Reparative effects of VCAM-1 high-performance MSC-derived exosomes on aged diabetic cardiomyocyte injury: a focus on
Xiaoyang Yin1, Yimeng Wei2, Yu Liu1
1Key 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.
Insights
High-performance mesenchymal stem cell exosomes effectively treat aged diabetic heart dysfunction by reducing ferroptosis, a key cell death pathway. These exosomes offer a promising therapeutic strategy for elderly patients with diabetic cardiomyopathy.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Cellular Biology
Background:
- Diabetic cardiomyopathy in the elderly involves age-related myocardial senescence and diabetes-induced injury, with ferroptosis as a potential mechanism.
- Mesenchymal stem cells (MSCs) and their exosomes show therapeutic potential, but their role in ferroptosis-mediated cardiac repair is unclear.
Purpose of the Study:
- To investigate the reparative effects of VCAM-1 high-performance MSC-derived exosomes on aged diabetic cardiomyocyte injury.
- To elucidate the ferroptosis-mediated mechanism underlying this repair process.
Main Methods:
- Established aged rat models of diabetic cardiomyopathy and high-glucose-damaged senescent cardiomyocytes.
- Treated models with VCAM-1⁺-UC-MSCs or their derived exosomes.
- Assessed cell phenotypes, cardiac function, senescence, ferroptosis markers, and the Ras/Raf/MEK/ERK/c-FOS pathway.
Main Results:
- Diabetic cardiomyopathy models exhibited mitochondrial damage, iron accumulation, elevated ROS and c-TnT, weakened cardiac function, and activated senescence and ferroptosis pathways.
- VCAM-1⁺ MSCs and their exosomes significantly alleviated these pathological changes and improved cardiac function.
- Exosomes derived from VCAM-1⁺-UC-MSCs demonstrated superior reparative effects compared to conventional MSC-derived exosomes.
Conclusions:
- VCAM-1⁺-UC-MSC-derived exosomes attenuate ferroptosis in cardiomyocytes by suppressing the Ras/Raf/MEK/ERK/c-FOS pathway.
- These exosomes ameliorate myocardial injury in elderly diabetic cardiomyopathy, offering a foundation for novel therapeutic strategies targeting MSCs and their exosomes.
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.
