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Engineering Extracellular Vesicles to Modulate Their Innate Mitochondrial Load

  • S.I. : 2022 CMBE Young Innovators
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Abstract

Introduction

Extracellular vesicles (EVs) are promising carriers for the delivery of biotherapeutic cargo such as RNA and proteins. We have previously demonstrated that the innate EV mitochondria in microvesicles (MVs), but not exosomes (EXOs) can be transferred to recipient BECs and mouse brain slice neurons. Here, we sought to determine if the innate EV mitochondrial load can be further increased via increasing mitochondrial biogenesis in the donor cells. We hypothesized that mitochondria-enriched EVs (“mito-EVs”) may increase the recipient BEC ATP levels to a greater extent than naïve MVs.

Methods

We treated NIH/3T3, a fibroblast cell line and hCMEC/D3, a human brain endothelial cell (BEC) line using resveratrol to activate peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), the central mediator of mitochondrial biogenesis. Naïve EVs and mito-EVs isolated from the non-activated and activated donor cells were characterized using transmission electron microscopy, dynamic light scattering and nanoparticle tracking analysis. The effect of mito-EVs on resulting ATP levels in the recipient BECs were determined using Cell Titer Glo ATP assay. The uptake of Mitotracker Red-stained EVs into recipient BECs and their colocalization with recipient BEC mitochondria were studied using flow cytometry and fluorescence microscopy.

Results

Resveratrol treatment increased PGC-1α expression in the donor cells. Mito-MVs but not mito-EXOs showed increased expression of mitochondrial markers ATP5A and TOMM20 compared to naïve MVs. TEM images showed that a greater number of mito-MVs contained mitochondria compared to naïve MVs. Mito-MVs but not mito-EXOs showed a larger particle diameter compared to their naïve EV counterparts from the non-activated cells suggesting increased mitochondria incorporation. Mito-EVs were generated at higher particle concentrations compared to naïve EVs from non-activated cells. Mito-EVs increased the cellular ATP levels and transferred their mitochondrial load into the recipient BECs. Mito-MV mitochondria also colocalized with recipient BEC mitochondria.

Conclusions

Our results suggest that the pharmacological modulation of mitochondrial biogenesis in the donor cells can change the mitochondrial load in the secreted MVs. Outcomes of physicochemical characterization studies and biological assays confirmed the superior effects of mito-MVs compared to naïve MVs—suggesting their potential to improve mitochondrial function in neurovascular and neurodegenerative diseases.

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Funding

Maura Farinelli and Abigail Sullivan’s NURE fellowship were supported through a grant from the National Institute of Neurological Disorders and Stroke (5R25NS100118-04) and this study was supported via start-up funds to Devika S. Manickam (Duquesne University).

Conflict of interest

The authors declare no conflicts of interest.

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Author notes

  1. Maura N. Farinelli and Abigail Sullivan have contributed equally to this study.

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, 453 Mellon Hall, Pittsburgh, PA, USA

    Kandarp M. Dave, Duncan X. Dobbins, Maura N. Farinelli, Abigail Sullivan & Devika S. Manickam

  2. Department of Biochemistry and Molecular Biology, Gettysburg College, Gettysburg, PA, USA

    Maura N. Farinelli

  3. Psychological and Brain Sciences, Villanova University, Villanova, PA, USA

    Abigail Sullivan

  4. Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA

    Jadranka Milosevic, Jeongyun Kim & Siyang Zheng

  5. Captis Diagnostics Inc, Pittsburgh, PA, USA

    Jadranka Milosevic

  6. Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA, USA

    Donna B. Stolz

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  1. Kandarp M. Dave
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Dave, K.M., Dobbins, D.X., Farinelli, M.N. et al. Engineering Extracellular Vesicles to Modulate Their Innate Mitochondrial Load. Cel. Mol. Bioeng. 15, 367–389 (2022). https://doi.org/10.1007/s12195-022-00738-8

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