Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures

Dave, Kandarp M.; Stolz, Donna B.; Venna, Venugopal Reddy; Quaicoe, Victoria; Maniskas, Michael E; Reynolds, Michael; Babidhan, Riyan; Dobbins, Duncan X.; Farinelli, Maura N.; Sullivan, Abigail; Bhatia, Tarun N.; Yankello, Hannah; Reddy, Rohan; Bae, Younsoo; Leak, Rehana K.; Shiva, Sruti; McCullough, Louise D.; Manickam, Devika S.

doi:10.1016/j.jconrel.2023.01.025

Cited by 18 publications

(29 citation statements)

References 88 publications

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“…We first determined the effect of the fluorescent dye chemistry used for EV labeling on the uptake of EVs into the recipient cells. We compared the cellular uptake of EVs labeled either with a lipophilic dye, PKH67 or calcein AM ester dye that is cleaved by intravesicular esterases in EVs with intact membranes [26, 37, 38]. We used flow cytometry as a quantitative tool to understand the uptake of EVs into the recipient cells.…”

Section: Resultsmentioning

confidence: 99%

Effect of homotypicvs. heterotypic interactions on the cellular uptake of extracellular vesicles

Jhaveri,

Khare,

Pinky

et al. 2023

Preprint

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Extracellular vehicles (EVs) are an emerging class of drug carriers and are largely known to be internalized into recipient cells via a combination of endocytic routes such as clathrin-mediated, caveolae-mediated and macropinocytosis pathways. In this work, (1) we investigated potential effects of homotypic vs. heterotypic interactions by studying the cellular uptake of homologous EVs (EV donor cells and recipient cells of the same type) vs. heterologous EVs (EV donor cells and recipient cells of different types) and (2) determined the route of EV internalization into low pinocytic/hard-to-deliver cell models such as brain endothelial cells (BECs). We used BECs and macrophages as low-pinocytic and phagocytic cell models, respectively, to study the effect of homotypic vs. heterotypic interactions on EV uptake in the recipient cells. Homotypic interactions led to a greater extent of uptake into the recipient BECs compared to heterotypic interactions. However, we did not see a complete reduction in EV uptake into recipient BECs when endocytic pathways were blocked using pharmacological inhibitors. Our results suggest that EVs primarily use membrane fusion to enter low-pinocytic recipient BECs instead of relying on endocytosis. Lipophilic PKH67 dye-labeled EVs but not intravesicular esterase-activated calcein ester-labeled EVs severely reduced particle uptake into BECs while phagocytic macrophages internalized both types of EV-labeled particles to comparable extents. Our results also highlight the importance of carefully choosing labeling dye chemistry to study EV uptake, especially in the case of low pinocytic cells such as BECs.

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Section: Resultsmentioning

confidence: 99%

Effect of homotypicvs. heterotypic interactions on the cellular uptake of extracellular vesicles

Jhaveri,

Khare,

Pinky

et al. 2023

Preprint

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“…EVs can traverse the BBB and facilitate substance transport between the blood and the brain, playing a crucial role in maintaining the BBB's structural and functional integrity. Recent research indicates that mitochondrial‐enriched endothelial cell‐derived exosomes can restore TJ integrity by increasing ATP levels and restoring mitochondrial function 132 . In addition, exercise has been demonstrated to improve the BBB's structure and function by promoting the expression of TJ‐related proteins, inducing endothelial cell proliferation, and altering the types of miRNAs in exosomes in peripheral blood 133 …”

Section: Regulation Of Evs On Biological Barriersmentioning

confidence: 99%

“…Recent research indicates that mitochondrial-enriched endothelial cell-derived exosomes can restore TJ integrity by increasing ATP levels and restoring mitochondrial function. 132 In addition, exercise has been demonstrated to improve the BBB's structure and function by promoting the expression of TJ-related proteins, inducing endothelial cell proliferation, and altering the types of miRNAs in exosomes in peripheral blood. 133 In certain pathological conditions, EVs have been observed to potentially contribute to the breakdown of the BBB, and facilitate brain inflammation and tumor metastasis.…”

Section: Regulation Of Evs On Bbbsmentioning

confidence: 99%

Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery

Zeng,

Li,

Xia

et al. 2024

Bioengineering & Transla Med

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The biological barriers of the body, such as the blood–brain, placental, intestinal, skin, and air‐blood, protect against invading viruses and bacteria while providing necessary physical support. However, these barriers also hinder the delivery of drugs to target tissues, reducing their therapeutic efficacy. Extracellular vesicles (EVs), nanostructures with a diameter ranging from 30 nm to 10 μm secreted by cells, offer a potential solution to this challenge. These natural vesicles can effectively pass through various biological barriers, facilitating intercellular communication. As a result, artificially engineered EVs that mimic or are superior to the natural ones have emerged as a promising drug delivery vehicle, capable of delivering drugs to almost any body part to treat various diseases. This review first provides an overview of the formation and cross‐species uptake of natural EVs from different organisms, including animals, plants, and bacteria. Later, it explores the current clinical applications, perspectives, and challenges associated with using engineered EVs as a drug delivery platform. Finally, it aims to inspire further research to help bioengineered EVs effectively cross biological barriers to treat diseases.

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“…We studied exosomes (EXOs) and microvesicles (MVs) separately and collectively refer to EXOs and MVs as extracellular vesicles (EVs) wherever applicable. EXOs and MVs were isolated from the conditioned medium of mBECs or hBECs using the differential ultracentrifugation method described earlier [31,35,36]. Briefly, mBECs and hBECs were cultured in complete growth medium in tissue culture flasks with a growth area of 175 cm 2 (T175).…”

Section: Isolation Of Exosomes and Microvesicles From Mbec And Hbec C...mentioning

confidence: 99%

“…This study was performed in accordance with the guidelines provided by the National Institute of Health and followed RIGOR guidelines. Only male animals were used in this study to allow comparisons to earlier studies [31] and to exclude potential sex and estrogen-related effects. Animals were randomly assigned to treatment groups.…”

Section: Measurement Of Mitochondrial Function Using Seahorse Analysismentioning

confidence: 99%

Mitochondria-containing extracellular vesicles from mousevs. human brain endothelial cells for ischemic stroke therapy

Dave,

Venna,

Rao

et al. 2024

Preprint

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Ischemic stroke-induced mitochondrial dysfunction in the blood-brain barrier-forming brain endothelial cells (BECs) results in long-term neurological dysfunction post-stroke. We previously reported that intravenous administration of human BEC (hBEC)-derived mitochondria-containing extracellular vesicles (EVs) showed a potential efficacy signal in a mouse middle cerebral artery occlusion (MCAo) model of stroke. We hypothesized that EVs harvested from donor species homologous to the recipient species (e.g., mouse) may improve therapeutic efficacy, and therefore, use of mouse BEC (mBEC)-derived EVs may improve post-stroke outcomes in MCAo mice. We investigated if EVs derived from the same species as the recipient cell (mBEC-EVs and recipient mBECs or hBECs-EVs and recipient hBECs) show a greater EV mitochondria delivery efficiency than cross-species EVs and recipient cells (mBEC-EVs and recipient hBECs or vice versa). Our results showed that mBEC-EVs outperformed hBEC-EVs in transferring EV mitochondria to the recipient ischemic mBECs, and improved mBEC mitochondrial function via increasing oxygen consumption rate. mBEC-EVs significantly reduced brain infarct volume and improved behavioral recovery compared to vehicle-injected MCAo mice. Our data suggests that mBEC-EVs show superior therapeutic efficacy in a mouse MCAo stroke model compared to hBEC-EVs, supporting the continued use of mBEC-EVs to optimize the therapeutic potential of mitochondria-containing EVs in preclinical studies.

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Mitochondria-containing extracellular vesicles (EV) reduce mouse brain infarct sizes and EV/HSP27 protect ischemic brain endothelial cultures

Cited by 18 publications

References 88 publications

Effect of homotypicvs. heterotypic interactions on the cellular uptake of extracellular vesicles

Effect of homotypicvs. heterotypic interactions on the cellular uptake of extracellular vesicles

Micro Trojan horses: Engineering extracellular vesicles crossing biological barriers for drug delivery

Mitochondria-containing extracellular vesicles from mousevs. human brain endothelial cells for ischemic stroke therapy

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