IL-4/C1q activated astrocyte-derived extracellular vesicles promote stroke infarct recovery by recruiting peripheral leukocytes
Regeneration of the necrotic infarct core is not currently a goal of clinical stroke therapies. However, restoring this region would be essential for complete and durable functional recovery after ischemic stroke. We engineered an injectable microporous annealed particle scaffold (MAPS) with covalently anchored extracellular vesicles (EVs) derived from primary astrocytes activated by IL-1α/TNF-α/C1q or IL-4/C1q, and delivered them into the infarct cavity of mice five days post-stroke. Only MAPS with IL-4/C1q-EVs induced robust revascularization, with perfused microvessels forming in the infarct center in 9 days, and motor function restored to near-baseline levels by 8 weeks. These regeneration and functional improvement were associated with selective recruitment of reparative neutrophils and macrophages into the infarct. Neutrophil depletion abrogated angiogenesis, demonstrating that neutrophils are required for mediating tissue repair. This immune-vascular crosstalk is associated with IL-4-induced enrichment of EV cargo, including adhesion- and angiogenesis-related miRNAs, such as miR-377-3p and miR-143-5p.
