Mitochondria-containing Extracellular Vesicles (EV) Reduce Mouse Brain Infarct Sizes and EV/HSP27 Protect Ischemic Brain Endothelial Cultures

• DOI: 10.1101/2021.10.29.466491
• Publication Date: 2021-11-01T03:25:14Z
• Authors: Kandarp M. Dave; Donna B. Stolz; Venugopal R. Venna; Victoria A. Quaicoe; Michael E. Maniskas; Michael John Reyn...; Riyan Babidhan; Duncan X. Dobbins; Maura N. Farinelli; Abigail Sullivan; Tarun N. Bhatia; Hannah Yankello; Rohan Reddy; Younsoo Bae; Rehana K. Leak; Sruti S. Shiva; Louise D. McCullough; Devika S Manickam
• Keywords: Hsp27

Abstract Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed innate mitochondrial load cell-derived extracellular vesicles (EVs) utilized mixtures EV/exogenous heat shock protein 27 (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) preserve their HSP27 effects). demonstrated that medium-to-large (m/lEV) but not small EVs (sEV) transferred load, which subsequently colocalized with network recipient primary human BECs. BECs treated m/lEVs increased relative ATP levels displayed superior function. Importantly, isolated from oligomycin (mitochondrial complex V inhibitor) or rotenone I inhibitor)-exposed (RTN-m/lEVs OGM-m/lEVs) did compared naïve m/lEVs. In contrast, RTN-sEV OGM-sEV functionality in increasing cellular was minimally impacted comparison sEVs. Intravenously administered showed reduction infarct sizes vehicle-injected mice mouse middle cerebral artery occlusion model ischemic stroke. formulated binary recombinant EVs: EV/HSP27 ternary cationic polymer poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV decreased paracellular permeability large molecular mass fluorescent tracers oxygen glucose-deprived This one-two-punch approach metabolic function is promising for BBB protection prevention long-term neurological dysfunction post-ischemic Graphical Highlights Medium-to-large (m/lEVs), contain mitochondria cells (BECs) oligomycin-exposed injected reduced dextran molecule across