Intercellular Communication: Novel Perspectives on Stroke Therapeutic Strategies

Stroke is one of the leading causes of death and disability globally, with ischemic stroke comprising approximately 87% of all cases. Although reperfusion therapies such as tissue-type Plasminogen Activator (tPA) are currently available, their clinical utility is severely limited by narrow therapeutic time windows and the risk of hemorrhagic transformation. Recent advances have revealed that ischemic stroke is not merely a localized vascular occlusion but a systemic pathological event governed by the Neurovascular Unit (NVU), including neurons, glial cells (astrocytes and microglia), vascular cells (endothelial cells and pericytes), and peripheral immune cells. Therefore, understanding the alterations in these diverse cell types and their underlying mechanisms holds significant importance for developing effective treatments for stroke. This review integrates current knowledge on the complex intercellular communication mechanisms within the NVU and at its periphery. We discuss how the functional polarization of astrocytes (neurotoxic A1 vs. neuroprotective A2) and microglia (M1/M2 phenotypes) dictate neuronal fate and neuroinflammatory responses. Additionally, we describe NVU-mediated regulation of cerebral blood flow and BBB permeability, as well as the interplay between peripheral and central immune responses in the context of stroke. Furthermore, we highlight novel communication modalities, specifically exosomes, which shuttle miRNAs and proteins to modulate distal inflammation, and Tunneling Nanotubes (TNTs), which facilitate the direct intercellular transfer of vital organelles, such as mitochondria. These dynamic interactions represent critical nodes for therapeutic intervention. Taken together, targeting the interactions of intercellular communication represents a promising frontier for achieving comprehensive functional recovery after ischemic stroke.