Endothelial progenitor cells and their secretome for stroke therapy: A narrative review

Stroke, stemming from either hemorrhagic or ischemic cerebrovascular events, remains a leading cause of mortality and morbidity worldwide. While there is currently no effective medical therapy for hemorrhagic strokes, ischemic strokes, constituting the majority of cases, benefit from limited curative interventions, namely thrombolysis with recombinant tissue plasminogen activator and endovascular thrombectomy. However, these options are constrained by narrow post-stroke therapeutic windows. Cerebral edema, characterized by blood-brain barrier disruption and endothelial dysfunction, is a major contributor to stroke-related mortality. Endothelial progenitor cells, released by bone marrow in response to ischemic injury, have in recent years emerged as key players in vascular repair, blood-brain barrier restoration, angiogenesis and vasculogenesis. Despite accumulating evidence, the definition and characterization of endothelial progenitor cells remain inconsistent which complicates their development as so-called efficacious novel therapeutics. Concomitant targeting of markers for stemness, immaturity, and endothelial cell maturity, including CD34, CD133, and KDR, helps delineate true endothelial progenitor cells from hematopoietic cells. The synthesis, recruitment, and functionality of endothelial progenitor cells are regulated by a variety of signaling pathways, notably stromal cell-derived factor-1α/chemokine receptor 4, vascular endothelial growth factor, endothelial nitric oxide synthase/nitric oxide, and Notch1/Jagged1. These processes are influenced by several physiopathological factors such as aging, inflammation, and ischemic injury. In translational studies, endothelial progenitor cells demonstrate robust potential in attenuating infarct size, inflammation, and apoptosis while inducing angiogenesis and improving motor and cognitive functions. Although autologous and allogeneic endothelial progenitor cell-based therapies have shown safety and some efficacy in early-phase clinical trials, results remain inconclusive, and large-scale studies are required to confirm or dismiss the current findings. Issues regarding the number, route, and frequency of endothelial progenitor cell administration also need addressing. For instance, routes of endothelial progenitor cell administration present varying degrees of invasiveness, efficacy, and feasibility. Emerging research highlights the endothelial progenitor cell secretome, composed of several growth factors, cytokines, and extracellular vesicles, as a cell-free therapeutic option. Secretome-based therapeutic interventions avoid many safety and logistical challenges of cell therapies while offering comparable regenerative benefits in preclinical stroke models. Temporal dynamics in secretome composition, especially those in post-stroke pro-angiogenic and anti-angiogenic factor bioavailability, indicate the requirement for precise therapeutic timing. Clinical studies also suggest ischemic injury itself, rather than comorbid risk factors, as the principal driver of secretome alterations such as tumor necrosis factor-α upregulation. In conclusion, endothelial progenitor cells and their secretome hold significant promise as novel therapeutics for stroke. However, unresolved issues surrounding cell characterization, delivery methods, optimal time of administration, and safety must be addressed through rigorous translational and clinical studies before their use in clinical settings.