Ischemic damage in brain tissue triggers a cascade of molecular and structural plastic changes, thus influencing a wide range of cell-to-cell interactions. Understanding and manipulating this scenario of intercellular connections is the Holy Grail for post-stroke neurorehabilitation. Here, we discuss the main findings in the literature related to post-stroke alterations in cell-to-cell interactions, which may be either detrimental or supportive for functional recovery. We consider both neural and non-neural cells, starting from astrocytes and reactive astrogliosis and moving to the roles of the oligodendrocytes in the support of vulnerable neurons and sprouting inhibition. We discuss the controversial role of microglia in neural inflammation after injury and we conclude with the description of post-stroke alterations in pyramidal and GABAergic cells interactions. For all of these sections, we review not only the spontaneous evolution in cellular interactions after ischemic injury, but also the experimental strategies which have targeted these interactions and that are inspiring novel therapeutic strategies for clinical application.

Microglia, the brain-resident immune cells, orchestrate neuroinflammatory responses and are crucial in the progression of neurological diseases, including ischemic stroke (IS), which accounts for approximately 85% of all strokes worldwide. Initially deemed detrimental, microglial activation has been shown to perform protective functions in the ischemic brain. Besides their effects on neurons, microglia play a role in promoting post-ischemic angiogenesis, a pivotal step for restoring oxygen and nutrient supply. However, the molecular mechanisms underlying microglia–endothelial cell interactions remain largely unresolved, particularly in humans. Using both in vitro and in vivo models, we investigated the angiogenic signature and properties of extracellular vesicles (EVs) released by human microglia upon hypoxia–reperfusion stimulation. EVs were isolated and characterized in terms of their size, concentration, and protein content. Their angiogenic potential was evaluated using endothelial cell assays and a zebrafish xenograft model. The in vivo effects were further assessed in a mouse model of ischemic stroke. Our findings identified key proteins orchestrating the pro-angiogenic functions of human microglial EVs under hypoxic conditions. In vitro assays demonstrated that hypoxic EVs (hypEVs) promoted endothelial cell migration and tube formation. In vivo, hypEVs induced vessel sprouting in zebrafish and increased microvessel density in the perilesional area of mice following ischemic stroke.