Abstract: Acute ischemic stroke remains a significant health concern owing to the limited efficacy of current therapeutic options. In recent years, Neuregulin-1 has exhibited promising neuroprotective effects in cerebral ischemia. However, the sources and functions of Neuregulin-1 have not yet been fully understood, which hinders its translation and broad application. Here, we collected paired clot and peripheral blood samples from patients with acute ischemic stroke to determine the sources of Neuregulin-1. In addition, we established an in vivo transient middle cerebral artery occlusion mouse model to investigate the therapeutic effects of Neuregulin-1 and its underlying molecular biological mechanisms. We observed a significant elevation in serum Neuregulin-1 levels among patients with acute ischemic stroke that correlated with severity of neurological impairment and clinical outcome. Using single-cell sequencing, we identified Neuregulin-1-positive macrophages among peripheral blood mononuclear cells that produced Neuregulin-1 postischemia. In addition, Neuregulin-1 promoted repair of the infarcted area, alleviating neuronal and myelin damage and improving overall behavioral recovery in mice. We found that Neuregulin-1 may exert these neuroprotective effects by promoting angiogenesis in the infarct area, and that this effect is mediated by Akt/mTOR/VEGF-dependent signaling. Our findings suggest that peripheral macrophages are a source of Neuregulin-1 post-stroke. Neuregulin-1 exerts its neuroprotective effects by promoting angiogenesis via Akt/mTOR/VEGF-dependent signaling, showing promising clinical translation potential.

Key words: acute ischemic stroke, angiogenesis, Clot, ErbB4, fluorescence-activated cell sorting, immune cell, inflammation, macrophages, Neuregulin-1, neuroprotection