Clinical state and future directions of stem cell therapy in stroke rehabilitation

Despite substantial advances in the acute management of stroke, it remains a leading cause of adult disability and mortality worldwide. Currently, the reperfusion modalities thrombolysis and thrombectomy benefit only a fraction of patients in the hyperacute phase of ischemic stroke. Thus, with the exception of vagal nerve stimulation combined with intensive physical therapy, there are no approved neuroprotective/neurorestorative therapies for stroke survivors. Stem cell therapy is a promising treatment for stroke patients and has been the focus of an increasing number of clinical trials over the past two decades. We provide a comprehensive overview of stem cell therapies available to stroke patients, focusing on the different types and doses of stem cells, timing and route of administration, patient selection, clinical outcomes, translational challenges, and future directions for the field. Information on ongoing and completed studies was retrieved from ClinicalTrials.gov, PubMed, Google Scholar, ICTRP, and Scopus. Autologous bone marrow-derived mononuclear cells (BMMNCs) are the most used, followed by autologous bone marrow stromal cells. IV therapy is typically applied in acute to subacute phases, while IT or IC routes are utilized in chronic phases. Although early-phase trials (Phase I/II) indicate strong safety and tolerability, definitive clinical effectiveness has yet to be unequivocally proven. Cochrane meta-analyses show NIH Stroke Scale improvements, though studies often have high bias and small sample sizes. Larger randomized, double-blind, placebo-controlled trials are ongoing to refine stem cell transplantation protocols, addressing cell type and source, dosage, timing, patient selection, the potential for combination therapies, and clinical efficacy.