Mechanisms and Functional Significance of Stroke-Induced Neurogenesis

No point in you reading this because your doctor will already have applied everything in here to your stroke protocols.
Pages and pages of references supporting this that your doctor will also be conversant in. Don't bother asking any questions about points in here, that would be questioning your doctors' competence. You would hate to hurt their fee fees. 
 http://journal.frontiersin.org/article/10.3389/fnins.2015.00458/full?

Quentin Marlier, Sebastien Verteneuil, Renaud Vandenbosch and Brigitte Malgrange^*

• GIGA-Neurosciences, University of Liege, C.H.U. Sart Tilman, Liege, Belgium

Stroke affects one in every six people worldwide, and is the leading cause of adult disability. After stroke, some limited spontaneous recovery occurs, the mechanisms of which remain largely unknown. Multiple, parallel approaches are being investigated to develop neuroprotective, reparative and regenerative strategies for the treatment of stroke. For years, clinical studies have tried to use exogenous cell therapy as a means of brain repair, with varying success. Since the rediscovery of adult neurogenesis and the identification of adult neural stem cells in the late nineties, one promising field of investigation is focused upon triggering and stimulating this self-repair system to replace the neurons lost following brain injury. For instance, it is has been demonstrated that the adult brain has the capacity to produce large numbers of new neurons in response to stroke. The purpose of this review is to provide an updated overview of stroke-induced adult neurogenesis, from a cellular and molecular perspective, to its impact on brain repair and functional recovery.

Introduction

Stroke is the second leading cause of death, the most common cause of adult-acquired disability and affects one in every six people worldwide (Moskowitz et al., 2010). The number of people who survive a stroke is increasing, and with an aging population, the incidence and prevalence of stroke are predicted to rise even more (Sun et al., 2012). Despite years of research, effective treatments remain elusive. Currently, the only proven therapy for acute ischemic stroke is systemic thrombolysis with recombinant tissue plasminogen activator (rtPA). To be effective, rtPA must be administered within a maximum of 4.5 h after the symptoms first start. This short timeframe and potential adverse effects have limited the use of rtPA to 3–5% of stroke patients (Ruan et al., 2015). Grafting stem cells represents a compelling alternative and offers both a wide array and an unlimited supply of cells. Indeed, the transplantation of neural stem cells (NSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), or induced pluripotent stem cells (iPSCs) could be used to replace neuronal loss after stroke (Kalladka and Muir, 2014). However, exogenous stem cell therapy has both technical and ethical issues. For instance, cell survival and migration rely heavily on the timing and mode of delivery (Li et al., 2010; Darsalia et al., 2011). Moreover, surgical procedure and toxicity (as cancer induction) increase the complexity of transplanted cell therapies (Kawai et al., 2010; Ben-David and Benvenisty, 2011). Finally, some ethical issues may arise from the use of fetal/embryonic cells.

Despite the fact that the central nervous system (CNS) has a limited repair capacity (Nakagomi et al., 2011), some degree of spontaneous recovery from brain ischemia invariably occurs (Yu et al., 2014). This repair process involves neurogenesis, angiogenesis, and axonal sprouting and synaptogenesis. Here we concentrate on the events that are associated with the production of new neurons and not the mechanisms that involve the reorganization of connectivity among surviving neurons, which is reviewed elsewhere (Jones and Adkins, 2015).

Recent experimental findings have raised the possibility that functional improvement after stroke may be induced through neuronal replacement by endogenous NSCs. Indeed, the original dogma that no new neurons are formed after birth has been definitively overturned during the past few decades. The discovery of the thymidine analog bromodeoxyuridine (BrdU)—that incorporates into DNA in S-phase and can be detected by immunohistochemistry—has allowed researchers to conclusively demonstrate the generation of new neurons in the brain of all adult mammals including humans (Eriksson et al., 1998; Gage, 2000). This production of new neurons in the adult brain—so-called adult neurogenesis—takes place in areas called neurogenic niches. The subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) are the two main neurogenic niches containing adult NSCs that proliferate, divide and differentiate into mature neurons. Recently, new evidence have highlighted that adult neurogenesis could also takes place in other brain areas, along the ventricular system, mostly in pathological conditions (Lin and Iacovitti, 2015).

The capacity to produce new neurons in the adult brain and the ability of the ischemia-injured adult brain to partially recover suggest a possible relationship between adult neurogenesis and stroke recovery. Indeed, many studies have shown an increase in cell proliferation in the rodent SVZ following ischemic injury (Thored et al., 2006), and evidence for stroke-induced neurogenesis in the human brain has also been reported (Jin et al., 2006). In addition, endogenous brain repair is not limited to neurogenic niches. Recent studies have shown that glial cells surrounding the infarct core can be reactivated following ischemia. Indeed, pericytes, oligodendrocyte precursors, and astrocytes are all able to differentiate into neurons following brain injury (Robel et al., 2011; Heinrich et al., 2014; Nakagomi et al., 2015; Torper et al., 2015). Moreover, surviving neurons may reorganize their connections in a manner that supports some degree of spontaneous improvement. Therefore, a promising field of investigation is focused on triggering and stimulating this self-repair system to replace dead neurons following an ischemic attack.