Reparative effects of VCAM-1 high-performance MSC-derived exosomes on aged diabetic cardiomyocyte injury: a focus on ferroptosis suppression.

Xiaoyang Yin, Yimeng Wei, Yu Liu, Gang Chen, Jing Chen, Jie Cheng, Yongming Liu, Hulai Wei

Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, No. 222, Tianshui South Road, Chengguan District, Lanzhou, 730000, Gansu Province, China. · pubmed

Paper

Abstract

Cardiac dysfunction in elderly diabetes, due to superimposition of age-related myocardial senescence and diabetes-induced injury, lacks effective therapeutic strategies. Ferroptosis may be a key mechanism underlying cardiomyocyte injury in diabetic cardiomyopathy. Mesenchymal stem cells (MSCs) and their exosomes show potential for repairing cardiomyocytes, restoring cardiac function, improving insulin sensitivity, and mitigating diabetes-related complications, but their mechanisms and relationship with ferroptosis remain unclear. The present study aimed to investigate reparative effects and ferroptosis-mediated mechanism of exosomes derived from VCAM-1 high-performance MSCs on aged diabetic cardiomyocyte injury. High-glucose-damaged senescent cardiomyocyte and aged rat model of diabetic cardiomyopathy were established and treated with VCAM-1⁺-UC-MSCs or -derived exosomes. Assessments of cell phenotypes, RNA sequencing, cardiac function, and markers of senescence and ferroptosis revealed significant mitochondrial damage, iron-ion accumulation, reactive oxygen species (ROS), and cardiac troponin (c-TnT) elevation in the damaged myocardial cells and rat heart tissues, along with weakened cardiac function and pronounced senescence and ferroptosis features, and activation of Ras/Raf/MEK/ERK/c-FOS pathway. VCAM-1⁺ MSCs or exosome administration significantly alleviated these effects, and improved cardiac function. Notably, the reparative effect of VCAM-1⁺-UC-MSCs-derived exosomes was superior to that of conventional MSCs-derived exosomes. In conclusion, VCAM-1⁺-UC-MSCs-derived exosomes attenuate cardiomyocyte ferroptosis by suppressing Ras/Raf/MEK/ERK/c-FOS pathway, thereby ameliorating myocardial injury resulting from superimposition of aging-caused myocardial senescence and diabetes-induced damage in elderly diabetic cardiomyopathy. This may lay a foundation for identifying potential prevention and treatment strategies and targets of MSCs and -derived exosomes on myocardial injury.

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Research summary

VCAM-1⁺-UC-MSCs-derived exosomes attenuate cardiomyocyte ferroptosis, improving myocardial injury in aged diabetic cardiomyopathy. The study addresses mechanisms of cellular injury related to aging and diabetes, which are critical factors in age-related diseases, thus contributing to potential therapeutic strategies for longevity.

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