A new perspective on mesenchymal stem cells and their derivatives in alleviating cerebral ischemia-reperfusion injury...

Cerebral Ischemia-Reperfusion Injury (CIRI) is a common pathological process in ischemic stroke. Its core detriment lies in the cascade of subsequent injuries triggered by blood flow restoration after cerebrovascular recanalization, primarily including oxidative stress burst, calcium overload, immune-inflammatory imbalance, and mitochondrial dysfunction, ultimately leading to massive neuronal apoptosis and necrosis. Mitochondria, as central hubs of cellular energy metabolism and apoptosis regulation, exhibit functional disturbances that represent the initiating and core link in CIRI. CIRI triggers complex remodeling of the immune network. This dysregulated immune-inflammatory response forms a vicious cycle with mitochondrial dysfunction, exacerbating brain tissue damage. Mesenchymal Stem Cells (MSCs) and their derivatives have demonstrated significant potential in treating CIRI due to their potent paracrine and immunomodulatory functions. MSCs can repair neuronal functional basis by enhancing mitochondrial biogenesis, improving energy metabolism, inhibiting mitochondrial pathway-mediated apoptosis, restoring dynamic balance, and promoting normal mitophagy. Although existing reviews have explored the role of MSCs or mitochondrial function in CIRI, few studies have systematically integrated the bidirectional regulatory relationship between dynamic mitochondrial function and immune network remodeling. Furthermore, an in-depth analysis of the temporal therapeutic effects of MSCs and their derivatives across different pathological stages of CIRI is lacking. To address this gap, this review proposes a therapeutic strategy: MSCs exert synergistic neuroprotective effects by improving mitochondrial function through multiple targets while systematically reshaping the imbalanced immune network. This review summarizes the latest evidence regarding the temporal therapeutic role of MSCs via the "immune-mitochondrial" axis at different stages of CIRI. It elucidates the pivotal role of mitochondria as a central hub connecting metabolic crisis and immune storm, and untangles novel mechanisms such as MSC-mediated mitochondrial transfer and immune cell metabolic reproprogramming, providing a theoretical foundation for developing novel stroke therapies based on cell therapy.