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Extracellular Vesicle-Inspired CArdiac Repair

Periodic Reporting for period 3 - EVICARE (Extracellular Vesicle-Inspired CArdiac Repair)

Reporting period: 2020-09-01 to 2022-02-28

Regenerative therapies for heart disease
More than 3.5 million new people are diagnosed with heart failure every year in Europe, with a long-term prognosis of 50% mortality within four years. There is urgent need for more innovative, regenerative therapies with the potential to change the course of the condition. Prof Dr Joost Sluijter at University Medical Center Utrecht is developing a promising therapy: stimulating cardiac repair with extracellular vesicles that are derived from progenitor cells. Membrane-encapsulated packages, containing a cocktail of stimulating factors, secreted by these early descendants of stem cells, could have a potent healing capacity. With the ERC grant, Prof Dr Sluijter aims 1) to improve delivery of these extracellular vesicles, 2) better understand their mechanism of action, and 3) design ways to stimulate their production and release by progenitor cells.
1) The EVICARE team-members have established the functional consequences of EV therapeutics in the setting of acute myocardial damage. Several important detrimental cardiac consequences upon injury are being affected, including local cell division, immune cell activation and connective tissue formation. We have tested and established several slow release systems, which can now be used to test if improved therapeutic benefits can be observed. The released EVs are still functional in vitro and can activate endothelial cell behaviour.
2) To explore and determine functional targets of our EVs, we started several projects on a cell- and organ level. For down-stream functional testing, we have established now multiple endothelial cell assays to study their behaviour, observed that isolated EVs have effects on different immune cells, and observed that fibrosis can be modulated upon EV exposure, however, high dosing is essential to achieve this.
3) To determine if EV release by progenitor cells can be stimulated, we explored the maximum effect that can be expected by interfering with endolysosomal trafficking. Although this was successful, we also realized that EV release can only be stimulated in a limited way and therefore focussed on other aspects to improve their production. We achieved higher functionality of extracellular vesicles by implementing different isolation techniques, including size-exclusion chromatography, by using different columns for their isolation, and introduced an alternative method for the biofabrication of cell-derived nanovesicles, moreover we implemented bioreactors for cell culture.
Isolating extracellular vesicles (EVs) in a reproducible and translatable is still a major challenge for many laboratories all over the world. We are making now major steps in understanding better which steps are essential and how to tackle the next problems towards large scale EV production for clinical applications. By implementing the latest isolation and sequencing technologies, we will understand targeting and mechanistically what is affected in the myocardial tissue upon injection into the failing heart.