Salvaging the No-Reflow Zone: Intra-arterial Cranial Bone-Derived MSCs Restore Neurovascular Integrity After Stroke

Successful macrovascular recanalization does not always translate into functional recovery, in part because early post-reperfusion injury can drive infarct expansion. Here, we investigated whether hyperacute intra-arterial transplantation of human cranial bone-derived mesenchymal stem cells (hcMSCs) immediately after reperfusion improves functional recovery after ischemic stroke. Transient middle cerebral artery occlusion was induced in adult rats, followed by intra-arterial administration of hcMSCs or vehicle immediately after reperfusion. Neurological and motor pathway recovery were assessed longitudinally using the modified neurological severity score and transcranial motor-evoked potentials. During the acute phase, molecular and histological analyses of peri-infarct tissue were performed and the transcriptomic profiles of hcMSCs compared with those of human bone marrow-derived mesenchymal stem cells (hbMSCs). Hyperacute intra-arterial hcMSC transplantation resulted in significantly faster neurological recovery compared with controls, accompanied by enhanced electrophysiological recovery of motor pathway function. These functional improvements were associated with preservation of neuronal structural integrity in the peri-infarct cortex, attenuation of inflammatory cytokines and apoptosis activity, and vascular endothelial growth factor upregulation. Further, transcriptomic analysis revealed that hcMSCs are enriched in neurotrophic, angiogenic, and immunoregulatory factors, providing a biological support for the observed therapeutic effects. Hyperacute intra-arterial hcMSC delivery immediately after reperfusion promotes functional and electrophysiological recovery in an experimental reperfusion model, likely through early modulation of inflammatory and apoptotic responses in the peri-infarct tissue. These findings support further investigation of hcMSC therapy as a biologically protective adjunctive strategy in the immediate post-recanalization setting.