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Pre-conditioning with Nicotinamide-mononucleotide Enhances Cardioprotective Potentials of Umbilical Cord-derived Mesenchymal Stem Cells in Diabetes: Role of Autophagy Flux

Qingmei Wang, Xuanguo Zhang

Background: The application of stem cell-based therapies has promising cardioprotective impacts in Ischemia- Reperfusion (IR) injury, especially in a comorbid condition like diabetes. Preconditioning of mesenchymal stem cells (MSCs) in vitro may improve their functions in vivo. Here, we have investigated the effects of preconditioning of human umbilical cord-derived MSCs with Nicotinamide-Mononucleotide (NMN) on myocardial infarct size, and the involvement of autophagy flux in diabetic rats.

Methods: Type 2 diabetes was induced by a high-fat diet and single-dose streptozotocin in Sprague Dawley rats (250 ± 20 g). Myocardial IR injury was applied through ligation of left coronary artery occlusion. NMN-preconditioned or unconditioned-MSCs were injected intra-myocardially at early reperfusion. Myocardial hemodynamics was recorded throughout the experiment. Cardiac injury was assessed using the measurement of infarct size and CK-mB release via planimetry and ELISA methods. Mitochondrial function was evaluated by fluorometric assays. Autophagy-related protein expression was evaluated using immunoblotting.

Results: Administration of NMN or MSCs alone had no significant protective effects. NMN-preconditioned MSCs significantly reduced myocardial infarction and CK-mB levels, restored IR-induced mitochondrial reactive oxygen species, membrane depolarization and ATP production, and improved cardiac hemodynamic following IR injury in diabetic rats. IR-induced overexpression of proteins Beclin-1, P62, and LC3-II and reduction of LC3-II/LC3-I ratio were significantly reversed following treatment with preconditioned-MSCs. The administration of chloroquine, an autophagy flux inhibitor, abolished these cardioprotective effects.

Conclusion: Therefore, NMN serves as a good preconditioning modality to increase the cardioprotective efficacy of MSCs in diabetic rats and the improvement of autophagy flux may play a significant role.