Forebrain neurogenesis after focal Ischemic and traumatic brain injury

Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or cognitive impairment.     

The role of seizure-induced neurogenesis in epileptogenesis and brain repair

Data accumulated over the past four decades have led to the widespread recognition that neurogenesis, the birth of new neurons, persists in the hippocampal dentate gyrus and rostral forebrain subventricular zone (SVZ) of the adult mammalian brain. Neural precursor cells located more caudally in the forebrain SVZ are thought to also give rise to glia throughout life. The continued production of neurons and glia suggests that the mature brain maintains an even greater potential for plasticity after injury than was previously recognized. Underscoring this idea are recent findings that seizures induced by various experimental manipulations increase neurogenesis in the adult rodent dentate gyrus. Although neurogenesis and gliogenesis in persistent germinative zones are altered in adult rodent models of temporal lobe epilepsy (TLE), the effects of seizure-induced neurogenesis in the epileptic brain, in terms of either a pathological or reparative role, are only beginning to be explored. Emerging data suggest that altered neurogenesis in the epileptic dentate gyrus may be pathological and promote abnormal hyperexcitability. However, the presence of endogenous neural progenitors in other proliferative regions may offer potential strategies for the development of anti-epileptogenic or neuronal replacement therapies.     

Rat forebrain neurogenesis and striatal neuron replacement after focal stroke

The persistence of neurogenesis in the forebrain subventricular zone (SVZ) of adult mammals suggests that the mature brain maintains the potential for neuronal replacement after injury. We examined whether focal ischemic injury in adult rat would increase SVZ neurogenesis and direct migration and neuronal differentiation of endogenous precursors in damaged regions. Focal stroke was induced in adult rats by 90-minute right middle cerebral artery occlusion (tMCAO). Cell proliferation and neurogenesis were assessed with bromodeoxyuridine (BrdU) labeling and immunostaining for cell type-specific markers. Brains examined 10-21 days after stroke showed markedly increased SVZ neurogenesis and chains of neuroblasts extending from the SVZ to the peri-infarct striatum. Many BrdU-labeled cells persisted in the striatum and cortex adjacent to infarcts, but at 35 days after tMCAO only BrdU-labeled cells in the neostriatum expressed neuronal markers. Newly generated cells in the injured neostriatum expressed markers of medium spiny neurons, which characterize most neostriatal neurons lost after tMCAO. These findings indicate that focal ischemic injury increases SVZ neurogenesis and directs neuroblast migration to sites of damage. Moreover, neuroblasts in the injured neostriatum appear to differentiate into a region-appropriate phenotype, which suggests that the mature brain is capable of replacing some neurons lost after ischemic injury.     

Neurogenesis and stroke

Stroke stimulates neurogenesis in select regions of the adult brain, and the newborn neurons that result can migrate to areas of ischemic injury, where they may have the capacity to enhance brain recovery. These observations suggest that stroke-induced neurogenesis may contribute to endogenous brain repair after stroke, and that the mechanisms that underlie neurogenesis may represent potential therapeutic targets. Alternatively, transplantation of exogenously derived neural cells might also be an approach to the treatment of stroke.     

Targeting hippocampal adult neurogenesis using transcription factors to reduce Alzheimer's disease‐associated memory impairments

Hippocampal adult neurogenesis results in the persisting formation of new neurons that contribute to hippocampal‐dependent learning and memory. This has led to the hypothesis that memory impairments associated with neurodegenerative diseases such as Alzheimer's disease may involve abnormal neurogenesis. Supporting this idea, evidence for decreased adult neurogenesis has been reported in the brain of Alzheimer's disease patients and in several mouse models of the disease. Thus, the development of strategies designed to stimulate the production of new neurons in the diseased brain has raised growing interest. In this review, we discuss putative strategies and present recent studies showing that it is now possible to instruct hippocampal endogenous neural progenitors to adopt an exclusive neuronal fate. We further report how such strategies lead to the rescue of cognitive functions in mouse models of Alzheimer's disease. Altogether, these findings provide the proof‐of‐concept that neurogenesis can be stimulated in the adult brain in vivo, and consequently overcomes pathological memory deficits.     

Therapeutic application of cell transplantation and increased neurogenesis in cerebral infarction]

Cerebral ischemia often results in neuronal loss, leading to the neurological deficits in stroke patients. To obtain the functional recovery after stroke, cell transplantation and enhancement of endogenous neurogenesis may have potential application. Recent evidence has demonstrated that neural stem cells exist in the adult mammalian brain. After cerebral ischemia, newly born neurons were found not only in hippocampal dentate and olfactory bulb but also in hippocampal CA1 and striatum, where neurons were lost after ischemia. Administration of neurotrophic factors or genes encoding them into the lateral venticule could enhance endogenous neurogenesis in experimental ischemia model. Furthermore, we have recently developed non-invasive gene transfer into macrophages infiltrating an infarct to stimulate proliferation of neural stem cells in cerebral infarction. Several strategies including gene therapy and pharmacological approach will be tried in stroke patients in near future. However, it remains unclear whether the number of new-born neurons from endogenous neural stem cells is sufficient for replacement of damaged neurons. Cell transplantation will have the advantage of preparing the large amount of transplanted cells. Human neural stem cells, embryonic stem cells and bone marrow-derived cells will be donor cells in stroke patients. Surprisingly, neuron-like cells derived from human teratoma cell line were already applied in stroke patients. However, ethical aspect will have to be discussed carefully before cells from other individuals are used as donor cells in stroke patients.     

Galectin-1 regulates neurogenesis in the subventricular zone and promotes functional recovery after stroke

Galectin-1 (Gal-1) has recently been identified as a key molecule that plays important roles in the regulation of neural progenitor cell proliferation in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus. To test the hypothesis that Gal-1 contributes to adult neurogenesis after focal ischemia, we studied the temporal profile of endogenous Gal-1 expression and the effects of human recombinant Gal-1 on neurogenesis and neurological functions in an experimental focal ischemic model. In the normal brain, Gal-1 expression was observed only in the SVZ. In the ischemic brain, Gal-1 expression was markedly upregulated in the SVZ and the area of selective neuronal death around the infarct in the striatum. The temporal profile of Gal-1 expression was correlated with that of neural progenitor cell proliferation in the SVZ of the ischemic hemisphere. Double-labeling studies revealed that Gal-1 was localized predominantly in both reactive astrocytes and SVZ astrocytes. Administration of Gal-1, which is known to have carbohydrate-binding ability, into the lateral ventricle increased neurogenesis in the ipsilateral SVZ and improved sensorimotor dysfunction after focal ischemia. By contrast, blockade of Gal-1 in the SVZ by the administration of anti-Gal-1 neutralizing antibody strongly inhibited neurogenesis and diminished neurological function. These results suggest that Gal-1 is one of the principal regulators of adult SVZ neurogenesis through its carbohydrate-binding ability and provide evidence that Gal-1 protein has a role in the improvement of sensorimotor function after stroke.     

Hypoxic-ischemic brain injury activates early hippocampal stem/progenitor cells to replace vulnerable neuroblasts

Although the phenomenon of ongoing neurogenesis in the hippocampus is well described, it remains unclear what relevance this has in terms of brain self-repair following injury. In a highly regulated developmental program, new neurons are added to the inner granular cell layer of the dentate gyrus (DG) where slowly dividing radial glial-like type 1 neural stem/progenitors (NSPs) give rise to rapidly proliferating type 2 neural progenitors which undergo selection and maturation into functional neurons. The induction of these early hippocampal progenitors after injury may represent an endogenous mechanism for brain recovery and remodeling. To determine what role early hippocampal progenitors play in remodeling following injury, we utilized a model of hypoxic-ischemic injury on young transgenic mice that express green fluorescent protein (GFP) specifically in neural progenitors. We demonstrate that this injury selectively activates programmed cell death in committed but immature neuroblasts, which is followed by proliferation of both early type 1 and later type 2 progenitors. This subsequently leads to newly generated neurons becoming stably incorporated into the DG.     

The potential of neural stem cells to repair stroke-induced brain damage

Acute injuries to CNS such as stroke induce neural progenitor proliferation in adult brain which might be an endogenous attempt to self-repair. This process is known to be altered by several exogenous and endogenous modulators including growth factors that could help to reinforce the post-stroke neurogenesis. Increasing the neurogenesis may be a future therapeutic option to decrease the cognitive and behavioral deficits following stroke. In addition, transplantation of various types of stem cells into the injured brain is currently thought to be an exciting option to replace the neurons lost in the post-ischemic brain. These include immortalized stem cell lines, neural progenitors prepared from embryonic and adult animals and mesenchymal stem cells. Using exogenous stem cells in addition to modulating endogenous neurogenesis, we may be able to repair the injured brain after a devastating stroke. This article reviewed the current literature of these two issues.     

Adult hippocampal neurogenesis in rodents and primates: endogenous, enhanced, and engrafted

Since the studies of Ramon y Cajal, a central postulate in neuroscience has been the view that the adult brain lacks the ability to regenerate its neurons. This dogma has been challenged in the last few decades, and mounting evidence has accumulated showing the existence of a phenomenon designated 'adult neurogenesis'. De novo generation of neurons by neural progenitor cells in the adult brain is thought to be preserved only in restricted brain areas, such as the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricle. Data in the last decade coming mostly from rodent models have clearly documented that precursor cells residing in the anterior portion of SVZ and the subgranular zone of DG are responsible for adding new neurons in the olfactory bulb and DG, respectively. This raised significant interest in the clinical potential of neural progenitor cells, and recent studies have documented that brain injury is capable of activating an endogenous program of neurogenesis resulting in neuronal replacement in various cerebral regions of rodents and primates. If the newly generated neurons in the adult brain prove to be functional, it could have a tremendous impact for cell replacement therapies. Here, we summarize current knowledge of the mechanisms affecting adult hippocampal neurogenesis in both rodents and primates, and discuss its implications in developing novel strategies for the treatment of human neurological diseases.     

Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice

The CNS has the potential to marshal strong reparative mechanisms, including activation of endogenous neurogenesis, after a brain injury such as stroke. However, the response of neural stem/progenitor cells to stroke is poorly understood. Recently, neural stem/progenitor cells have been identified in the cerebral cortex, as well as previously recognized regions such as the subventricular or subgranular zones of the hippocampus, suggesting that a contribution of cortex-derived neural stem/progenitor cells may repair ischemic lesions of the cerebral cortex. In the present study, using a highly reproducible murine model of cortical infarction, we have found nestin-positive cells in the post-stroke cerebral cortex, but not in the non-ischemic cortex. Cells obtained from the ischemic core of the post-stroke cerebral cortex formed neurosphere-like cell clusters expressing nestin; such cells had the capacity for self-renewal and differentiated into electrophysiologically functional neurons, astrocytes and myelin-producing oligodendrocytes. Nestin-positive cells from the stroke-affected cortex migrated into the peri-infarct area and differentiated into glial cells in vivo . Although we could not detect differentiation of nestin-positive cells into neurons in vivo , our current observations indicate that endogenous neural stem/progenitors with the potential to become neurons can develop within post-stroke cerebral cortex.     

Differential regulation of vascular endothelial growth factor-C and its receptor in the rat hippocampus following transient forebrain ischemia

We investigated the changes in the expression of vascular endothelial growth factor-C (VEGF-C) and its receptor, VEGFR-3, in the rat hippocampus following transient forebrain ischemia. The expression profiles of VEGF-C and VEGFR-3 were very similar in the control hippocampi, where both genes were constitutively expressed in neurons in the pyramidal cell and granule cell layers. The spatiotemporal expression pattern of VEGF-C was similar to that of VEGFR-3 in the ischemic hippocampus, and in the CA1 and dentate hilar regions both VEGF-C and VEGFR-3 were strongly expressed in activated glial cells rather than in neurons. Most of the activated glial cells expressing both genes were reactive astrocytes, although some were a subpopulation of brain macrophages. In the dentate gyrus, however, VEGFR-3 expression was transiently increased in the innermost layer of granule cells on days 7–10 after reperfusion, coinciding with an increase in polysialylated neural cell adhesion molecule staining—a marker for immature neurons. These data suggest that VEGF-C may be involved in glial reaction via paracrine or autocrine mechanisms in the ischemic brain and may carry out specific roles in adult hippocampal neurogenesis during ischemic insults.     

New neurons for injured brains? The emergence of new genetic model organisms to study brain regeneration

Neuronal circuits in the adult brain have long been viewed as static and stable. However, research in the past 20 years has shown that specialized regions of the adult brain, which harbor adult neural stem cells, continue to produce new neurons in a wide range of species. Brain plasticity is also observed after injury. Depending on the extent and permissive environment of neurogenic regions, different organisms show great variability in their capacity to replace lost neurons by endogenous neurogenesis. In Zebrafish and Drosophila, the formation of new neurons from progenitor cells in the adult brain was only discovered recently. Here, we compare properties of adult neural stem cells, their niches and regenerative responses from mammals to flies. Current models of brain injury have revealed that specific injury-induced genetic programs and comparison of neuronal fitness are implicated in brain repair. We highlight the potential of these recently implemented models of brain regeneration to identify novel regulators of stem cell activation and regenerative neurogenesis.     

Neuronal damage following non-lethal but repeated cerebral ischemia in the gerbil

Summary Brief, non-lethal transient forebrain ischemia in the gerbil can injure selectively vulnerable neurons when such ischemia is induced repeatedly. The influence of the number and interval of the ischemic insults on neuronal damage, as well as the time course of damage, following repeated 2-min forebrain ischemia were examined. A single 2-min forebrain ischemia were examined. A single 2-min ischemic insult caused no morphological neuronal damage. A moderate number of hippocampal CA1 neurons were destroyed following two ischemic insults with a 1-h interval, and destruction of almost all CA1 neurons resulted from three or five insults at 1-h intervals. Three and five insults also resulted in moderate to severe damage to the striatum and thalamus, depending on the number of episodes. Although three ischemic insults at 1-h intervals caused severe neuronal damage, this number of insults at 5-min and 4-h intervals caused destruction of relatively few neurons, and non neurons were destroyed at 12-h intervals. Following three ischemic insults at 1-h intervals, damage to the striatum, neocortex, hippocampal CA4 subfield and thalamus was observed at 6–24 h of survival, whereas damage to the hippocampal CA1 subfield appeared at 2–4 days. The results indicate that even a brief non-lethal ischemic insult can produce severe neuronal damage in selectively vulnerable regions when it is induced repeatedly at a certain interval. The severity of neuronal damage was dependent on the number and interval of ischemic episodes.     

Meteorin is a chemokinetic factor in neuroblast migration and promotes stroke-induced striatal neurogenesis

Ischemic stroke affecting the adult brain causes increased progenitor proliferation in the subventricular zone (SVZ) and generation of neuroblasts, which migrate into the damaged striatum and differentiate to mature neurons. Meteorin (METRN), a newly discovered neurotrophic factor, is highly expressed in neural progenitor cells and immature neurons during development, suggesting that it may be involved in neurogenesis. Here, we show that METRN promotes migration of neuroblasts from SVZ explants of postnatal rats and stroke-subjected adult rats via a chemokinetic mechanism, and reduces N-methyl-D-asparate-induced apoptotic cell death in SVZ cells in vitro. Stroke induced by middle cerebral artery occlusion upregulates the expression of endogenous METRN in cells with neuronal phenotype in striatum. Recombinant METRN infused into the stroke-damaged brain stimulates cell proliferation in SVZ, promotes neuroblast migration, and increases the number of immature and mature neurons in the ischemic striatum. Our findings identify METRN as a new factor promoting neurogenesis both in vitro and in vivo by multiple mechanisms. Further work will be needed to translate METRN's actions on endogenous neurogenesis into improved recovery after stroke.     

Insulin-like growth factor-I and neurogenesis in the adult mammalian brain

In most brain regions of highly developed mammals, the majority of neurogenesis is terminated soon after birth. However, new neurons are continually generated throughout life in the subventricular zone and the dentate gyrus of the hippocampus. Insulin-like growth factor-I (IGF-I) is a polypeptide hormone that has demonstrated effects on these progenitor cells. IGF-I induces proliferation of isolated progenitors in culture, as well as affecting various aspects of neuronal induction and maturation. Moreover, systemic infusion of IGF-I increases both proliferation and neurogenesis in the adult rat hippocampus, and uptake of serum IGF-I by the brain parenchyma mediates the increase in neurogenesis induced by exercise. Neurogenesis in the adult brain is regulated by many factors including aging, chronic stress, depression and brain injury. Aging is associated with reductions in both hippocampal neurogenesis and IGF-I levels, and administration of IGF-I to old rats increases neurogenesis and reverses cognitive impairments. Similarly, stress and depression also inhibit neurogenesis, possibly via the associated reductions in serotonin or increases in circulating glucocorticoids. As both of these changes have the potential to down regulate IGF-I production by neural cells, stress may inhibit neurogenesis indirectly via downregulation of IGF-I. In contrast, brain injury stimulates neurogenesis, and is associated with upregulation of IGF-I in the brain. Thus, there is a tight correlation between IGF-I and neurogenesis in the adult brain under different conditions. Further studies are needed to clarify whether IGF-I does indeed mediate neurogenesis in these situations.     

The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury

Traumatic brain injury （TBI） is the leading cause of death and disability of persons under 45 years old in the United States, affecting over 1.5 million individtials each year. It had been th ought that recovery from such injuries is severely limited due to the inability of the adult bra in to replace damaged neurons. However, recent studies indicate that the mature mammalian central nervous system （CNS） has the potential to replenish damaged neurons by proliferation and neuronal differentiation of adult neural stem/progenitor cells residing in the neurogenic regions in the brain. Furthermore, increasing evidence indicates that these endogenous stem/ progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. In support of this notion, heightened levels of cell proliferation and neurogenesis have been ob- served in response to brain trauma or insults suggesting that the brain has the inherent potential to restore populations of damaged or destroyed neurons. This review will discuss the potential functions of adult neurogenesis and recent development of strategies aiming at harnessing this neurogenic capacity in order to repopulate and repair the injured brain.     

Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor

The present view of the neuroprotective functions and mechanisms of action of vascular endothelial growth factor (VEGF) is based on studies of neuronal ischemic/hypoxic models in vivo and in vitro. Endogenous neuronal VEGF increases in the ischemic brain and plays a neuroprotective role in the pathophysiologic processes that follow stroke. Exogenous VEGF, directly administered or overexpressed by gene delivery into rat brains, reduces ischemic brain infarct and decreases hypoxic neuronal death. The main neuroprotective mechanisms of VEGF include: (1) modulation of the phosphatidylinositol 3'-kinase (PI3K)/Akt/nuclear factor-kappaB signaling pathway, inhibition of caspase-3 activity, and reduction of ischemic neuronal apoptosis; (2) inhibition of outward delayed rectifier potassium channel currents and increase of ischemia-induced tyrosine phosphorylation of Kv1.2 potassium channel proteins via activation of the PI3K pathway; and (3) enhancement of proliferation and migration of neural progenitors in the subventricular zone and improvement of striatal neurogenesis and maturation of newborn neurons in adult rat brains after stroke.