Highly purified extracellular vesicles from human cardiomyocytes demonstrate preferential uptake by human endothelial cells

Zwi‐Dantsis, Limor; Winter, Charles W.; Kauscher, Ulrike; Ferrini, Arianna; Wang, Brian; Whittaker, Thomas E; Hood, Steve R.; Terracciano, Cesare; Stevens, Molly M.

doi:10.1039/d0nr04278a

Cited by 17 publications

(16 citation statements)

References 61 publications

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“…There is still no consensus on which of the uptake mechanisms is more important; however, available evidence shows that internalization is an active process that is significantly decreased at 4 • C or after blocking protein interactions using specific antibodies. The high degree of EV heterogenicity depending on their cellular origin contributes significantly to their uptake and available evidence suggests that this can be selectively enhanced by choosing specific cell models [13,58].…”

Section: Ev Cellular Uptakementioning

confidence: 99%

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues

et al. 2020

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Extracellular vesicles (EVs) are important mediators of intercellular communication that participate in many physiological/pathological processes. As such, EVs have unique properties related to their origin, which can be exploited for drug delivery applications in cell regeneration, immunosuppression, inflammation, cancer treatment or cardioprotection. Moreover, their cell-like membrane organization facilitates uptake and accumulation in specific tissues and organs, which can be exploited to improve selectivity of cargo delivery. The combination of these properties with the inclusion of drugs or imaging agents can significantly improve therapeutic efficacy and selectivity, reduce the undesirable side effects of drugs or permit earlier diagnosis of diseases. In this review, we will describe the natural properties of EVs isolated from different cell sources and discuss strategies that can be applied to increase the efficacy of targeting drugs or other contents to specific locations. The potential risks associated with the use of EVs will also be addressed.

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Section: Ev Cellular Uptakementioning

confidence: 99%

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues

et al. 2020

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“…We previously reported that MP possess similar immune regulatory properties as MSC with respect to the modulation of monocyte function after being taken up by these cells (16). We also found that MP, like naturally occurring extracellular vesicles, are efficiently taken up by endothelial cells and modulate their function (unpublished data), and (17,18). However, the specificity and mechanisms of MP uptake by target cells remain unclear.…”

Section: Introductionmentioning

confidence: 89%

Mesenchymal Stromal Cell Derived Membrane Particles Are Internalized by Macrophages and Endothelial Cells Through Receptor-Mediated Endocytosis and Phagocytosis

Gonçalves

Korevaar

Virumbrales³

et al. 2021

Front. Immunol.

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Mesenchymal stromal cells (MSC) are a promising therapy for inflammatory diseases. However, MSC are large and become trapped in the lungs after intravenous infusion, where they have a short survival time. To steer MSC immunoregulatory therapy beyond the lungs, we generated nm-sized particles from MSC membranes (membrane particles, MP), which have immunomodulatory properties, and investigated their internalization and mode of interaction in macrophages subtypes and human umbilical vein endothelial cells (HUVEC) under control and inflammatory conditions. We found that macrophages and HUVEC take up MP in a dose, time, and temperature-dependent manner. Specific inhibitors for endocytotic pathways revealed that MP internalization depends on heparan sulfate proteoglycan-, dynamin-, and clathrin-mediated endocytosis but does not involve caveolin-mediated endocytosis. MP uptake also involved the actin cytoskeleton and phosphoinositide 3-kinase, which are implicated in macropinocytosis and phagocytosis. Anti-inflammatory M2 macrophages take up more MP than pro-inflammatory M1 macrophages. In contrast, inflammatory conditions did not affect the MP uptake by HUVEC. Moreover, MP induced both anti- and pro-inflammatory responses in macrophages and HUVEC by affecting gene expression and cell surface proteins. Our findings on the mechanisms of uptake of MP under different conditions help the development of target-cell specific MP therapy to modulate immune responses.

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“…Notably, the reduction of protein contaminants could affect EV uptake. Highly purified EVs appear to have preferential uptake by cells [ 28 ]. For example, human endothelial cells uptake EVs isolated from human cardiomyocytes that were highly purified by size-exclusion chromatography (SEC) [ 28 ].…”

Section: Traditional Strategies For Customizing Extracellular Vesicle...mentioning

confidence: 99%

Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context

et al. 2022

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Extracellular vesicles (EVs) are advanced therapeutic strategies that can be used to efficiently treat diseases. Promising features of EVs include their innate therapeutic properties and ability to be engineered as targeted drug delivery systems. However, regulation of EV uptake is one challenge of EV therapy that must be overcome to achieve an efficient therapeutic outcome. Numerous efforts to improve the factors that affect EV uptake include the selection of a cell source, cell cultivation procedure, extraction and purification methods, storage, and administration routes. Limitations of rapid clearance, targeted delivery, and off-targeting of EVs are current challenges that must be circumvented. EV engineering can potentially overcome these limitations and provide an ideal therapeutic use for EVs. In this paper, we intend to discuss traditional strategies and their limitations, and then review recent advances in EV engineering that can be used to customize and control EV uptake for future clinical applications.

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Highly purified extracellular vesicles from human cardiomyocytes demonstrate preferential uptake by human endothelial cells

Abstract: Highly purified EVs isolated from human cardiomyocytes show differential uptake in cardiac cell types.

Cited by 17 publications

References 61 publications

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues

Mesenchymal Stromal Cell Derived Membrane Particles Are Internalized by Macrophages and Endothelial Cells Through Receptor-Mediated Endocytosis and Phagocytosis

Engineering strategies for customizing extracellular vesicle uptake in a therapeutic context

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