Stroke and Mesenchimal Stromal Cells: Mechanisms of Neuroprotection and Future Prospects

Abstract

EditorialStroke is the second cause of morbidity and mortality worldwide [1]. The reduced blood flow generates ischemia area due to multiple processes such as excitotoxicity, ionic imbalance, depolarization of the peri-infarcted area, oxidative stress, inflammation and apoptosis, leading to neuronal death [2]. Mitochondria exert a crucial role in antioxidant cell defense; various studies related mitochondrial dysfunction to the pathophysiology of acute neurologic deficit in cerebral ischemia [3]. The lack of oxygen and glucose supply to the brain after stroke results in a drastic reduction in mitochondrial ATP production triggering necrotic cell death mechanisms. Further, reactive oxygen species (ROS) generation by mitochondria plays a critical role in neuronal damage. Excessive ROS can be scavenged by the action of antioxidant enzymes including superoxide dismutase, catalase and cytosolic and mitochondrial glutathione peroxidase [4]. However, in the case of huge ROS overproduction as observed during reperfusion, endogenous antioxidant capacity is quickly depleted [5], further inducing oxidative damage of cell macromolecules, cell damage and death [6].To date the only pharmacological treatment currently approved for stroke is based upon systemic thrombolysis by i.v. injection of tissue plasminogen activator (t-PA). Unfortunately, less than 5% of all patients can be treated with t-PA because of drug adverse effects and the narrow therapeutic window (< 4.5 hours) [7]. Despite extensive preclinical studies, little progress has been made toward the development of new effective therapies so that the current mantra in stroke treatment is "time is brain". An urgent need is to identify and characterize a therapeutic approach directly aimed at preserving neuronal viability by specifically targeting key pathogenic pathways in brain ischemia. Recently the enormous potential of cell transplantation therapy for stroke have been highlighted. The absence of ethical concerns and the good results found in experimental animal models make mesenchymal stromal cells (MSCs) one of the most promising types of stem cells for translational applications. Although bone marrow was the first source to be identified [8], MSCs have been successfully isolated from adipose tissue, pancreas, liver, skeletal muscle, dermis, synovial membrane, and trabecular bone [9]. In vitroexpanded MSCs also have remarkable properties due to their capacity to produce a variety of growth factors, cytokines, chemokines and proteases that likely could play immunomodulatory roles after their migration into inflamed regions [10].Recently many evidences have shown the efficacy of MSCs treatment both in in vitro [11] and in vivo models of ischemia [12]. Treatment, in vitro, with MSCs protected a neuronal cell line against oxygen-glucose deprivation damage through the secretion of vascular endothelial growth factor and interleukin-6 (IL-6). The application of MSCs induce neuroprotection through NFkB activation leading an increase of IL-6 production that causes a decrea...