Bone marrow-derived mesenchymal stem cells for ischemic stroke: mechanisms, delivery strategies, clinical evidence, and translational challenges

Ischemic stroke remains a major global health burden because of its high incidence, disability, and mortality. Current reperfusion therapies are constrained by narrow therapeutic windows and have limited capacity to reverse established neuronal injury or promote long-term functional recovery, highlighting the need for strategies that support neural repair and neurovascular remodeling. Bone marrow-derived mesenchymal stem cells (BMSCs) have been widely investigated as candidate therapeutic products for ischemic stroke because of their paracrine, immunomodulatory, trophic, angiogenic, and microenvironment-regulating properties. Current evidence suggests that their therapeutic effects are more likely mediated by regulation of the post-ischemic microenvironment than by direct neuronal replacement. This narrative review discusses BMSC-based strategies for ischemic stroke by integrating evidence from preclinical models, early clinical studies, and translational research. We summarize major proposed mechanisms, including regulation of neuroinflammation, suppression of apoptosis and oxidative stress, blood-brain barrier protection, angiogenesis, neurotrophic support, axonal remodeling, and myelin repair. Emerging mechanisms, such as autophagy regulation, mitochondrial transfer, and extracellular vesicle-mediated effects, are also discussed according to their current level of evidence. In addition, this review evaluates delivery routes, functional enhancement strategies, BMSC-derived extracellular vesicles, combination approaches, clinical evidence, and key translational barriers. Particular attention is given to the distinction between experimentally supported mechanisms, early clinical safety and feasibility signals, and unresolved issues related to optimal dose, administration timing, route-dependent biodistribution, product heterogeneity, mechanism-linked potency assays, and Good Manufacturing Practice-compatible manufacturing. This review provides a balanced framework for understanding the therapeutic potential, current limitations, and future development requirements of BMSC-based therapies for ischemic stroke.