Stroke is the 4th leading cause of death in the United States and the leading cause of severe long-term disability worldwide and the number of patients suffered from stroke is on the increase at present, with no effective treatment for most cases. Currently, thrombolysis with recombinant tissue plasminogen activator (rt-PA) remains the only FDA approved treatment for acute ischemic stroke, but the short therapeutic time window makes this treatment applicable to only a minority of stroke patients (Brott and Bogousslavsky 2000). Therefore, the development of new effective therapies is needed to improve functional neurological recovery in stroke patients.

Endogenous Neural stem cells (NSCs) resident in the brain neurogenic regions raise the possibility of developing neural repair strategies for stroke . Researches in experimental stroke in animal models over the past decade have demonstrated that ischemic stroke enhances endogenous neural stem cells proliferation in SVZ and SGZ of dentate gyrus and promotes SVZ NSC migration to the ischemic infarct regions (Jin et al. 2001; Thored et al. 2006). Moreover, stroke-induced neurogenesis has also been reported in the adult human brain (Jin et al. 2006). These promising findings in stroke have brought hope to develop neurorestorative therapy which aims to enhance endogenous neurogenesis after stroke and thereby contribute to the functional recovery. This chapter aims to provide an understanding the role of endogenous neural stem cells in stroke and to describe current knowledge of how stroke induces endogenous neural stem cells proliferation , migration and differentiation .

It is well accepted that NSCs are primarily present in the adult SVZ and SGZ of dentate gyrus. Based on the morphology, protein expression, proliferation kinetics, and differentiation potential, three types of SVZ cells have been identified: type A (neuroblasts), type B (GFAP-positive progenitors) and type C (transit amplifying cells) (Zhao et al. 2008). GFAP, Nestin and Sox2 -positive type B cells are considered as the primary NSCs in the SVZ. This population resides in the wall of lateral ventricle and gives rise to actively dividing type C cells. Type C cells, which are negative for GFAP but express Mash1 and EGF receptor, generate type A cells that migrate into the olfactory bulb via the rostral migratory stream (RMS). In the SGZ of dentate gyrus, two types of NSCs, type 1(GFAP+SOX2+) and type 2(GFAP-) NSCs are present, maintaining a reciprocal relationship in the DG of hippocampus (Suh et al. 2007).

Proliferation is the first step of endogenous NSCs’ response to ischemic stroke injury. It is reported that ischemic injury alone is sufficient to promote the proliferation of endogenous NSCs and thereby expands the NSCs pool (Zhang et al. 2007). The expansion of the NSCs pool is an essential factor in the development of endogenous neurorestorative strategies after stroke . Stroke induces early expansion of the NSCs pool by increasing the proportion of proliferating cells and shortening the length of cell cycle (Zhang et al. 2008b). In the adult rat brain, the proportion of actively dividing SVZ NSCs is about 15–21 % and the length of cell cycle of this population is approximately 18–21 h (Zhang et al. 2006). Stroke increases the proportion of proliferating SVZ NSCs, starting 2 days (24 %) and reaches a maximum at 7 days (31 %) after stroke. Two weeks after stroke, the level of proliferation returns to the baseline. Concurrently, stroke changes the cell cycle length of NSCs. The length of cell cycle shortens to 11 h at 2 days after stroke, which is significantly shorter than cell cycle length of 18–21 h in normal brain. Alteration of the G1 phase of SVZ NSCs may contribute to stroke-induced changes of the cell cycle length. Furthermore, studies by Zhang and his colleagues also revealed that stroke transiently switches NSCs division from asymmetric to symmetric (Zhang et al. 2004b). Symmetric division gives rise to two identical daughter cells that stay in the SVZ to maintain the NSCs pool, whereas asymmetric division generates two different daughter cells and the basal daughter becomes a young migratory cell that migrates away. The switching NSCs division from asymmetric to symmetric amplifies the pool of NSCs.

In order for proliferating NSCs to contribute to the functional recovery, it is necessary for these NSCs to migrate from birthplace to the ischemic region. In the normal adult brain, the SVZ neuroblasts are destined to follow rostral migratory stream to migrate to the olfactory bulb. However, many of these SVZ neuroblasts migrate from the SVZ through the brain parenchyma into the ischemic injury region after ischemic stroke, as revealed by several studies (Arvidsson et al. 2002; Jin et al. 2003; Thored et al. 2006). This redirected migration is associated with cellular interactions between immature migrating neuroblasts, astrocytic processes and blood vessels (Yamashita et al. 2006). However, ischemic stroke also up-regulate inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs), which blocks neuroblast migration (Carmichael 2005). Stroke not only up-regulates attractive factors for neuroblast migration but also forms peri-infarct scar and produces barrier molecule to inhibit neuroblast migration. The net neuroblast migration is dependent on the balance of inhibitory molecules and attractive factors.