Identification of Schwann Cells in Human Intracranial Arteries: Potential Regulatory Role in Atherosclerotic Plaque Progression

Abstract Intracranial atherosclerosis (ICAS), a common cause of ischemic stroke, remains a therapeutic challenge due to complex intracranial anatomy and intervention risks. Although ICAS develops intracranially, cerebral artery innervation originates in the peripheral nervous system. The scarcity of human intracranial specimens has hindered investigations into the potential role of Schwann cells (SCs) in neurovascular homeostasis. Using multimodal analysis of plaque‐bearing and non‐plaque‐bearing intracranial artery samples from the same postmortem individuals (n = 16 donors), SCs associated with myelinated neural structures are identified. Quantitative ultrastructural evaluation reveals a 4.3‐fold increase in SC‐derived myelin sheaths within plaque‐bearing vessels ( P <0.001). Single‐cell RNA sequencing (scRNA‐seq) of SCs demonstrates significant upregulation of genes involved in axonogenesis, axon ensheathment, axon guidance, synaptic transmission, and synaptic integration. Cell–cell communication analysis shows enhanced interactions between SCs and vascular smooth muscle cells (VSMCs) in plaque‐bearing vessels. Synaptic‐like structures are observed in the walls of intracranial arteries, along with a 2.9‐fold increase in VSMC‐innervating myelinated fibers ( P <0.001). Ligand–receptor analysis indicates SPP1–ITGB1 signaling as a potential mediator of SCs‐VSMCs crosstalk. This study provides evidence for the involvement of SCs in ICAS pathobiology and proposes novel neurovascular targets for precision therapies in cerebrovascular disease.