Ischemic stroke is one of the major health problems worldwide. The only FDA approved anti-thrombotic drug for acute ischemic stroke is the tissue plasminogen activator. Several studies have been devoted to assessing the therapeutic potential of different types of stem cells such as neural stem cells (NSCs), mesenchymal stem cells, embryonic stem cells, and human induced pluripotent stem cell-derived NSCs as treatments for ischemic stroke. The results of these studies are intriguing but many of them have presented conflicting results. Additionally, the mechanism(s) by which engrafted stem/progenitor cells exert their actions are to a large extent unknown. In this review, we will provide a synopsis of different preclinical and clinical studies related to the use of stem cell-based stroke therapy, and explore possible beneficial/detrimental outcomes associated with the use of different types of stem cells. Due to limited/short time window implemented in most of the recorded clinical trials about the use of stem cells as potential therapeutic intervention for stroke, further clinical trials evaluating the efficacy of the intervention in a longer time window after cellular engraftments are still needed.
The number of stroke-related deaths is increasing and stroke remains one of the major causes of deaths and disability worldwide (1, 2). Between 1990 and 2010, the global incidence rate of stroke seemed to be stable, while other parameters such as the incidence of first stroke, prevalence of stroke, disability-adjusted life-years lost due to stroke, and the number of stroke-related deaths increased by 68, 84, 12, and 26%, respectively (1). Differences between rates and numbers might reflect variations in population structure, increase in life expectancy, and the global improvement of health care services.
Two main types of stroke are recognized: ischemic and hemorrhagic stroke. Ischemic stroke accounts for over 80% of the total number of strokes. Thrombolysis and/or thrombectomy is the only validated therapeutic strategy for ischemic stroke (3, 4). Neurorestorative stem cell-based therapy is currently a major priority for stroke research (5, 6). Following ischemic events an inflammatory cascade, is initiated eventually leading to damage of brain tissue.
Different Cellular Sources Used for Stem Cell-Based Therapy of Stroke
The drastic damage to brain tissues following ischemic stroke includes not only destruction of a heterogeneous population of brain cell types, but also major disruption of neuronal connections and vascular systems. Several types of stem/progenitor cells such as embryonic stem cells (ESCs), neural stem/precursor cells, mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and induced neurons have been assessed as potential cellular-based therapy for stroke. The results of studies of these different cellular types are conflicting. In some studies, the engrafted cells survived, proliferated, differentiated, and restored lost neuronal and vascular elements. Other studies have shown only a limited neurorestorative ability on the part of transplanted cells. In the next section of this review, we elaborate on different stem cell types used for cellular-based therapy of stroke (Figure 1).
Figure 1. Stem cells and neural progenitor cells have been used to replace neural tissue death following a cerebral insult. Adult (mesenchymal and neural stem cells) and embryonic stem cells (ESCs) exhibited excellent differentiation capacity toward the neural phenotypes (neurons, oligodendrocytes, and astrocytes) in vitro and in vivo. In our view instead, induced pluripotent stem cells (iPSCs) constitute the greatest prospect for a future cell therapy. iPSCs are derived directly from the patient’s connective tissue through a small biopsy and exhibit the same properties of ESCs, overcoming the problems related to immune rejection, and bypassing the need for embryos. They can be generated in a patient-matched manner, implicating that each individual could have their own pluripotent stem cell line. Finally, iPSCs can be used in personalized drug discovery and to understand and deepen the patient-specific basis of disease (7–10).