NPC-EVs ameliorate ischemic brain injury by enhancing microglial phagocytosis and anti- inflammatory responses via TREM2-mediated lipid metabolic reprogramming

Abstract Inflammation is one of the hallmarks during the pathophysiology of ischemic stroke, among which microglia, as resident immune cells of the brain, play a pivotal role. Despite the latter, recent studies analyzing the precise mechanism by which microglia affect post-stroke neurological outcome remain somewhat limited. Elucidating these mechanisms, however, remains a prerequisite before translational stroke trials are in order. Extracellular vesicles (EVs), significant mediators of intercellular communication, have been demonstrated to possess multiple function of neural repair and neuroregeneration in the pathogenesis and progression of CNS diseases. However, the regulatory role of neural progenitor cell-derived EVs (NPC-EVs) on the phagocytic capacity of microglia post-stroke remains elusive. Using an in vitro stroke model, NPC-EVs effectively drive cultured microglia towards an anti-inflammatory phenotype. Such morphological changes correlate with distinct functional properties of these microglia, which show reduced secretion patterns of pro-inflammatory cytokines and chemokines. In line with this, secretion patterns of anti-inflammatory products are significantly increased, facilitating the efficiency of microglial phagocytosis dependent on TREM2-centric pathways in an in vitro stroke model. NPC-EVs mitigate neuroinflammation and neuronal apoptosis via modulating microglial lipid metabolism, yielding improved neurological recovery in ischemic stroke mice. This provides a novel paradigm for EV-mediated intercellular communication mechanisms and suggests a promising therapeutic potential for NPC-derived EVs in the treatment of ischemic stroke.