Context-specific regulation of extracellular vesicle biogenesis and cargo selection

Dixson, Andrew C.; Dawson, T. Renee; Vizio, Dolores Di; Weaver, Alissa M.

doi:10.1038/s41580-023-00576-0

Cited by 219 publications

(239 citation statements)

References 361 publications

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“…Challenges exist for studying EV cargo selection. 58,59 However, the sheer number of ECs living at the interface of the circulation and blood vessel wall and potential for polarized sEV communication would inform several biologic processes. As a basic tenet, directional EV release necessitates a polarized structure capable of maintaining discrete compartments.…”

Section: Discussionmentioning

confidence: 99%

Endothelial cells secrete small extracellular vesicles bidirectionally containing distinct cargo to uniquely reprogram vascular cells in the circulation and vessel wall

Raju

Botts

Blaser

et al. 2023

Preprint

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Rationale: Extracellular vesicles (EVs) contain bioactive cargo including microRNAs (miRNAs) and proteins that are released by cells as a form of cell-cell communication. Endothelial cells (ECs) form the innermost lining of all blood vessels and thereby interface with cells in the circulation as well as cells residing in the vascular wall. It is unknown whether ECs have the capacity to release EVs capable of governing recipient cells within two separate compartments, and how this is affected by endothelial activation commonly seen in atheroprone regions. Objective: Given their boundary location, we propose that ECs utilize bidirectional release of distinct EV cargo in quiescent and activated states to communicate with cells within the circulation and blood vessel wall. Methods and Results: EVs were isolated from primary human aortic endothelial cells (ECs) (+/- IL-1beta activation), quantified, and analysed by miRNA transcriptomics and proteomics. Compared to quiescent ECs, activated ECs increased EV release, with miRNA and protein cargo that were related to atherosclerosis. RNA sequencing of EV-treated monocytes and smooth muscle cells (SMCs) revealed that EVs from activated ECs altered pathways that were pro-inflammatory and atherogenic. Apical and basolateral EV release was assessed using ECs on transwells. ECs released more EVs apically, which increased with activation. Apical and basolateral EV cargo contained distinct transcriptomes and proteomes that were altered by EC activation. Notably, basolateral EC-EVs displayed greater changes in the EV secretome, with pathways specific to atherosclerosis. In silico analysis determined that compartment-specific cargo released by the apical and basolateral surfaces of ECs can reprogram monocytes and SMCs, respectively. Conclusions: The demonstration that ECs are capable of polarized EV cargo loading and directional EV secretion reveals a novel paradigm for endothelial communication, which may ultimately enhance our ability to design endothelial-based therapeutics for cardiovascular diseases such as atherosclerosis where ECs are persistently activated.

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Section: Discussionmentioning

confidence: 99%

Endothelial cells secrete small extracellular vesicles bidirectionally containing distinct cargo to uniquely reprogram vascular cells in the circulation and vessel wall

Raju

Botts

Blaser

et al. 2023

Preprint

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“…These cross-talks have remained conserved throughout evolution and play a role in “inter-kingdom” mutual communications ( 118 ). This way, EVs can mediate (attenuate or promote) cell death, inflammation, and immune responses in a context-dependent mode ( 119 , 120 ). Extracellular matrix-bound EVs are a recently-introduced subset of EVs with predicted roles in tissue repair and regeneration, which may be mediated by their active or passive tissue traversing or extracellular matrix (ECM) remodeling capacity ( 121 ).…”

Section: Extracellular Vesicles a New Therapeutic Paradigm For Autoim...mentioning

confidence: 99%

Extracellular vesicles and their cells of origin: Open issues in autoimmune diseases

et al. 2023

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The conventional therapeutic approaches to treat autoimmune diseases through suppressing the immune system, such as steroidal and non-steroidal anti-inflammatory drugs, are not adequately practical. Moreover, these regimens are associated with considerable complications. Designing tolerogenic therapeutic strategies based on stem cells, immune cells, and their extracellular vesicles (EVs) seems to open a promising path to managing autoimmune diseases’ vast burden. Mesenchymal stem/stromal cells (MSCs), dendritic cells, and regulatory T cells (Tregs) are the main cell types applied to restore a tolerogenic immune status; MSCs play a more beneficial role due to their amenable properties and extensive cross-talks with different immune cells. With existing concerns about the employment of cells, new cell-free therapeutic paradigms, such as EV-based therapies, are gaining attention in this field. Additionally, EVs’ unique properties have made them to be known as smart immunomodulators and are considered as a potential substitute for cell therapy. This review provides an overview of the advantages and disadvantages of cell-based and EV-based methods for treating autoimmune diseases. The study also presents an outlook on the future of EVs to be implemented in clinics for autoimmune patients.

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“…This has recently been confirmed for EVs secreted by starving cells, where starvation significantly affects the protein composition of EVs [ 106 ]. The altering of the EV content in response to environmental stresses has also been discussed in a recently published review [ 107 ]. In addition to activating the EV secretion in stress conditions, it is possible to overexpress some proteins in EV-secreting cells, which can enhance the EV release into the extracellular space [ 108 ].…”

Section: Challenges Of Ev Application As Drug Delivery Carriersmentioning

confidence: 99%

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

Oshchepkova

Zenkova

Vlassov

2023

IJMS

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Extracellular vesicles (EVs) are membrane vesicles released into the extracellular milieu by cells of various origins. They contain different biological cargoes, protecting them from degradation by environmental factors. There is an opinion that EVs have a number of advantages over synthetic carriers, creating new opportunities for drug delivery. In this review, we discuss the ability of EVs to function as carriers for therapeutic nucleic acids (tNAs), challenges associated with the use of such carriers in vivo, and various strategies for tNA loading into EVs.

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Context-specific regulation of extracellular vesicle biogenesis and cargo selection

Cited by 219 publications

References 361 publications

Endothelial cells secrete small extracellular vesicles bidirectionally containing distinct cargo to uniquely reprogram vascular cells in the circulation and vessel wall

Endothelial cells secrete small extracellular vesicles bidirectionally containing distinct cargo to uniquely reprogram vascular cells in the circulation and vessel wall

Extracellular vesicles and their cells of origin: Open issues in autoimmune diseases

Extracellular Vesicles for Therapeutic Nucleic Acid Delivery: Loading Strategies and Challenges

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