Human Amnion-Derived Mesenchymal Stromal Cell Exosomes Promote Neuroprotection and Neurovascular Remodeling after Cerebral Ischemia.

Abstract

BACKGROUND: Ischemic stroke remains a leading cause of death and long-term disability worldwide, and effective neuroprotective therapies applicable to a broad patient population are still limited. Although mesenchymal stromal cell-derived exosomes (MSC-EXO) have emerged as promising cell-free therapeutic agents, evidence regarding exosomes derived from human amnion-derived mesenchymal stromal cells (AMSC-EXO) in cerebral ischemia remains scarce. METHODS: Human AMSC-EXO were isolated from conditioned media of cultured human amnion-derived mesenchymal stromal cells and characterized by nanoparticle tracking analysis and exosomal marker expression. Male mice were subjected to middle cerebral artery occlusion and randomly assigned to receive intravenous AMSC-EXO or vehicle 24 h after ischemia. Neurological function, motor coordination, and spatial working memory were assessed at 3 and 14 days. Post-ischemic neuroinflammation, neuronal degeneration, and endothelial cell proliferation were evaluated by immunohistochemistry and enzyme-linked immunosorbent assay in a blinded manner. RESULTS: Systemic administration of AMSC-EXO significantly improved neurological outcomes and motor performance after cerebral ischemia and enhanced spatial working memory. AMSC-EXO treatment markedly suppressed microglial activation and reduced the expression of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, and interleukin-6, in the ischemic brain. In addition, neuronal degeneration in the cortical infarct border zone was significantly attenuated. At later stages, AMSC-EXO significantly increased the number of proliferating endothelial cells, suggesting a potential involvement in neurovascular remodeling. CONCLUSION: Human AMSC-derived exosomes exert neuroprotective and neurovascular restorative effects after cerebral ischemia by suppressing post-ischemic neuroinflammation, reducing neuronal cell death, and promoting endothelial cell proliferation. AMSC-EXO represents a promising, scalable, and cell-free therapeutic strategy for ischemic stroke.