• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Neurochem. Author manuscript; available in PMC Jun 25, 2012.
Published in final edited form as:
PMCID: PMC3382108
NIHMSID: NIHMS385836

EFFECTS OF NEUROINFLAMMATION ON THE REGENERATIVE CAPACITY OF BRAIN STEM CELLS

Abstract

In the adult brain, neurogenesis under physiological conditions occurs in the subventricular zone and in the dentate gyrus. Although the exact molecular mechanisms that regulate neural stem cell proliferation and differentiation are largely unknown, several factors have been shown to affect neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction. Furthermore, in pathological conditions of the central nervous system associated with neuroinflammation, inflammatory mediators such as cytokines and chemokines can affect the capacity of brain stem cells and alter neurogenesis.

In this review, we summarize the state of the art on the effects of neuroinflammation on adult neurogenesis and discuss the use of the LPS-model to study the effects of inflammation and reactive-microglia on brain stem cells and neurogenesis. Furthermore, we discuss the possible causes underlying reduced neurogenesis with normal aging and potential anti-inflammatory, pro-neurogenic interventions aimed at improving memory deficits in normal and pathological aging and in neurodegenerative diseases.

Keywords: neurogenesis, brain, inflammation, lipopolysaccharide, aging

Adult neurogenesis

In the adult mammalian brain, neural stem cells are localized in two areas: the subventricular zone (SVZ), a layer extending along the lateral wall of the lateral ventricle (Doetsch & Scharff 2001), and the subgranular zone of the dentate gyrus (DG) of the hippocampus (Limke & Rao 2002), a thin cell layer between the granule cell layer and dentate hilus (Seri et al. 2001). Hippocampal neurogenesis plays a role in the maintenance of normal hippocampal function, learning and memory (Gould et al. 1999, Shors et al. 2001). Several hippocampus-dependent learning tasks increase the proliferation of neuronal progenitors in the SGZ and promote the survival of newly generated neurons (Gould et al. 1999, Drapeau et al. 2007).

Like hippocampal progenitor cells, SVZ stem cells are tightly controlled under physiological conditions (Morshead et al. 1994, Morshead et al. 1998), and in addition to their role in maintaining brain homeostasis, are involved in neuronal replacement in response to aberrant conditions. Although little is known about the exact molecular mechanisms that regulate neural stem cells niche, several factors are known to affect neurogenesis. Self-renewal, proliferation, differentiation and migration of these cells vary, depending on the local microenvironment characterizing the different types of brain injury.

By mechanisms as yet unknown, brain stem cells become “activated” after neuronal injury and preferentially migrate at the sites of pathology, indicating that mediators at the injury site can guide the migration of precursor cells (Arvidsson et al. 2002, Nakatomi et al. 2002). The recently discovered potential of cellular regeneration in the diseased brain has gained a lot of interest among basic and clinical neuroscientists, and further studies are required to understand the mechanisms of neurogenesis and the potential therapeutic use of stem cells in pathological conditions of the CNS.

Effects of neuroinflammation on neurogenesis

Until fairly recently, the brain was considered an immunologically privileged site, not susceptible to immune activation due to the presence of the blood brain barrier (BBB) (Lucas et al. 2006). However, it became increasingly clear that the CNS is immunologically specialized, and immune cells and mediators are found in the CNS under both normal and pathological states, while neurons are interacting with and regulating immune cells (Lucin & Wyss-Coray 2009).

Following brain injury or exposure to pathogens, an inflammatory response is driven by the activation of resident microglia, local invasion of circulating immune cells, and production of cytokines, chemokines, neurotransmitters, and reactive oxygen species. These inflammatory components are essential to recruit cells of the immune system to the compromised area. Microglia, the resident macrophages of brain parenchyma, play a central role in the inflammatory response. In healthy brain, microglia are present in a resting state, but they can rapidly react to subtle microenvironmental alterations by changing morphology and acquiring an array of functions, including phagocytosis and secretion of inflammatory mediators (Perry 2004, Liu & Hong 2003). Reactive microglia migrate along a chemotactic gradient to reach the site of injury and phagocytose cellular debris or foreign materials. Reactive microglia can release chemokines to attract more microglia and secrete inflammatory factors to further propagate neuroinflammation. A variety of cytotoxic substances released by activated microglia can cause neuronal damage by enhancing oxidative stress and activating cell-death pathways (Choi et al. 2009). Overactivation of microglia cells can result from a variety of injury signals, such as oxidative stress molecules, Aβ oligomers, ischemia, brain trauma, which all promote erroneous signaling cascades in microglia cells and induce proinflammatory cytokine production (Fernandez et al. 2008, Morales et al. 2010). Morales and colleagues postulated that neuroinflammation induced by activation of the innate immune system is a major driving force in Alzheimer’s disease pathogenesis. Proinflammatory cytokines, such as TNF-α, IL-1β and IL-6, which are activated in Alzheimer’s disease, signal through different neuronal receptors, thus activating protein kinases involved in tau hyperphosphorylation (Morales et al. 2010).

Although a well-regulated inflammatory process is essential for tissue repair, an excessive or protracted inflammatory response can result in a more severe and chronic neuroinflammatory cycle that promotes neurodegenerative diseases (Gao & Hong 2008) and is thought to play an important role in the development and/or progression of neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and multiple sclerosis (Stolp & Dziegielewska 2009, Hemmer et al. 2004).

Several findings support a role for inflammation in the pathogenesis of neurodegenerative disorders. Specifically, in postmortem brain from Alzheimer’s disease patients activated microglia surrounding amyloid plaques (Rozemuller et al. 2005) and / or injured neurons (Klegeris et al. 2007), increased levels of proinflammatory cytokines and complement activation (Rozemuller et al. 2005) have been reported. Supporting a role for inflammation in the pathogenesis of Alzheimer’s disease, epidemiological studies indicate that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) has a protective effect and significantly lowers the risk of developing Alzheimer’s disease later in life (Rozemuller et al. 2005, Klegeris & McGeer 2005, McGeer & McGeer 2007). Furthermore, genetic polymorphisms for several inflammatory cytokines and their receptors modulate the risk of disease (Bossu et al. 2007), and animal and cell culture models show that modulation of inflammation is effective in curbing the disease process (Rozemuller et al. 2005). These evidences are not specific to Alzheimer’s disease, since neuroinflammation significantly contributes to the pathogenesis of many neurodegenerative diseases (Klegeris et al. 2007). Innate immune response associated with gliosis, in particular microglial cell activation, is an important neuropathological feature of Parkinson’s disease in humans and in animal models of the disease. Activated microglial cells might contribute to dopaminergic cell death by releasing cytotoxic inflammatory compounds such as proinflammatory cytokines (TNF-α, interleukin-1β, and interferon-γ) (Hirsch & Hunot 2009). The link between inflammation, oxidative stress and Parkinson’s disease is supported by an overwhelming number of studies that implicate inflammatory processes in the progressive loss of nigral dopaminergic neurons. However, despite the promising data on neuroprotective effects of anti-inflammatory agents in animal models, it remains to be determined whether anti-inflammatory therapy in humans could have a beneficial effect in preventing or slowing down progression of Parkinson’s disease (Tansey & Goldberg 2010). Therapeutic intervention aimed at prevention or downregulation of immune-associated mechanisms represents a promising approach to stop disease progression. With the available knowledge of the cellular and molecular network implicated in the immune-associated damage to dopaminergic neurons, several immunotherapeutic approaches are possible, some of which have already been applied or tested in other neurological disorders (Hirsch & Hunot 2009).

Damaged neurons can be repaired by the activation of endogenous neuronal stem cells, which migrate to regions of brain injury, differentiate into neuronal cells, and integrate appropriately into neuronal circuits (Belmadani et al. 2006). The potential of stem cells has been demonstrated in vitro and in vivo using animal models of brain inflammation and disease (Abrous et al. 2005, Gage 2002). However, it is important to emphasize that the inflammatory environment may influence the temporal and spatial relationship in the neural stem cell niche and thus, alter self-renewal, survival, migration and neuronal differentiation of stem cells (Martino & Pluchino 2006).

Inflammation is a complex process that, depending on the conditions, can either enhance or suppress neurogenesis. The discrepancies between the pro- and anti-neurogenic properties of inflammation may depend on how microglia, macrophages and/or astrocytes are activated and on the duration of inflammation (Fig. 1). Although the effects of brain inflammation on neuronal injury and neurogenesis in various CNS disorders have been a matter of intense investigation in recent years, the mechanisms, function and significance of the modulation of neurogenesis during inflammatory processes remain to be elucidated. It has been suggested that activated microglia in inflammatory settings can inhibit neurogenesis (Butovsky et al. 2006). Indeed, mediators released by the immune cells, like cytokines and nitric oxide (NO), negatively regulate adult neurogenesis (Vallieres et al. 2002, Monje et al. 2003, Liu et al. 2006). However, recent evidence suggests that activated microglia are not always detrimental for neurogenesis, but, under certain conditions, can be beneficial (Hanisch & Kettenmann 2007). For instance, both neurogenesis and oligodendrogenesis are induced by microglia activated by interleukin-4 (IL-4) or low level of interferon (IFN)-γ [59]. IFN-γ also enhanced neuronal differentiation when directly administered to neural stem cells (NSC) or neuronal cell lines (Song et al. 2005, Wong et al. 2004), and IFN-γ transgenic mice exhibited increased NSC proliferation and differentiation in the adult DG, which was associated with neuroprotection and improved spatial cognitive performance (Baron et al. 2008).

Figure 1
Effects of neuroinflammation on neurogenesis

Exercise has been demonstrated as another positive factor that stimulates plasticity, neurogenesis and enhances cognitive functions by reducing pro-inflammatory conditions and increasing growth factor levels (Cotman et al. 2007). Supporting a positive effect of exercise on neurogenesis during inflammation, treadmill exercise has been shown to counteract the suppressive effects of peripheral LPS on hippocampal neurogenesis, learning and memory (Wu et al. 2007).

Environmental enrichment also stimulates hippocampal neurogenesis in adult mice and increases the number of dendritic spines, extent of branching, and number of synapses per neuron (van Praag et al. 2000). The beneficial effects of environmental enrichment may be due to the inhibition of the expression of pro-inflammatory genes in the brain (Dong et al. 2007).

Lipopolysaccharide-induced neuroinflammation and effects on neurogenesis

In the CNS, LPS binds to a CD14 receptor, a glycosylphosphatidylinositol-linked membrane protein, and together with the extracellular adaptor proteins MD-2 binds to the toll-like receptor 4 (TLR4) expressed by microglia (Beutler 2004), causing a direct activation of brain innate immunity (Montine et al. 2002, Aid et al. 2008). TLR-4 is the key transmembrane receptor for LPS effect because mice with either a point or null mutation in the TLR4 gene are insensitive to LPS (Palsson-McDermott & O’Neill 2004, Rosenberg 2002). Transduction through TLR-4 results in a cascade of intracellular events that leads to the transcription of inflammatory and immune response genes (Bonow et al. 2009).

LPS induces an increase in the synthesis of inflammatory mediators, like cytokines, primarily interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, chemokines, products of arachidonic acid metabolism, free radicals generated by NADPH oxidase, myeloperoxidase and inducible nitric oxide synthase (iNOS) (Montine et al. 2002, Quan et al. 1994). Cytokines and chemokines, in turn, mediate the recruitment of polymorphonuclear leucocytes and monocytes from the bone marrow.

LPS-induced neuroinflammation has been shown to severely affect CNS cognitive function, length and spine density, dopaminergic cells, learning, memory, and neurogenesis (Quan et al. 1994, Monje et al. 2003, Shaw et al. 2001). A recent study showed that soluble factors released from microglia can direct the migration of neural precursor cells (Shapiro et al. 2008), and several reports demonstrated migration and regeneration of neural cells to sites of brain injury (Arvidsson et al. 2002, Nakatomi et al. 2002, Snyder et al. 1997).

The link between brain inflammation and neurogenesis, and the role of microglia in the modulation of neurogenesis under pathological conditions are under intense investigation. To study the effects of inflammation on the regenerative capacity of brain stem cells, several studies have focused on the microglia reaction after an acute injury and after administration of LPS (Ekdahl et al. 2003, Monje et al. 2003). TLR4 is abundantly expressed by neural stem/ progenitor cells and LPS decreases the proliferation of cultured neural stem/ progenitor cells via a nuclear factor-kappa B (NF-κB)-dependent mechanism (Rolls et al. 2007). Indeed, the absence of TLR4 results in enhanced proliferation and neuronal differentiation (Rolls et al. 2007). Additional studies in vitro indicate that TLR4 directly modulates self-renewal and the cell-fate decision of neuronal progenitor cells (Rolls et al. 2007).

Activated microglia has been identified as the putative candidate responsible for downregulating hippocampal neurogenesis after LPS-induced neuroinflammation (Ekdahl et al. 2003, Monje et al. 2003). Activated microglia were localized in close proximity to the newly formed cells, and there was a negative correlation between the number of activated microglia in the neurogenic zone and the number of surviving new hippocampal neurons (Ekdahl et al. 2003). This hypothesis is supported by a number of in vitro studies demonstrating that the survival of new hippocampal neurons is reduced when they are co-cultured with microglial cells activated by LPS, or exposed to their conditioned medium (Monje et al. 2003, Liu et al. 2005, Cacci et al. 2008). Because an IL-6 antibody selectively restored hippocampal neurogenesis, this effect was likely mediated by IL-6 (Nakanishi et al. 2007, Monje et al. 2003). Supporting this concept, transgenic mice with chronic astroglial expression of IL-6 show a substantial decrease in the production of new neurons (Vallieres et al. 2002).

Other pro-inflammatory cytokines could contribute to the inhibition of neurogenesis. For instance, IL-1β can reduce neurogenesis in the DG (Goshen et al. 2008, Spulber et al. 2008), whereas TNF-α seems to play a detrimental role in neural survival/differentiation (Liu et al. 2005, Monje et al. 2003). When added to adult hippocampal progenitor cell cultures, TNF-α decreased neurogenesis by 50% (Monje et al. 2003). Increased production of TNF-α by microglial cells during hippocampal inflammation could contribute to the death of new hippocampal progenitor cells (Vezzani et al. 2002).

Another inflammatory mediator, NO, is a negative regulator of neurogenesis. A significant increase in SVZ cell proliferation has been demonstrated in neuronal NOS (nNOS) deficient mice (Sun et al. 2005), or after inhibition of nNOS activity (Cheng et al. 2003, Moreno-Lopez et al. 2004). Furthermore, pathological concentrations of NO in vitro have a skewing effect on NSC differentiation, diverting a pro-neuronal to a pro-astroglial fate (Covacu et al. 2006).

Neuroinflammation inhibits neurogenesis by a variety of mechanisms, including an alteration in the relationship between progenitor cells and cells of the neurovasculature, a direct effect of activated microglia on the precursor cells, or stimulation of the hypothalamic-pituitary-adrenal axis (Monje et al. 2003). However, little is known on how a pathological environment with reactive-microglia affects the differentiation of precursor cells. An invariant feature of damage to the CNS is the migration of microglia cells to the site of injury and their subsequent activation. There is some evidence that newborn neurons generated from stem cells could partially replace dead cells following brain injury (Thored et al. 2006, Nakatomi et al. 2002). Therefore, the identification of suitable tools to direct microglial state towards a pro-neurogenic phenotype could represent a new strategy to promote brain regenerative processes (Thored et al. 2006, Nakatomi et al. 2002).

“Aging brain”: a matter of hot debate

Evidence of morphological alterations of microglia with normal aging led to the hypothesis that microglia become dysfunctional in the aged brain (Streit et al. 2004). Senescence may impair the ability of microglia to function and respond to stimuli normally and increase the vulnerability to neurodegenerative diseases. The most prominent and early feature of microglia senescence is a morphological alteration characterized by deramification, cytoplasmic beading/spheroid formation, shortened and twisted cytoplasmic processes, and partial or complete cytoplasmic fragmentation (Streit et al. 2004).

Markers of inflammation and microglia and astrocytes activation are significantly increased in the hippocampus of aged mice (Kuzumaki et al. 2010), rats (Aid & Bosetti 2007, Kuzumaki et al.) and humans (David et al. 1997, Sheffield & Berman 1998). These age-associated changes may underlie the alteration of microglial function and their responses to injury.

Microglia isolated from aging brains have increased basal levels of IL-6, which could exacerbate cognitive deficits associated with neuroinflammation (Sparkman et al. 2006). Furthermore, increased IL-6, IL-1β and TNF-α production in response to LPS stimulation when compared with microglia derived from young brains, suggesting that aging microglia are over-responsive to inflammatory stimuli (Xie et al. 2003, Ye & Johnson 1999).

Memory deficits seen during normal or pathological aging may be linked to alterations in neurogenesis. Decreased neurogenesis in the hippocampus has been recognized as one of the mechanisms of age-related brain dysfunction (Kuzumaki et al. 2010). However, the molecular mechanisms underlying the decrease in neurogenesis with aging remain unclear.

It has been suggested that the age-related deficit in hippocampal-dependent learning is in part due to an increase in IL-1β (Gemma & Bickford 2007). Indeed, the upregulation of IL-1β expression coupled with a downregulation of IL-4 expression in the aging brain is associated with impaired long term potentiation, one of the major cellular pathways involved in learning and memory (Nolan et al. 2005). A key anti-inflammatory action of IL-4 results from its ability to antagonize the effects of IL-1β or to inhibit the synthesis of IL-1β m RNA and protein; in fact co-treatment of LPS-stimulated hippocampal neurons with IL-4 abrogated the increased expression of IL-1β (Nolan et al. 2005).

IL-1β in the hippocampus (Murray & Lynch 1998, Kuzumaki et al. 2010, Lynch 2010) has been proposed to contribute to the anti-neurogenic effect by suppressing hippocampal neurogenesis in the aging brain (Koo & Duman 2008) via epigenetic modifications (Kuzumaki et al. 2010). Indeed, aging induces a significant increase in histone H3-lysine 9 trimethylation at the promoter of a neural progenitor cell marker (NeuroD) in the hippocampus (Kuzumaki et al. 2010). Overall, these data suggest that IL-1β, which levels are increased with aging, can exert an epigenetic modulation of neural progenitor cells.

The reasons for decreased neurogenesis with aging may be related to an intrinsic inability to respond to the proliferative stimulation in the neurogenic niche, a reduction of proliferative stem cells number, or activated microglia and neuroinflammation. Neural stem cells therapy has considerable potential to repopulate damaged areas of the adult and aging brain. Understanding the basis for reduced neurogenesis in the aging brain is necessary to determine the functional importance of new neurons and the potential therapeutic use of neural stem cells for repair.

Stem cell technology: a potential regenerative strategy for aging and disease

Neurogenesis by endogenous brain stem cells cannot fully compensate for the neuronal loss observed in aging and, particularly, in neurodegenerative diseases. One reason for this limited response is the lack of trophic support and inhibitory signals within the brain microenvironment (Croft & Przyborski 2009), indicative of oxidative stress (Kelly et al. 2010) and age-related neuroinflammation. These observations stimulated a search for agents that could increase neurogenesis and enhance neuroprotection.

A number of humoral growth factors have been shown to modulate the mitotic expansion and the neuronal stem cells differentiation. To promote the integration of newly formed neurons into the mature brain circuit, several groups have focused on brain-derived neurotrophic factor (BDNF) (Cho et al. 2007). Decreased levels of BDNF have been reported in normal aging (Hattiangady et al. 2005) and neurodegenerative diseases, where discrete brain regions affected by loss of neurons have decreased levels of BDNF, which can contribute to lack of trophic support for neurons and to subsequent neurodegeneration (Hock et al. 2000). There is evidence that BDNF can promote survival and neuronal differentiation of hippocampal progenitor cells and improve learning and memory (Shetty et al. 2004, Hattiangady et al. 2005). Thus, exogenous BDNF could potentially promote the formation of new neurons in the aged or diseased brain (Pencea et al. 2001). In addition to BDNF, studies have shown that intracerebroventricular infusion of fibroblast growth factor-2 (FGF-2) or nerve growth factor (NGF) can also enhance neurogenesis and improve learning and memory deficits in the aged brain (Shetty et al. 2005, Rai et al. 2007, Fischer 1994). Insulin-like growth factor-I (IGF-I) is another promising candidate to regulate and restore neurogenesis in the aging brain since it influences neuronal production during development and then decreases with age (Lichtenwalner et al. 2001).

Antioxidant agents (Kelly et al. 2010, Lynch et al. 2007, Lim et al. 2005), and endocannabinoids (Marchalant et al. 2009) have an anti-inflammatory effects and improve age-related deficits in spatial learning during normal and pathological aging.

An alternative approach for restoring function following neuronal loss is implantation of stem progenitor cells (Prockop et al. 2003, Munoz et al. 2005).

Progenitor cells can be generated from several sources and show great promise for many clinical applications, including disease modeling, drug screening, and regenerative medicine (Marchetto et al. 2010). Recently, it has been shown that forced expression of some transcription factors, in human fibroblasts and adipose stem cells can reprogram the cells to a pluripotent state. These induced pluripotent stem cells (iPSC) exhibit similar properties of human embryonic cells, can self-renew, and are capable to give rise to all cells types including neuronal differentation (Liu et al. 2010). Cell reprogramming and successful generation of iPCS-derived neurons that became functionally intergrated after transplantation has been reported for several neurodegenerative diseases like Parkinson’s and Huntington’ diseases (Park et al. 2008, Soldner et al. 2009, Marchetto et al. 2010). Mouse iPSC-derived precursors were differentiated into dopamine neurons (DA) and transplanted into a model of DA neurons depletion, were functionally integrated in the striatum and improved symptoms of rats with Parkinson’s disease (Wernig et al. 2008). Promising results were obtained by Aubry and collegues also with human embryonic stem cells, which after transplantation matured into striatal neurons in a rat model of Huntington’s disease (Aubry et al. 2008).

As well, mesenchymal stem cells (MSCs) of adult bone marrow and amniotic fluid (Cipriani et al. 2007, Tsai et al. 2006) are regarded as potential candidates for regenerative medicine. Recent reports have shown that adult bone marrow and amniotic fluid contain a subpopulation of mesenchymal stem cells that can be isolated and have the capacity to differentiate into multiple lineages (Pittenger et al. 1999, Woodbury et al. 2000), including neurons, and are capable of replacing damaged neuronal tissue (Cipriani et al. 2007, Kim et al. 2009). The neuroprotective effect of MSCs may be mediated by their differentiation into neuron-like cells, but also their ability to produce various trophic factors that may contribute to functional recovery, neuronal cell survival, and stimulation of endogenous regeneration (Barry & Murphy 2004, Kim et al. 2009).

Experimental evidence from transplant studies indicates an amplification of the endogenous neurogenic response to injury in MSC-treated animals (Barry & Murphy 2004, Cicchetti et al. 2002, Mahmood et al. 2005), suggesting that one therapeutic benefit of MSCs is to promote the formation and survival of new neurons in the adult brain from resident neuronal stem cells in the SVZ (Chen & Swanson 2003, Chen et al. 2001) and in the hippocampal DG (Ben-Shaanan et al. 2008, Munoz et al. 2005). MSCs-implanted cells also have the remarkable ability to migrate to sites of tissue damage and stimulate repair either by differentiating into tissue-specific cells or by creating a milieu that enhances the repair of endogenous cells (Alvarez-Buylla et al. 2002, Cipriani et al. 2007). These effects on brain plasticity are thought to be mediated primarily by the release of cytokines and growth factors produced by MSCs, which activate endogenous restorative and regenerative processes within the host brain (Chen et al. 2005, Biebl et al. 2000).

Several studies in vitro and in vivo showed that MCSs implantation has protective, anti-inflammatory effects (Gerdoni et al. 2007, Guo et al. 2007), and can dramatically decrease neural damage (Gao & Hong 2008, Dong et al. 2007, Kim et al. 2009). Human MSCs inhibited LPS-stimulated microglial activation and the production of pro-inflammatory mediators (Zhou et al. 2009). Furthermore, MSCs inhibited T-cell proliferation, decreased IFN-γ production, and increased IL-4 production, indicating a shift in T cells from a pro-inflammatory (IFN-γ-producing) state to an anti-inflammatory (IL-4-producing) state (Aggarwal & Pittenger 2005). Nevertheless, the potential immunomodulatory effects of MSCs on primary microglia remain to be fully evaluated. MSCs may respond to inflammatory cues and significantly increase production of neurotrophic factors, which may be involved in anti-inflammatory mechanisms (Zhou et al. 2009).

Recently, Lee and colleagues showed that intracerebral transplantation of MSCs into double-transgenic Alzheimer’s mice significantly reduced amyloid beta plaques, inflammation and improved cognitive functions (Lee et al. 2010). Furthermore, a first clinical pilot study with MSCs transplanted into the striatum of patients with advanced Parkinson’s disease showed some clinical improvements without any adverse events during the observation period (Venkataramana et al. 2010). Thus, stem cells could be a viable therapeutic approach to return the brain to homeostasis, enhance or induce neurogenesis, and represent ideal candidates for the treatment of neurodegenerative diseases.

In summary, the presence of neuronal progenitor cells in adult human and rodent brain, the regenerative capacity of stem cells, and the recent development of stem cells technology open new areas of research aimed at stimulating neuronal regeneration in the brain during aging, neuroinflammation and neurodegenerative diseases. A better understanding of the mechanisms that modulate the inhibition versus the stimulation of neurogenesis during neuroinflammation, and that modulate the integration of stem cells transplanted in diseased brain could help to develop novel anti-inflammatory approach with a potential application in neurodegenerative diseases with a strong inflammatory component.

Abbreviations

SVZ
subventricular zone
SGL
subgranular zone
DG
dentate gyrus
GCL
granule cell layer
CNS
central nervous system
OB
olfactory bulb
RMS
rostral migratory stream
BBB
blood brain barrier
NSC
neural stem cells
LPS
lipopolysaccharide
TLR4
toll-like receptor 4
iNOS
inducible nitric oxide synthase
IL-4
interleukin- 4
IL-6
interleukin- 6
IL-1β
interleukin- 1β
TNF-α
tumor necrosis factor-α
INF-γ
interferon-γ
NO
nitric oxide
MyD88
myeloid differentiation primary response gene
PKCα/β
protein kinase Cα/β
NF--κB
nuclear factor-kappaB
nNOS
neuronal nitric oxide synthase
H3K9
histone H3-lysine 9
MSC
mesenchymal stem cells
BDNF
brain-derived neurotrophic factor
NGF
nerve growth factor
FGF
fibroblast growth factor
IGF-I
insulin-like grow factor-I
MSC
mesenchymal stem cells
iPSC
induced pluripotent stem cells

References

  • Abrous DN, Koehl M, Le Moal M. Adult neurogenesis: from precursors to network and physiology. Physiol Rev. 2005;85:523–569. [PubMed]
  • Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822. [PubMed]
  • Aid S, Bosetti F. Gene expression of cyclooxygenase-1 and Ca(2+)-independent phospholipase A(2) is altered in rat hippocampus during normal aging. Brain Res Bull. 2007;73:108–113. [PMC free article] [PubMed]
  • Aid S, Langenbach R, Bosetti F. Neuroinflammatory response to lipopolysaccharide is exacerbated in mice genetically deficient in cyclooxygenase-2. J Neuroinflammation. 2008;5:17. [PMC free article] [PubMed]
  • Alvarez-Buylla A, Seri B, Doetsch F. Identification of neural stem cells in the adult vertebrate brain. Brain Res Bull. 2002;57:751–758. [PubMed]
  • Arvidsson A, Collin T, Kirik D, Kokaia Z, Lindvall O. Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat Med. 2002;8:963–970. [PubMed]
  • Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier AL. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A. 2008;105:16707–16712. [PMC free article] [PubMed]
  • Baron R, Nemirovsky A, Harpaz I, Cohen H, Owens T, Monsonego A. IFN-gamma enhances neurogenesis in wild-type mice and in a mouse model of Alzheimer’s disease. FASEB J. 2008;22:2843–2852. [PubMed]
  • Barry FP, Murphy JM. Mesenchymal stem cells: clinical applications and biological characterization. Int J Biochem Cell Biol. 2004;36:568–584. [PubMed]
  • Belmadani A, Tran PB, Ren D, Miller RJ. Chemokines regulate the migration of neural progenitors to sites of neuroinflammation. J Neurosci. 2006;26:3182–3191. [PMC free article] [PubMed]
  • Ben-Shaanan TL, Ben-Hur T, Yanai J. Transplantation of neural progenitors enhances production of endogenous cells in the impaired brain. Mol Psychiatry. 2008;13:222–231. [PubMed]
  • Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004;430:257–263. [PubMed]
  • Biebl M, Cooper CM, Winkler J, Kuhn HG. Analysis of neurogenesis and programmed cell death reveals a self-renewing capacity in the adult rat brain. Neurosci Lett. 2000;291:17–20. [PubMed]
  • Bonow RH, Aid S, Zhang Y, Becker KG, Bosetti F. The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice. Pharmacogenomics J. 2009;9:116–126. [PMC free article] [PubMed]
  • Bossu P, Ciaramella A, Moro ML, et al. Interleukin 18 gene polymorphisms predict risk and outcome of Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2007;78:807–811. [PMC free article] [PubMed]
  • Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci. 2006;31:149–160. [PubMed]
  • Cacci E, Ajmone-Cat MA, Anelli T, Biagioni S, Minghetti L. In vitro neuronal and glial differentiation from embryonic or adult neural precursor cells are differently affected by chronic or acute activation of microglia. Glia. 2008;56:412–425. [PubMed]
  • Chen H, Jacobs E, Schwarzschild MA, McCullough ML, Calle EE, Thun MJ, Ascherio A. Nonsteroidal antiinflammatory drug use and the risk for Parkinson’s disease. Ann Neurol. 2005;58:963–967. [PubMed]
  • Chen J, Li Y, Wang L, Lu M, Zhang X, Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci. 2001;189:49–57. [PubMed]
  • Chen Y, Swanson RA. Astrocytes and brain injury. J Cereb Blood Flow Metab. 2003;23:137–149. [PubMed]
  • Cheng A, Wang S, Cai J, Rao MS, Mattson MP. Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol. 2003;258:319–333. [PubMed]
  • Cho SR, Benraiss A, Chmielnicki E, Samdani A, Economides A, Goldman SA. Induction of neostriatal neurogenesis slows disease progression in a transgenic murine model of Huntington disease. J Clin Invest. 2007;117:2889–2902. [PMC free article] [PubMed]
  • Choi SH, Aid S, Bosetti F. The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol Sci. 2009;30:174–181. [PMC free article] [PubMed]
  • Cicchetti F, Brownell AL, Williams K, Chen YI, Livni E, Isacson O. Neuroinflammation of the nigrostriatal pathway during progressive 6-OHDA dopamine degeneration in rats monitored by immunohistochemistry and PET imaging. Eur J Neurosci. 2002;15:991–998. [PubMed]
  • Cipriani S, Bonini D, Marchina E, Balgkouranidou I, Caimi L, Grassi Zucconi G, Barlati S. Mesenchymal cells from human amniotic fluid survive and migrate after transplantation into adult rat brain. Cell Biol Int. 2007;31:845–850. [PubMed]
  • Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30:464–472. [PubMed]
  • Covacu R, Danilov AI, Rasmussen BS, et al. Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis. Stem Cells. 2006;24:2792–2800. [PubMed]
  • Croft AP, Przyborski SA. Mesenchymal stem cells expressing neural antigens instruct a neurogenic cell fate on neural stem cells. Exp Neurol. 2009;216:329–341. [PubMed]
  • David JP, Ghozali F, Fallet-Bianco C, Wattez A, Delaine S, Boniface B, Di Menza C, Delacourte A. Glial reaction in the hippocampal formation is highly correlated with aging in human brain. Neurosci Lett. 1997;235:53–56. [PubMed]
  • Doetsch F, Scharff C. Challenges for brain repair: insights from adult neurogenesis in birds and mammals. Brain Behav Evol. 2001;58:306–322. [PubMed]
  • Dong S, Li C, Wu P, Tsien JZ, Hu Y. Environment enrichment rescues the neurodegenerative phenotypes in presenilins-deficient mice. Eur J Neurosci. 2007;26:101–112. [PubMed]
  • Drapeau E, Montaron MF, Aguerre S, Abrous DN. Learning-induced survival of new neurons depends on the cognitive status of aged rats. J Neurosci. 2007;27:6037–6044. [PubMed]
  • Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O. Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci U S A. 2003;100:13632–13637. [PMC free article] [PubMed]
  • Fernandez JA, Rojo L, Kuljis RO, Maccioni RB. The damage signals hypothesis of Alzheimer’s disease pathogenesis. J Alzheimers Dis. 2008;14:329–333. [PubMed]
  • Fischer W. Nerve growth factor reverses spatial memory impairments in aged rats. Neurochem Int. 1994;25:47–52. [PubMed]
  • Gage FH. Neurogenesis in the adult brain. J Neurosci. 2002;22:612–613. [PubMed]
  • Gao HM, Hong JS. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 2008;29:357–365. [PubMed]
  • Gemma C, Bickford PC. Interleukin-1beta and caspase-1: players in the regulation of age-related cognitive dysfunction. Rev Neurosci. 2007;18:137–148. [PubMed]
  • Gerdoni E, Gallo B, Casazza S, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol. 2007;61:219–227. [PubMed]
  • Goshen I, Kreisel T, Ben-Menachem-Zidon O, Licht T, Weidenfeld J, Ben-Hur T, Yirmiya R. Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry. 2008;13:717–728. [PubMed]
  • Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci. 1999;2:260–265. [PubMed]
  • Guo J, Lin GS, Bao CY, Hu ZM, Hu MY. Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation. 2007;30:97–104. [PubMed]
  • Hanisch UK, Kettenmann H. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci. 2007;10:1387–1394. [PubMed]
  • Hattiangady B, Rao MS, Shetty GA, Shetty AK. Brain-derived neurotrophic factor, phosphorylated cyclic AMP response element binding protein and neuropeptide Y decline as early as middle age in the dentate gyrus and CA1 and CA3 subfields of the hippocampus. Exp Neurol. 2005;195:353–371. [PubMed]
  • Hemmer B, Cepok S, Zhou D, Sommer N. Multiple sclerosis -- a coordinated immune attack across the blood brain barrier. Curr Neurovasc Res. 2004;1:141–150. [PubMed]
  • Hirsch EC, Hunot S. Neuroinflammation in Parkinson’s disease: a target for neuroprotection? Lancet Neurol. 2009;8:382–397. [PubMed]
  • Hock C, Heese K, Hulette C, Rosenberg C, Otten U. Region-specific neurotrophin imbalances in Alzheimer disease: decreased levels of brain-derived neurotrophic factor and increased levels of nerve growth factor in hippocampus and cortical areas. Arch Neurol. 2000;57:846–851. [PubMed]
  • Kelly L, Grehan B, Chiesa AD, O’Mara SM, Downer E, Sahyoun G, Massey KA, Nicolaou A, Lynch MA. The polyunsaturated fatty acids, EPA and DPA exert a protective effect in the hippocampus of the aged rat. Neurobiol Aging 2010 [PubMed]
  • Kim YJ, Park HJ, Lee G, Bang OY, Ahn YH, Joe E, Kim HO, Lee PH. Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia. 2009;57:13–23. [PubMed]
  • Klegeris A, McGeer EG, McGeer PL. Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol. 2007;20:351–357. [PubMed]
  • Klegeris A, McGeer PL. Non-steroidal anti-inflammatory drugs (NSAIDs) and other anti-inflammatory agents in the treatment of neurodegenerative disease. Curr Alzheimer Res. 2005;2:355–365. [PubMed]
  • Koo JW, Duman RS. IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A. 2008;105:751–756. [PMC free article] [PubMed]
  • Kuzumaki N, Ikegami D, Imai S, et al. Enhanced IL-1beta production in response to the activation of hippocampal glial cells impairs neurogenesis in aged mice. Synapse. 2010;64:721–728. [PubMed]
  • Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS. Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta deposition and rescues memory deficits in Alzheimer’s disease mice by modulation of immune responses. Stem Cells. 2010;28:329–343. [PubMed]
  • Lichtenwalner RJ, Forbes ME, Bennett SA, Lynch CD, Sonntag WE, Riddle DR. Intracerebroventricular infusion of insulin-like growth factor-I ameliorates the age-related decline in hippocampal neurogenesis. Neuroscience. 2001;107:603–613. [PubMed]
  • Lim GP, Calon F, Morihara T, Yang F, Teter B, Ubeda O, Salem N, Jr, Frautschy SA, Cole GM. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J Neurosci. 2005;25:3032–3040. [PubMed]
  • Limke TL, Rao MS. Neural stem cells in aging and disease. J Cell Mol Med. 2002;6:475–496. [PubMed]
  • Liu B, Hong JS. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther. 2003;304:1–7. [PubMed]
  • Liu BF, Gao EJ, Zeng XZ, Ji M, Cai Q, Lu Q, Yang H, Xu QY. Proliferation of neural precursors in the subventricular zone after chemical lesions of the nigrostriatal pathway in rat brain. Brain Res. 2006;1106:30–39. [PubMed]
  • Liu J, Sumer H, Leung J, Upton K, Dottori M, Pebay A, Verma PJ. Late passage human fibroblasts induced to pluripotency are capable of directed neuronal differentiation. Cell Transplant 2010 [PubMed]
  • Liu YP, Lin HI, Tzeng SF. Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture. Brain Res. 2005;1054:152–158. [PubMed]
  • Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006;147(Suppl 1):S232–240. [PMC free article] [PubMed]
  • Lucin KM, Wyss-Coray T. Immune activation in brain aging and neurodegeneration: too much or too little? Neuron. 2009;64:110–122. [PMC free article] [PubMed]
  • Lynch AM, Loane DJ, Minogue AM, Clarke RM, Kilroy D, Nally RE, Roche OJ, O’Connell F, Lynch MA. Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus. Neurobiol Aging. 2007;28:845–855. [PubMed]
  • Lynch MA. Age-related neuroinflammatory changes negatively impact on neuronal function. Front Aging Neurosci. 2010;1:6. [PMC free article] [PubMed]
  • Mahmood A, Lu D, Qu C, Goussev A, Chopp M. Human marrow stromal cell treatment provides long-lasting benefit after traumatic brain injury in rats. Neurosurgery. 2005;57:1026–1031. discussion 1026–1031. [PMC free article] [PubMed]
  • Marchalant Y, Brothers HM, Norman GJ, Karelina K, DeVries AC, Wenk GL. Cannabinoids attenuate the effects of aging upon neuroinflammation and neurogenesis. Neurobiol Dis. 2009;34:300–307. [PubMed]
  • Marchetto MC, Winner B, Gage FH. Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Hum Mol Genet. 2010;19:R71–76. [PMC free article] [PubMed]
  • Martino G, Pluchino S. The therapeutic potential of neural stem cells. Nat Rev Neurosci. 2006;7:395–406. [PubMed]
  • McGeer PL, McGeer EG. NSAIDs and Alzheimer disease: epidemiological, animal model and clinical studies. Neurobiol Aging. 2007;28:639–647. [PubMed]
  • Monje ML, Toda H, Palmer TD. Inflammatory blockade restores adult hippocampal neurogenesis. Science. 2003;302:1760–1765. [PubMed]
  • Montine TJ, Milatovic D, Gupta RC, Valyi-Nagy T, Morrow JD, Breyer RM. Neuronal oxidative damage from activated innate immunity is EP2 receptor-dependent. J Neurochem. 2002;83:463–470. [PubMed]
  • Morales I, Farias G, Maccioni RB. Neuroimmunomodulation in the pathogenesis of Alzheimer’s disease. Neuroimmunomodulation. 2010;17:202–204. [PubMed]
  • Moreno-Lopez B, Romero-Grimaldi C, Noval JA, Murillo-Carretero M, Matarredona ER, Estrada C. Nitric oxide is a physiological inhibitor of neurogenesis in the adult mouse subventricular zone and olfactory bulb. J Neurosci. 2004;24:85–95. [PubMed]
  • Morshead CM, Craig CG, van der Kooy D. In vivo clonal analyses reveal the properties of endogenous neural stem cell proliferation in the adult mammalian forebrain. Development. 1998;125:2251–2261. [PubMed]
  • Morshead CM, Reynolds BA, Craig CG, McBurney MW, Staines WA, Morassutti D, Weiss S, van der Kooy D. Neural stem cells in the adult mammalian forebrain: a relatively quiescent subpopulation of subependymal cells. Neuron. 1994;13:1071–1082. [PubMed]
  • Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A. 2005;102:18171–18176. [PMC free article] [PubMed]
  • Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1 beta is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci. 1998;18:2974–2981. [PubMed]
  • Nakanishi M, Niidome T, Matsuda S, Akaike A, Kihara T, Sugimoto H. Microglia-derived interleukin-6 and leukaemia inhibitory factor promote astrocytic differentiation of neural stem/progenitor cells. Eur J Neurosci. 2007;25:649–658. [PubMed]
  • Nakatomi H, Kuriu T, Okabe S, Yamamoto S, Hatano O, Kawahara N, Tamura A, Kirino T, Nakafuku M. Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell. 2002;110:429–441. [PubMed]
  • Nolan Y, Maher FO, Martin DS, Clarke RM, Brady MT, Bolton AE, Mills KH, Lynch MA. Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J Biol Chem. 2005;280:9354–9362. [PubMed]
  • Palsson-McDermott EM, O’Neill LA. Signal transduction by the lipopolysaccharide receptor, Toll-like receptor-4. Immunology. 2004;113:153–162. [PMC free article] [PubMed]
  • Park IH, Arora N, Huo H, et al. Disease-specific induced pluripotent stem cells. Cell. 2008;134:877–886. [PMC free article] [PubMed]
  • Pencea V, Bingaman KD, Wiegand SJ, Luskin MB. Infusion of brain-derived neurotrophic factor into the lateral ventricle of the adult rat leads to new neurons in the parenchyma of the striatum, septum, thalamus, and hypothalamus. J Neurosci. 2001;21:6706–6717. [PubMed]
  • Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun. 2004;18:407–413. [PubMed]
  • Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–147. [PubMed]
  • Prockop DJ, Gregory CA, Spees JL. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A. 2003;100(Suppl 1):11917–11923. [PMC free article] [PubMed]
  • Quan N, Sundar SK, Weiss JM. Induction of interleukin-1 in various brain regions after peripheral and central injections of lipopolysaccharide. J Neuroimmunol. 1994;49:125–134. [PubMed]
  • Rai KS, Hattiangady B, Shetty AK. Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions. Eur J Neurosci. 2007;26:1765–1779. [PubMed]
  • Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol. 2007;9:1081–1088. [PubMed]
  • Rosenberg GA. Matrix metalloproteinases in neuroinflammation. Glia. 2002;39:279–291. [PubMed]
  • Rozemuller AJ, van Gool WA, Eikelenboom P. The neuroinflammatory response in plaques and amyloid angiopathy in Alzheimer’s disease: therapeutic implications. Curr Drug Targets CNS Neurol Disord. 2005;4:223–233. [PubMed]
  • Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A. Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci. 2001;21:7153–7160. [PubMed]
  • Shapiro LA, Wang L, Ribak CE. Rapid astrocyte and microglial activation following pilocarpine-induced seizures in rats. Epilepsia. 2008;49(Suppl 2):33–41. [PubMed]
  • Shaw KN, Commins S, O’Mara SM. Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus. Behav Brain Res. 2001;124:47–54. [PubMed]
  • Sheffield LG, Berman NE. Microglial expression of MHC class II increases in normal aging of nonhuman primates. Neurobiol Aging. 1998;19:47–55. [PubMed]
  • Shetty AK, Hattiangady B, Shetty GA. Stem/progenitor cell proliferation factors FGF-2, IGF-1, and VEGF exhibit early decline during the course of aging in the hippocampus: role of astrocytes. Glia. 2005;51:173–186. [PubMed]
  • Shetty AK, Rao MS, Hattiangady B, Zaman V, Shetty GA. Hippocampal neurotrophin levels after injury: Relationship to the age of the hippocampus at the time of injury. J Neurosci Res. 2004;78:520–532. [PubMed]
  • Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001;410:372–376. [PubMed]
  • Snyder EY, Yoon C, Flax JD, Macklis JD. Multipotent neural precursors can differentiate toward replacement of neurons undergoing targeted apoptotic degeneration in adult mouse neocortex. Proc Natl Acad Sci U S A. 1997;94:11663–11668. [PMC free article] [PubMed]
  • Soldner F, Hockemeyer D, Beard C, et al. Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors. Cell. 2009;136:964–977. [PMC free article] [PubMed]
  • Song JH, Wang CX, Song DK, Wang P, Shuaib A, Hao C. Interferon gamma induces neurite outgrowth by up-regulation of p35 neuron-specific cyclin-dependent kinase 5 activator via activation of ERK1/2 pathway. J Biol Chem. 2005;280:12896–12901. [PubMed]
  • Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci. 2006;26:10709–10716. [PubMed]
  • Spulber S, Oprica M, Bartfai T, Winblad B, Schultzberg M. Blunted neurogenesis and gliosis due to transgenic overexpression of human soluble IL-1ra in the mouse. Eur J Neurosci. 2008;27:549–558. [PubMed]
  • Stolp HB, Dziegielewska KM. Review: Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases. Neuropathol Appl Neurobiol. 2009;35:132–146. [PubMed]
  • Streit WJ, Sammons NW, Kuhns AJ, Sparks DL. Dystrophic microglia in the aging human brain. Glia. 2004;45:208–212. [PubMed]
  • Sun Y, Jin K, Childs JT, Xie L, Mao XO, Greenberg DA. Neuronal nitric oxide synthase and ischemia-induced neurogenesis. J Cereb Blood Flow Metab. 2005;25:485–492. [PubMed]
  • Tansey MG, Goldberg MS. Neuroinflammation in Parkinson’s disease: its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis. 2010;37:510–518. [PMC free article] [PubMed]
  • Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, Ekdahl CT, Kokaia Z, Lindvall O. Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells. 2006;24:739–747. [PubMed]
  • Tsai MS, Hwang SM, Tsai YL, Cheng FC, Lee JL, Chang YJ. Clonal amniotic fluid-derived stem cells express characteristics of both mesenchymal and neural stem cells. Biol Reprod. 2006;74:545–551. [PubMed]
  • Vallieres L, Campbell IL, Gage FH, Sawchenko PE. Reduced hippocampalneurogenesis in adult transgenic mice with chronic astrocytic production of interleukin-6. J Neurosci. 2002;22:486–492. [PubMed]
  • van Praag H, Kempermann G, Gage FH. Neural consequences of environmental enrichment. Nat Rev Neurosci. 2000;1:191–198. [PubMed]
  • Venkataramana NK, Kumar SK, Balaraju S, et al. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Transl Res. 2010;155:62–70. [PubMed]
  • Vezzani A, Moneta D, Richichi C, Aliprandi M, Burrows SJ, Ravizza T, Perego C, De Simoni MG. Functional role of inflammatory cytokines and antiinflammatory molecules in seizures and epileptogenesis. Epilepsia. 2002;43(Suppl 5):30–35. [PubMed]
  • Wernig M, Zhao JP, Pruszak J, et al. Neurons derived from reprogrammed fibroblasts functionally integrate into the fetal brain and improve symptoms of rats with Parkinson’s disease. Proc Natl Acad Sci U S A. 2008;105:5856–5861. [PMC free article] [PubMed]
  • Wong G, Goldshmit Y, Turnley AM. Interferon-gamma but not TNF alpha promotes neuronal differentiation and neurite outgrowth of murine adult neural stem cells. Exp Neurol. 2004;187:171–177. [PubMed]
  • Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res. 2000;61:364–370. [PubMed]
  • Wu CW, Chen YC, Yu L, Chen HI, Jen CJ, Huang AM, Tsai HJ, Chang YT, Kuo YM. Treadmill exercise counteracts the suppressive effects of peripheral lipopolysaccharide on hippocampal neurogenesis and learning and memory. J Neurochem. 2007;103:2471–2481. [PubMed]
  • Xie Z, Morgan TE, Rozovsky I, Finch CE. Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity. Exp Neurol. 2003;182:135–141. [PubMed]
  • Ye SM, Johnson RW. Increased interleukin-6 expression by microglia from brain of aged mice. J Neuroimmunol. 1999;93:139–148. [PubMed]
  • Zhou C, Zhang C, Chi S, Xu Y, Teng J, Wang H, Song Y, Zhao R. Effects of human marrow stromal cells on activation of microglial cells and production of inflammatory factors induced by lipopolysaccharide. Brain Res. 2009;1269:23–30. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...