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. Author manuscript; available in PMC: 2012 Jun 25.
Published in final edited form as: J Neurochem. 2011 Jan 19;116(6):947–956. doi: 10.1111/j.1471-4159.2010.07168.x

EFFECTS OF NEUROINFLAMMATION ON THE REGENERATIVE CAPACITY OF BRAIN STEM CELLS

Isabella Russo 1,2, Sergio Barlati 2, Francesca Bosetti 1,*
PMCID: PMC3382108  NIHMSID: NIHMS385836  PMID: 21198642

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.

Figure 1

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LPS-induced neuroinflammation causes reactive microgliosis, which contributes to neuronal dysfunction and degeneration by releasing inflammatory and neurotoxic factors (IL-6, TNF-α, IL-1β, NO, ROS). These pro-inflammatory mediators can alter the “neural stem cell” niche, leading to decrease in proliferation and neuronal differentiation of progenitor cells, which results in inhibition of neurogenesis. In contrast, other factors such as humoral growth factors, endocannabinoids, antioxidant agents, MSCs and iPSC-derived neurons implantation, IFN-γ, physical exercise and environmental enrichment can stimulate 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

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