OPTIMIZATION OF EXTRACELLULAR VESICLES-BASED THERAPY IN THE TREATMENT OF ISCHEMIC STROKE
Poster Session on the Friday 25th of April at 4:30PM at ISEV Congress in Vienna
Ons BEN HADJ HASSEN1, Sarah RAZAFINDRAKOTO2, Jérôme TOUTAIN1, Isis BLANCHARD1, Viktoriia IVANOVA1, Charlène RENOULT1,3, Xavier LAFFRAY4, Minh-Bao HUYNH4, Carole BRUNAUD1, Karim BORDJI1, Gael LE DOUARON4, Wilton Albeiro Gomez HENAO4, Mohand Ou Idir OUDJA4, Agnès CHOPPIN3, Denis BARRITAULT3, Dulce PAPY-GARCIA4, Amanda SILVA BRUN2*, Franck CHIAPPINI3*, Omar TOUZANI1*, Florence GAZEAU2*, Myriam BERNAUDIN1*
*co-authorship
(1) Université de Caen-Normandie, CNRS, Normandie Université, ISTCT UMR6030, GIP CYCERON, F-14000 Caen, France
(2) NABI, Université Paris Cité, INSERM U1334, CNRS UMR8175, 75006 Paris.
(3) OTR3, 4 rue Française, 75001 Paris, France
(4) Glycobiology, cell growth and tissue repair research unit (Gly-CRRET), Université Paris Est Créteil (UPEC), F-94010, Créteil, France
Introduction: Ischemic stroke remains a major health problem. Extracellular vesicles (EV), derived from mesenchymal stem cells (MSC), have been shown to mitigate brain damage and improve neurorepair and neurological outcome following ischemic stroke. Though promising, EV production and their route of delivery remain a major challenge. Here, the effects of EV generated by an innovative turbulence approach were characterized on stroke-induced brain lesion and neurological deficits in the rat.
Methods: EV were isolated from human adipocyte tissue stromal cells (hASC) using a patented high-yield turbulence bioproduction process. EV were quantified and characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), ExoView and proteomic analyses. Rats were subjected to a transient occlusion (1h) of the middle cerebral artery (tMCAO) and treated with EV at reperfusion time (1010 EV/rat; I.A.) or 24h later (1011 EV/rat; I.V.). MRI were performed at 1 and 14 days after tMCAO to quantify brain lesion volume. Behavioral tests were carried out up to 40 days post-tMCAO.
Results: NTA, TEM and proteomic analyses confirmed EV characteristics (size, shape, tetraspanin expressions). While I.V. EV administration showed limited therapeutic effects. I.A. EV delivery at reperfusion time reduced the lesion volume 24h post-tMCAo compared to the control group (p< 0.05). Moreover, 7 days after tMCAO, rats treated with EV immediately after reperfusion tend to improve their neurological score (p= 0.07) and showed a significantly better limb placing test performance (p<0.05). In addition, these rats were less lateralized compared to the control ones in the corner test and performed better in the adhesive test 30 days after tMCAO (p< 0.01). In contrast, I.V. EV administration 24h post-tMCAO showed only a significant effect on spatial memory (p< 0.05, t-test). Immuno-histological analyses of brain tissues are ongoing to investigate post-ischemic cellular effects.
Summary: These results suggest that 1) MSC-derived EV produced by an original turbulence method are efficacious on stroke-induced brain lesion and neurological deficits and 2) optimizing the administration route and timing enhances the efficacy of EV after stroke. Overall, the results showed that MSC-derived EV produced by an original turbulence method are promising as an efficient therapeutic intervention in ischemic stroke.
