Mechanistic and Therapeutic Implications of Extracellular Vesicles as a Potential Link Between Covid-19 and Cardiovascular Disease Manifestations

Abstract

Extracellular vesicles (EVs), which are cell released double layered membrane particles, have been found in every circulating body fluid, and provide a tool for conveying diverse information between cells, influencing both physiological and pathological conditions. Viruses can hijack the EVs secretory pathway to exit infected cells and use EVs endocytic routes to enter uninfected cells, suggesting that EVs and viruses can share common cell entry and biogenesis mechanisms. SARS-CoV-2 is responsible of the coronavirus disease 2019 (Covid-19), which may be accompanied by severe multi-organ manifestations. EVs may contribute to virus spreading via transfer of virus docking receptors such as CD9 and ACE2. Covid-19 is known to affect the renin angiotensin system (RAS), and could promote secretion of harmful EVs. In this scenario EVs might be linked to cardiovascular manifestations of the Covid-19 disease through unbalance in RAS. In contrast EVs derived from mesenchymal stem cells or cardiosphere derived cells, may promote cardiovascular function due to their beneficial effect on angiogenesis, fibrosis, contractility and immuno-modulation. In this article we assessed the potential impact of EVs in cardiovascular manifestations of Covid-19 and highlight potential strategies to control the extracellular signaling for future therapies.

Cell therapy strategies for COVID-19: Current approaches and potential applications

“…In the context of MSCs, a study conducted to evaluate patient age on the efficacy of MSC cell therapy in ischemic cardiomyopathy showed that older patients did not have an impaired response. Although these studies are not directly translatable to other cell types or patients with COVID-19, they nevertheless represent a starting point for future investigation (135)(136)(137)(138)(139)(140). Cell dosing and number of injections should be tailored to patient-specific responses and tolerance of treatment.…”

Anti-SARS-CoV-2 Activity of Extracellular Vesicle Inhibitors: Screening, Validation, and Combination with Remdesivir

“…To date, little is known about the SARS-CoV-2 egress. SARS-CoV-2 may use the multivesicular body (MVB)-like structure for packaging virions that will be released to the extracellular space via exocytosis [ 28 , 40 , 41 , 42 , 43 , 44 ]. Alternatively, SARS-CoV-2 may release from infected cells via unconventional egress by lysosomal exocytosis instead of the conventional biosynthetic secretory pathway [ 42 , 45 ], by which it will likely be released as microvesicles [ 28 , 43 ].…”

“…Alternatively, SARS-CoV-2 may release from infected cells via unconventional egress by lysosomal exocytosis instead of the conventional biosynthetic secretory pathway [ 42 , 45 ], by which it will likely be released as microvesicles [ 28 , 43 ]. SARS-CoV-2 may also be released through a shedding microvesicles bud from infected cells [ 43 , 44 ]. The release of microvesicles can be triggered by Ca 2+ activating calpain, calcium-dependent cysteine proteases [ 29 ].…”

AMDV Vaccine: Challenges and Perspectives

“…Alternatively, another new vaccination method that is actively being explored involves the use of cell-derived bi-layered extracellular vesicles (EVs) such as exosomes, microvesicles and apoptotic bodies [ 156 , 157 ]. Indeed, these have great advantages in terms of delivery and can increase overall immunogenicity since they have immunostimulatory molecules on their surfaces such as MHC class I or II molecules [ 156 , 158 ].…”

“…Alternatively, another new vaccination method that is actively being explored involves the use of cell-derived bi-layered extracellular vesicles (EVs) such as exosomes, microvesicles and apoptotic bodies [ 156 , 157 ]. Indeed, these have great advantages in terms of delivery and can increase overall immunogenicity since they have immunostimulatory molecules on their surfaces such as MHC class I or II molecules [ 156 , 158 ]. Further, exosomes have the capacity to carry pathogen antigens, as was shown by Montaner-Tarbes et al in a study analyzing exosomes from pigs infected with porcine reproductive and respiratory virus (PRRSV) [ 159 ].…”