Neural stem cell transplantation therapy for brain ischemic stroke: Review and perspectives

Abstract

Brain ischemic stroke is one of the most common causes of death and disability, currently has no efficient therapeutic strategy in clinic. Due to irreversible functional neurons loss and neural tissue injury, stem cell transplantation may be the most promising treatment approach. Neural stem cells (NSCs) as the special type of stem cells only exist in the nervous system, can differentiate into neurons, astrocytes, and oligodendrocytes, and have the abilities to compensate insufficient endogenous nerve cells and improve the inflammatory microenvironment of cell survival. In this review, we focused on the important role of NSCs therapy for brain ischemic stroke, mainly introduced the methods of optimizing the therapeutic efficacy of NSC transplantation, such as transfection and overexpression of specific genes, pretreatment of NSCs with inflammatory factors, and co-transplantation with cytokines. Next, we discussed the potential problems of NSC transplantation which seriously limited their rapid clinical transformation and application. Finally, we expected a new research topic in the field of stem cell research. Based on the bystander effect, exosomes derived from NSCs can overcome many of the risks and difficulties associated with cell therapy. Thus, as natural seed resource of nervous system, NSCs-based cell-free treatment is a newly therapy strategy, will play more important role in treating ischemic stroke in the future.

Keywords: Cytokines; Exosomes; Ischemic stroke; Neural stem cells; Transplantation.

Figure 1

The pathological processes of brain ischemic stroke. After blood was interrupted in local brain tissue, there was a series of cascade reactions following by: BBB destruction, vascular permeability increased, cerebral edema generation, inflammatory factors infiltration, oxygen free radicals and ROS production, neuro-inflammation occurrence etc, induced local nerve cell necrosis and axon network disruption, resulting in reduction of functional neurons and an irreversible neurological function defects of the brain. BBB: Blood-brain barrier; ROS: Reactive oxygen species.

Figure 2

Transplanted exogenous neural stem cells therapy for brain ischemic stroke. After exogenous NSCs were transplanted into the ischemic brain, they can induce the endogenous NSCs activation of SVZ region. Then both exogenous and endogenous NSCs migrated to the cortical site of ischemic injury, differentiated to glia cells and neurons which contributed to glial scar formation and nerve tissue repair. Furthermore, it had two main mechanisms for reconstructing ischemic neural tissue in vivo: exogenous and activated endogenous stem cells directly compensated the lost nerve tissue by differentiating into nerve cells, transplanted NSCs improved the harmful inflammatory microenvironment around the ischemic regions via the bystander effect. NSCs: Neural stem cells; SVZ: Subventricular zone.

Figure 3

Exosomes derived from neural stem cells are critical for the benefits of stem cell-based therapy. NSCs-exosomes can overcome many of the risks and difficulties associated with stem-cell-based therapy. The exosomes contain the active ingredients of cells, can cross the BBB freely, mediate the immunomodulatory, have no immune tolerance, load drugs and can be labelled for targeted therapy etc. Currently NSCs-exosomes as stem cell-free molecules may be the most promising treatment candidate of stem cell-based therapy for ischemic stroke. NSCs: Neural stem cells; BBB: Blood-brain barrier.