Extracellular Vesicles as Therapeutic Agents for Cardiac Fibrosis

Abstract

Heart disease remains an increasing major public health challenge in the United States and worldwide. A common end-organ feature in diseased hearts is myocardial fibrosis, which stiffens the heart and interferes with normal pump function, leading to pump failure. The development of cells for regenerative therapy has been met with many pitfalls on its path to clinical translation. Recognizing that regenerative cells secrete therapeutically bioactive vesicles has paved the way to circumvent many failures of cell therapy. In this review, we provide an overview of extracellular vesicles (EVs), with a focus on their utility as therapeutic agents for cardiac regeneration. We also highlight the engineering potential of EVs to enhance their therapeutic application.

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

“…Indeed, several studies have described beneficial effect of MSCs-derived EVs following myocardial injury by increasing angiogenesis ( Liang et al, 2016 ; Gong et al, 2017 ) improving cardiac contractility ( Kang et al, 2015 ; Ma et al, 2017 ; Mayourian et al, 2017 ). Moreover stem cells derived from cardiac tissues, i.e., cardiosphere derived cells (CDC), produce EVs able to reduce inflammation and fibrosis signaling ( Gray et al, 2015 ; Gallet et al, 2017 ; Rogers et al, 2020 ). The intercellular communication between macrophages, fibroblasts and endothelial cells orchestrates the progression of chronic heart failure and elicit myocardial fibrosis.…”

The Cellular Stress Response Interactome and Extracellular Matrix Cross-Talk during Fibrosis: A Stressed Extra-Matrix Affair

“…Mitochondria and endoplasmic reticulum (ER) in cardiomyocytes are overrepresented organelles to co-ordinate the increased metabolic demands and maintain active calcium stores for smooth flow. Endoplasmic reticulum and mitochondria quality control circuits are also integral to cardiac function, and deregulation of these pathways are strongly implicated in cardiac diseases including heart failure [57][58][59][60][61][62][63]. ECM remodeling is emerging to coincide with metabolic rewiring in cardiomyocytes and matrixguided control of mitochondrial function in cardiomyocytes is seen as a potential therapeutic target in cardiac fibrosis, repair, regeneration and tissue engineering [64].…”

“…The global co-and post-transcriptional mechanisms implicated in cardiac fibrosis are not well established, however, emerging studies are geared at extracting the subtle communications to identify intersection points between the cellular stress regulating pathways, regulatory non-coding RNAs, RNA metabolism intermediates/mediators and cardiac RNA binding proteins (RBFox, HuR, MBNL2, PUM2, QKI, CELF1, MBNL1, PTBP1) in context of cardiac diseases including fibrosis [66,[112][113][114][115][116][117][118][119][120]. A recent study implicated NUP155 subdomain hotspot with enriched allelic variants of the gene that suggests important role of RNA metabolism in cardiac disease and development [121].…”

Stem Cell-Derived Exosomes Potential Therapeutic Roles in Cardiovascular Diseases

“…Reports suggest that 17.7 million population succumb to death every year due to the risk of cardiovascular diseases (CVDs), which claims 31% of the total deaths worldwide (1). According to the recent studies (3)(4)(5), naturally produced membranous vesicles have the potential capability of targeting the recipient cells specifically and delivering their bioactive constituents. Owing to this characteristic, these vesicles could emerge as a potential candidate in the field of regenerative medicine.…”

“…The cellular waste from the lining cells are known to be discarded by means of releasing secretory vesicles called as exosomes (9,10). Recent studies (4,(11)(12)(13)(14) have indicated that exosomes are escalated into crucial agents in cell-cell signaling and find application in normal physiology, such as myocardial angiogenesis, cardiac development, and the formation of vesicles during the maturation of reticulocytes. Exosomes bring about intracellular communication by way of particular modes, such as direct interaction by cell-to-cell contact, electrical, as well as long range signals and some chemical molecular interaction processed extracellularly (15)(16)(17).…”