Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells have unique characteristics that promote cerebral angiogenesis, brain remodeling and neurological recovery after focal cerebral ischemia in mice

• DOI: 10.1007/s00395-021-00881-9
• Publication Date: 2021-06-08T17:03:17Z
• Authors: Jonas Gregorius; Chen Wang; Oumaima Stambouli; Tanja Hussner; Yachao Qi; Tobias Tertel; Verena Börger; Ayan Mohamud Yusuf; Nina Hagemann; Dongpei Yin; Robin Dittrich; Yanis Mouloud; Fabian D. Mairinger; Fouzi El Magraoui; Aurel Popa-Wagner; Christoph Kleinsc...; Thorsten R. Doeppner; Matthias Gunzer; Helmut E. Meyer; Bernd Giebel; Dirk M. Hermann
• Keywords: Neuronal survival ; Angiogenic Proteins/genetics [MeSH] ; Mice, Inbred C57BL [MeSH] ; Original Contribution ; Cell Movement [MeSH] ; Tube formation ; Angiogenic Proteins/metabolism [MeSH] ; Infarction, Middle Cerebral Artery/metabolism [MeSH] ; Male [MeSH] ; Extracellular Vesicles/metabolism [MeSH] ; Neovascularization, Physiologic [MeSH] ; MicroRNAs/genetics [MeSH] ; Polymorphonuclear neutrophil ; Disease Models, Animal [MeSH] ; Infarction, Middle Cerebral Artery/surgery [MeSH] ; Cell Hypoxia [MeSH] ; Endothelial Cells/metabolism [MeSH] ; Cell Proliferation [MeSH] ; Infarction, Middle Cerebral Artery/physiopathology [MeSH] ; Recovery of Function [MeSH] ; Humans [MeSH] ; Microvascular network characteristics ; MicroRNAs/metabolism [MeSH] ; Neurons/metabolism [MeSH] ; Extracellular Vesicles/transplantation [MeSH] ; Microvessels/physiopathology [MeSH] ; Animals [MeSH] ; Endothelial migration ; Time Factors [MeSH] ; Mesenchymal Stem Cells/metabolism [MeSH] ; Microvessels/metabolism [MeSH] ; Brain/blood supply [MeSH] ; Vascular Remodeling [MeSH] ; Neurons/pathology [MeSH] ; Signal Transduction [MeSH] ; Cells, Cultured [MeSH] ; Microvascular remodeling; Male; 0301 basic medicine; Medizin; Neovascularization, Physiologic; Extracellular Vesicles; 03 medical and health sciences; Cell Movement; Animals; Humans; Angiogenic Proteins; Cells, Cultured; Cell Proliferation; Neurons; Brain; Endothelial Cells; Infarction, Middle Cerebral Artery; Mesenchymal Stem Cells; Original Contribution; Recovery of Function; Cell Hypoxia; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; MicroRNAs; Microvessels

Abstract Obtained from the right cell-type, mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) promote stroke recovery. Within this process, microvascular remodeling plays a central role. Herein, we evaluated effects of MSC-sEVs on proliferation, migration, and tube formation human cerebral endothelial cells (hCMEC/D3) in vitro post-ischemic angiogenesis, brain neurological recovery after middle artery occlusion (MCAO) mice. In vitro, sEVs obtained hypoxic (1% O 2 ), but not ‘normoxic’ (21% ) MSCs dose-dependently promoted increased survival. regulated distinct set miRNAs hCMEC/D3 previously linked to three being upregulated (miR-126-3p, miR-140-5p, let-7c-5p) downregulated (miR-186-5p, miR-370-3p, miR-409-3p). LC/MS–MS revealed 52 proteins differentially abundant MSCs. 19 were enriched (among them involved matrix–receptor interaction, focal adhesion, leukocyte transendothelial protein digestion, absorption), 33 reduced associated with metabolic pathways, actin cytoskeleton) MSC-sEVs. Post-MCAO, length branching point density ischemic tissue assessed by 3D light sheet microscopy over up 56 days, delayed neuronal degeneration atrophy, enhanced sEV-induced angiogenesis vivo depended presence polymorphonuclear neutrophils. neutrophil-depleted mice, did influence remodeling. have angiogenic properties. Hypoxic preconditioning enhances restorative