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Purification and Transplantation of Myogenic Progenitor Cell Derived Exosomes to Improve Cardiac Function in Duchenne Muscular Dystrophic Mice
Published on: April 10, 2019
Plasma exosomes protect the myocardium from ischemia-reperfusion injury
Jose M Vicencio1, Derek M Yellon1, Vivek Sivaraman1
1The Hatter Cardiovascular Institute, University College London, London, United Kingdom.
Insights
Endogenous plasma exosomes protect the heart from injury by activating a signaling pathway involving heat shock protein 70 (HSP70) and toll-like receptor 4 (TLR4). This discovery offers new insights into exosome-mediated cardioprotection.
Area of Science:
- Cell Biology
- Cardiovascular Research
- Nanomedicine
Background:
- Exosomes, nanoscale vesicles in blood, transmit signals but their cardiac effects and mechanisms are unexplored.
- Endogenous plasma exosomes are hypothesized to signal to the heart and protect against ischemia-reperfusion injury.
Purpose of the Study:
- Isolate and characterize exosomes from rats and humans.
- Evaluate exosome cardioprotective effects.
- Identify molecular mechanisms of exosome-mediated protection.
Main Methods:
- Exosome isolation from blood using standard techniques.
- Characterization via electron microscopy and nanoparticle tracking.
- Assessment of cardioprotection in various ischemia-reperfusion models.
- Signaling pathway analysis using Western blot and inhibitors.
Main Results:
- Isolated exosomes confirmed by size and markers (CD63, CD81, HSP70).
- Exosomes demonstrated potent cardioprotection across all models.
- Identified a pro-survival pathway in cardiomyocytes involving toll-like receptor 4 (TLR4) and heat shock protein 27 (HSP27).
- HSP70/TLR4 axis confirmed as critical for exosome-mediated cardioprotection.
Conclusions:
- Exosomes deliver protective signals to the heart.
- The HSP70/TLR4 pathway is essential for exosome-mediated cardioprotection.
- This highlights a novel therapeutic target for cardiac protection.
Background:
Exosomes are nanometer-sized vesicles released from cells into the blood, where they can transmit signals throughout the body. Shown to act on the heart, exosomes' composition and the signaling pathways they activate have not been explored. We hypothesized that endogenous plasma exosomes can communicate signals to the heart and provide protection against ischemia and reperfusion injury.
Objectives:
This study sought to isolate and characterize exosomes from rats and healthy volunteers, evaluate their cardioprotective actions, and identify the molecular mechanisms involved.
Methods:
The exosome-rich fraction was isolated from the blood of adult rats and human volunteers and was analyzed by protein marker expression, transmission electron microscopy, and nanoparticle tracking analysis. This was then used in ex vivo, in vivo, and in vitro settings of ischemia-reperfusion, with the protective signaling pathways activated on cardiomyocytes identified using Western blot analyses and chemical inhibitors.
Results:
Exosomes exhibited the expected size and expressed marker proteins CD63, CD81, and heat shock protein (HSP) 70. The exosome-rich fraction was powerfully cardioprotective in all tested models of cardiac ischemia-reperfusion injury. We identified a pro-survival signaling pathway activated in cardiomyocytes involving toll-like receptor (TLR) 4 and various kinases, leading to activation of the cardioprotective HSP27. Cardioprotection was prevented by a neutralizing antibody against a conserved HSP70 epitope expressed on the exosome surface and by blocking TLR4 in cardiomyocytes, identifying the HSP70/TLR4 communication axis as a critical component in exosome-mediated cardioprotection.
Conclusions:
Exosomes deliver endogenous protective signals to the myocardium by a pathway involving TLR4 and classic cardioprotective HSPs.
