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

Autor: Dave KM; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Stolz DB; Center for Biologic Imaging, University of Pittsburgh Medical School, Pittsburgh, PA, USA., Venna VR; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA., Quaicoe VA; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA., Maniskas ME; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA., Reynolds MJ; Pittsburgh Heart Lung Blood Vascular Institute, University of Pittsburgh Medical School, Pittsburgh, PA, USA., Babidhan R; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Dobbins DX; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Farinelli MN; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA; Department of Biochemistry and Molecular Biology, Gettysburg College, Gettysburg, PA, USA., Sullivan A; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA; Psychological and Brain Sciences, Villanova University, Villanova, PA, USA., Bhatia TN; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Yankello H; Departments of Chemical and Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA., Reddy R; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Bae Y; Department of Pharmaceutical Sciences, College of Pharmacy, The University of Kentucky, Lexington, KY, USA., Leak RK; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA., Shiva SS; Pittsburgh Heart Lung Blood Vascular Institute, University of Pittsburgh Medical School, Pittsburgh, PA, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh Medical School, Pittsburgh, PA, USA., McCullough LD; Department of Neurology, McGovern Medical School, University of Texas Health Science Center, Houston, TX, USA., Manickam DS; Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA, USA. Electronic address: soundaramanickd@duq.edu.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2023 Feb; Vol. 354, pp. 368-393. Date of Electronic Publication: 2023 Jan 18.
DOI: 10.1016/j.jconrel.2023.01.025
Abstrakt: Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of BEC-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous 27 kDa heat shock protein (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, that subsequently colocalized with the mitochondrial network of the recipient primary human BECs. Recipient BECs treated with m/lEVs showed increased relative ATP levels and mitochondrial function. To determine if the m/lEV-meditated increase in recipient BEC ATP levels was associated with m/lEV mitochondria, we isolated m/lEVs from donor BECs pre-treated with oligomycin A (OGM, mitochondria electron transport complex V inhibitor), referred to as OGM-m/lEVs. BECs treated with naïve m/lEVs showed a significant increase in ATP levels compared to untreated OGD cells, OGM-m/lEVs treated BECs showed a loss of ATP levels suggesting that the m/lEV-mediated increase in ATP levels is likely a function of their innate mitochondrial load. In contrast, sEV-mediated ATP increases were not affected by inhibition of mitochondrial function in the donor BECs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EVs with a cationic polymer, poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two punch approach to increase BEC metabolic function and tight junction integrity may be a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.
(Copyright © 2023 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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