Cell Therapy as Metabolic Rescue after Ischemic Stroke: Rewiring Bioenergetics, Redox Homeostasis, and Neurovascular Repair

Ischemic stroke represents a dynamic metabolic disorder of the neurovascular unit (NVU) rather than a static vascular occlusion followed by neuronal demise. Immediate oxygen and glucose deprivation rapidly deplete ATP, disrupt the transmembrane ionic gradients, increase glutamate excitotoxicity, and overload mitochondrial with calcium. These events alter glycolytic, lipid, amino acid, and redox pathways. During the subacute and chronic phases, astrocytes, microglia, macrophages, endothelial cells, pericytes, oligodendrocytes, and surviving neurons continue to remodel substrate utilization. These phase-specific metabolic programs either accelerate infarct expansion and blood-brain barrier disruption or facilitate angiogenesis, synaptic plasticity, and tissue repair. Consequently, cell-based therapeutic paradigms have shifted from direct neuronal replacement toward metabolic rescue. Transplanted cells and cell-free derivatives deliver trophic factors, extracellular vesicles, microRNAs, antioxidant signals, mitochondrial cues, and immunoregulatory factors. These signals enhance mitochondrial fitness, restore redox homeostasis, attenuate pro-inflammatory glycolysis, and stabilize endothelial-pericyte coupling to stabilize a permissive neurorehabilitation microenvironment. This review synthesizes post-stroke metabolic landscapes and evaluates how mesenchymal stromal, neural stem/progenitor, endothelial progenitor, cord blood-derived, and mononuclear cells, and extracellular vesicles, may be incorporated into a phase-specific translational framework supported by target-engagement biomarkers and standardized potency assays.