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

• Published in: Journal of controlled release Vol. 373; pp. 803 - 822
• Main Authors: Dave, Kandarp M., Venna, Venugopal R., Rao, Krithika S., Stolz, Donna B., Brady, Bodhi, Quaicoe, Victoria A., Maniskas, Michael E., Hildebrand, Ella E., Green, Dawson, Chen, Mingxi, Milosevic, Jadranka, Zheng, Si-yang, Shiva, Sruti S., McCullough, Louise D., S Manickam, Devika
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-09-2024
• Subjects: BBB metabolic protection; Brain endothelial cells (BECs); Exosomes (120K EVs); Extracellular vesicles (EVs); Ischemic stroke; Microvesicles (20K EVs); Mitochondria; Extracellular vesicles (EVs); Mitochondria; BBB metabolic protection; Microvesicles (20K EVs); Exosomes (120K EVs); Ischemic stroke; Brain endothelial cells (BECs)
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2024.07.065

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 data from a pilot study where 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 potential differences in the mitochondria transfer of EVs derived from the same species as the recipient cell (mBEC-EVs and recipient mBECs or hBECs-EVs and recipient hBECs) vs. cross-species EVs and recipient cells (mBEC-EVs and recipient hBECs or vice versa). Our results showed that while both hBEC- and mBEC-EVs transferred EV mitochondria, mBEC-EVs outperformed hBEC-EVs in increasing ATP levels and improved recipient mBEC mitochondrial function via increasing oxygen consumption rates. mBEC-EVs significantly reduced brain infarct volume and neurological deficit scores compared to vehicle-injected MCAo mice. The superior therapeutic efficacy of mBEC-EVs in MCAo mice support the continued use of mBEC-EVs to optimize the therapeutic potential of mitochondria-containing EVs in preclinical mouse models.
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