Ischemic stroke is a major cause of death and disability, intensely demanding innovative and accessible therapeutic strategies. Approaches presenting a prolonged period for therapeutic intervention and new treatment administration routes are promising tools for stroke treatment. Here, we evaluated the potential neuroprotective properties of nasally administered human adipose tissue mesenchymal stem cell (hAT-MSC)-derived extracellular vesicles (EVs) obtained from healthy individuals who underwent liposuction. After a single intranasal EV (200 µg/kg) administered 24 h after a focal permanent ischemic stroke in rats, a higher number of EVs, improvement of the blood–brain barrier, and re-stabilization of vascularization were observed in the recoverable peri-infarct zone, as well as a significant decrease in infarct volume. In addition, EV treatment recovered long-term motor (front paws symmetry) and behavioral impairment (short- and long-term memory and anxiety-like behavior) induced by ischemic stroke. In line with these findings, our work highlights hAT-MSC-derived EVs as a promising therapeutic strategy for stroke.

This study aimed to compare the effects of a permanent ischemic stroke model (focal ischemia by thermocoagulation of pial vessels) on sensorimotor function (cylinder test and adhesive removal test), behavioral tasks (novelty habituation memory-open field task), and cerebral infarct size in adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats over 42 days after the occurrence of stroke. We observed that the stroke caused asymmetry in the front paws and delayed adhesive removal. These effects were spontaneously reduced in WKY rats, but not in SHR. Short- and long-term novelty habituation memories were abolished by stroke in WYK and SHR. On the 3rd day after stroke, the size of the focal cerebral infarct was the same in WKY and SHR. However, on the 7th day, the infarct size decreased in WKY rats, but not SHR. These results suggested that SAH impairment of sensorimotor recovery in rats subjected to cerebral ischemia could be related to augmented focal cerebral infarct size. Moreover, the behavioral tasks used in this study were unaffected by Systemic Arterial Hypertension. Our results highlight the need for animal models of comorbidities in stroke research.

This study aimed to analyze the effects of systemic arterial hypertension (SAH) in a model of permanent ischemic stroke (focal ischemia due to thermocoagulation of pial vessels) on sensorimotor function (cylinder test and patch removal test), behavioral tasks (novelty habituation memory open field task) and cerebral infarct size in adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) for 42 days after the occurrence of a stroke. We observed that the stroke caused asymmetry in the front paws and delayed adhesive removal. These effects were spontaneously reduced in WKY rats, but not in SHR. Short- and long-term novelty habituation memories were abolished by stroke in WYK and SHR. On the 3rd day after stroke, the size of the focal cerebral infarct was the same in WKY and SHR. However, on the 7th day, the infarct size decreased in WKY rats, but not SHR. These results suggested that SAH impairment of sensorimotor recovery in rats subjected to cerebral ischemia could be related to augmented focal cerebral infarct size. Moreover, the behavioral tasks used in this study were unaffected by Systemic Arterial Hypertension. Our results highlight the need for animal models of comorbidities in stroke research.

Background: Ischemic stroke (IS) is a risk factor for Alzheimer's disease (AD). In this context, microglial reactivity, a cellular response present in both conditions, has emerged as a promising target for therapeutic development. In a previous meta‐analysis, we showed that mesenchymal stem cell‐derived extracellular vesicles (MSC‐EVs) modulate microglial reactivity in animal models of IS. However, microglial responses dynamically change during early and late phases of IS. Thus, we aimed to investigate whether the effects of MSC‐EVs on microglia are different depending on disease phase. Methods: The meta‐analysis protocol was registered in PROSPERO (CDR42023463152) and followed the PRISMA 2020 statement. We searched EMBASE, PubMed, and Web of Science until January 2025 for studies assessing microglial reactivity following MSC‐EVs treatment in animal models of IS. We calculated standardized mean differences (SMD) via an inverse‐variance weight random‐effects model using the metaviz and metafor packages in R. Subgroup analyses were performed based on IS phases, defined as early (48–72h post‐ischemia) and late (≥168h). Results: Database search identified 386 studies, of which 35 were included (Figure 1). MSC‐EVs significantly reduced the number of Iba1+ cells and Iba1+ cells co‐expressing the pro‐inflammatory markers CD16, CD32, and iNOS in both early (SMD = ‐2.85 [95% CI: ‐4.12, ‐1.57], p <0.001; SMD = ‐1.98 [95% CI: ‐3.46, ‐0.51], p = 0.008; Figure 2B and 2E, respectively) and late (SMD = ‐1.07 [95% CI: ‐1.74, ‐0.40], p = 0.002; SMD = ‐1.41 [95% CI: ‐2.31, ‐0.51], p <0.001; Figure 2C and 2F, respectively) subgroups. Conversely, MSC‐EVs significantly increased the number of Iba1+ cells co‐expressing the anti‐inflammatory markers Arg‐1 and CD206 in both early (SMD = 2.01 [95% CI: 1.02, 3.00], p <0.001; Figure 2H) and late (SMD = 1.14 [95% CI: 0.56, 1.72], p <0.001; Figure 2I) subgroups. Conclusion: We demonstrated that MSC‐EVs consistently decreased pro‐inflammatory and increased anti‐inflammatory microglial responses in animal models of IS regardless of disease phase. These findings indicate that MSC‐EVs exert persistent modulatory effects on microglia, potentially contributing to the recovery of damaged brain tissue in IS and, consequently, in AD.