db vs. db/+ mice (n=4, p<0.05). The impaired EPC angiogenesis of >70% (Matrigel tube formation, n=4, vs. db/+) and increased EPC apoptosis (TUNEL staining, n=3, p<0.05 vs. db/+) in diabetes were rescued following miR-27b mimic transfection (n=3, p<0.05 vs. db/db + scramble). p53 and Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice (by 23% and 58%, respectively, vs. db/+), which were suppressed by miR-27b mimic (n=3, p<0.05 vs. db/db + scramble). Excisional wound (6-mm diameter) closure was markedly delayed in db/db vs. db/+ mice (n=5, p<0.05), accompanied by poorer wound angiogenesis (Laser Doppler detection, n=5, p<0.05) and elevated expression of p53 (> 72%) and Bax/Bcl-2 ratio (> 55%) (both n=5 vs. db/+). Local delivery of miR-27b mimic or cell therapy using diabetic EPCs (10 6 ) with miR-27b mimic transfection significantly accelerated wound closure rates (n=5, p<0.05), with a concomitant augmentation of wound perfusion in db/db mice (n=5, p<0.05). Conclusion: miR-27b retards EPC apoptosis and accelerates wound healing in type 2 diabetic mice, at least in part, via suppressing p53 and Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing EPC dysfunction in diabetes for successful autologous cell therapy.
Published Version
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