Circulating extracellular vesicles promote recovery in a preclinical model of intracerebral hemorrhage

Laso-García F, Casado-Fernández L, Piniella D et al. Mol Ther Nucleic Acids. 2023 Mar 21;32:247-262. doi: 10.1016/j.omtn.2023.03.006. eCollection 2023 Jun 13. PMID: 37090418

Abstract: Circulating extracellular vesicles (EVs) are proposed to participate in enhancing pathways of recovery after stroke through paracrine signaling. To verify this hypothesis in a proof-ofconcept study, blood-derived allogenic EVs from rats and xenogenic EVs from humans who experienced spontaneous good recovery after an intracerebral hemorrhage (ICH) were administered intravenously to rats at 24 h after a subcortical ICH. At 28 days, both treatments improved the motor function assessment scales score, showed greater fiber preservation in the perilesional zone (diffusion tensor-fractional anisotropy MRI), increased immunofluorescence markers of myelin (MOG), and decreased astrocyte markers (GFAP) compared with controls. Comparison of the protein cargo of circulating EVs at 28 days from animals with good vs. poor recovery showed down expression of immune system activation pathways (CO4, KLKB1, PROC, FA9, and C1QA) and of restorative processes such as axon guidance (RAC1), myelination (MBP), and synaptic vesicle trafficking (SYN1), which is in line with better tissue preservation. Up-expression of PCSK9 (neuron differentiation) in xenogenic EVs-treated animals suggests
enhancement of repair pathways. In conclusion, the administration of blood-derived EVs improved recovery after ICH. These findings open a new and promising opportunity for
further development of restorative therapies to improve the outcomes after an ICH.

Funding: The experimental animal model study was approved by the Ethics Committee for Research in Animals at the La Paz University Hospital and authorized by the Madrid Regional Government. Animal care and experimental procedures were designed in accordance with our medical school’s Ethical Committee for the Care and Use of Animals
in Research (Ref. PROEX 159/17) according to the Spanish (RD 1201/ 2005 and RD53/2013) and EU (86/609/CEE, 2003/65/CE, and 2010/ 63/EU) rules. This work was supported by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union (European Regional Development Fund -FEDER) under grant PI17/01922 and PI20/00243; Invictus plus network under grant RD16/0019/0005; RICORS network under grant RD21/0006/0012; Miguel Servet under grant CP15/00069 and CPII20/00002 to M.G.-F. and CP20/00024 to L.O.-O.; Sara Borrell under grant CD19/00033 to M.P.-M., CD20/00112 to M.d.P.C.-V. and CD21/00059 to J.A.-O.; Ministerio de Universidades, Plan de Recuperación, Transformación y Resiliencia, Universidad Autónoma de Madrid under grant CA1/RSUE/2021-00753 to D.P.-A.; and the Spanish Ministry of Health-ISCIII under grant FI18/00026 to F.L.-G. and FI17/00188 to M.C.G.-d.F.