Abstract
Aims: Intravenous mesenchymal stem cells (MSCs) confer considerable cardiovascular benefits to patients. The lung, but not the heart, is the main trapped site for intravenous MSCs. It remains unclear how intravenous MSCs bridge this spatial gap between the lung and the heart to achieve cardiac repair. To investigate how intravenous MSCs, like an endocrine reservoir, secrete specific miRNA-enriched extracellular vesicles (EVs) gradually and continuously to alleviate doxorubicin (Dox)-induced cardiotoxicity. Methods and results: MSCs were isolated from human placenta tissue, and multiple molecular imaging was generated by modifying MSCs-DF or MSCs-Gluc transduced with firefly luciferase ( Fluc ) / enhanced green fluorescence protein (eGFP) or Gaussia luciferase (Gluc) lactadherin fusion protein. The Dox-induced cardiotoxicity murine model was constructed and an equal sum of MSCs was infused into mice by single high dose (5 х 10 6 MSCs) or repeated low dose (1 х 10 6 MSCs, 5 times) intravenously. Dox-induced cardiotoxicity, characterized by cardiac atrophy, left ventricular dysfunction, and injured myocardium, was alleviated by low doses of repeated MSCs. These cardioprotective effects were attributed to the suppression of GRP78 triggering stress-induced apoptosis of the endoplasmic reticulum (ER) in cardiomyocytes. Our results confirmed that miR-181a-5p in EVs derived from MSCs (MSC-EVs) inhibited GRP78. Intravenous MSCs-DF were trapped in the lung vasculature, secreted EVs into serum, which was confirmed by the detection of eGFP + EVs. Gluc activity increased in serum EVs from mice administrated with MSCs-Gluc. MiR-181a-5p, which inhibits GRP78 with high efficacy, expressed an increase in serum EVs and myocardium after injecting repeated low-dose MSCs. Up-regulation or down-regulation of miR-181a-5p levels in MSC-EVs had enhanced or weakened therapeutic effects on Dox-induced cardiotoxicity by modulating ER stress-induced apoptosis. Conclusion: This study identifies intravenous MSCs, recognized as an endocrine reservoir, secrete EVs enriched with miR-181a-5p in the blood to confer indirect cardioprotection against Dox-induced cardiotoxicity.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
