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New roles for astrocytes: The nightlife of an astrocyte. La vida loca!

Philip J. Horner1 and Theo D. Palmer2
University of Washington, Department of Neurosurgery, Harborview R&T Building, 325 Ninth Ave Box 359655, Seattle, WA 98104, USA 2 Stanford University, Department of Neurosurgery, MSLS P309, Mail Code 5487, 1201 Welch Road, Stanford, CA 94305-5487, USA
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Like a newly popular nightspot, the biology of adult stem cells has emerged from obscurity to become one of the most lively new disciplines of the decade. The neurosciences have not escaped this trendy pastime and, from amid the noise and excitement, the astrocyte emerges as a beguiling companion to the adult neural stem cell. A once receding partner to neurons and oligodendrocytes, the astrocyte even takes on an alter ego of the stem cell itself (S. Goldman, this issue of TINS). Putting ego aside, the astrocyte is also (and perhaps more importantly) an integral component of neural progenitor hotspots, where the craziness or la vida loca of the nightlife might not be so wild when compared with our traditional understanding of the astrocyte. Here, astrocytes contribute to the instructive conuence of location, atmosphere and cellular neighbors that dene the daily vida local or everyday local life of an adult stem cell. This review discusses astrocytes as inuential components in the local stem cell niche. In development, neuroepithelial stem cells of the ventricular zone produce the majority of the neurons and glia present in the newborn brain. As development nears completion, stem cell activity switches to the distinct and relatively restricted patterns of activity present through out adult life. In the unperturbed brain, this activity yields two end products: gliogenesis, which persists throughout the CNS, and neurogenesis, which is restricted to the olfactory bulb and hippocampus. There appears to be considerable overlap in the cells and signals that mediate gliogenesis versus neurogenesis and discrimination between these two outcomes could, in part, rest in the hands of the local astrocyte. Distinguished by their expression of glial brillary acidic protein (GFAP), astrocytes could contribute to cell genesis both as the stem cells themselves and as an inuential components of the gliogenic or neurogenic stem cell niche. In the adult brain, dividing cells are antigenically distinct in different regions. For example, in white and gray matter, the predominant dividing cell is immunoreactive for NG2, O4, and/or A2B5 early ganglioside markers for glial progenitors [1 5]. The use of these markers as indicating glial commitment is a distinction earned primarily from the well-documented fact that these
Corresponding authors: Philip J. Horner (phorner@u.washington.edu), Theo D. Palmer (tpalmer@stanford.edu).

cells generate only glia in vivo. However, these same glial progenitors can produce neurons if their environment is sufciently altered [6 9]. These data form a tantalizing premise that the brain is divided into zones or niches that control cell fate decisions and not the other way around. This article discusses the various guises that stem-like cells don within an instructive niche and contrasts the varying roles of astrocytes within these niches. As reviewed by Steve Goldman in this issue of TINS, the concept of glia as stem cells has gained considerable weight with the observation that cortical neurogenesis is mediated by radial glia within the early ventricular zone [10 12]. The production of neurons slowly turns into the production of glia in a temporal and region-specic manner [13]. Near birth, neurons and glia are simultaneously produced and the migrating stem cell progeny are antigenically distinct [14] and show clear differential migration depending on the lineage chosen [15,16]. In the adult, stem cells that remain in the subventricular zone retain attributes that are reminiscent of radial glia and under most circumstances would be identied as astrocytes in histological evaluation [12]. But it is likely that the cells that are generically labeled as GFAP-positive astrocytes are diverse. For example, Filippov and colleagues evaluated nestin-positive precursors within the hippocampus and found that progenitors within the subgranular zone can be divided into two categories: those that display traditional astrocyte properties (i.e. GFAP immunoreactivity, passive currents under patch-clamp conditions, and a process-bearing morphology, some of these processes forming vascular endfeet) and a putative actively dividing progenitor pool that expresses nestin but not astrocytic passive currents or GFAP [17]. Although many of the relatively quiescent nestin-positive processbearing cells are GFAP positive, none are positive for the astrocytic marker S100b that is common to neighboring astrocytes. The implication is that the term astrocyte in the context of stem cells might not be sufcient to distinguish the roles of GFAP-positive cells as stem cells versus their role as traditional S100b-positive astrocytes or as instructor cells within a stem cell niche. When considering stem cells within various niches of the adult brain, it is clear that patterns of cell behavior and fate correlate strongly with changes in antigenic phenotype. Early patterning events within stem cell progeny orchestrate this segregation and, if left unperturbed,

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regional differentiation would continue invariably towards an ultimate fate and function that is locally specied. For example, when stem cell progeny depart the subventricular zone, they continue to divide within the parenchyma of the brain and spinal cord where they produce almost exclusively oligodendrocytes [18,19]. However, if interrupted at an early stage by removal of the local inuences [6 9] or if this environment is altered by injury or exogenous growth factors, the subtly differentiated glial or neuronal progenitors can alter their fate and make neurons as well as glia in locations where neurogenesis is normally undetectable [20 24]. Given the interest in utilizing neural stem cells in brain repair, there is considerable motivation to understand more fully the local environments that regulate stem cell activity and to determine how this signaling evokes a given outward display of phenotypes. Even more importantly, one must understand relationships between these phenotypes and the point at which consolidation of a lineagespecic genetic program becomes immutable. Astrocytes and the gliogenic niche Persistent and prevalent gliogenesis in the adult CNS Continuing gliogenesis in the adult has been documented and accepted since the 1960s [2529] but there are differences between development and the adult that are noteworthy. During the transition from birth to adulthood, there is an attenuation of progenitor proliferation and migration and the vast majority of glia produced in adulthood are oligodendrocytes [19,3032]. In addition, adult gliogenesis becomes primarily a local phenomenon (rather than via migration of progenitors from the subventricular zone [16]). With local production of glia also come regional differences in the type of glia produced. Subcortical white matter progenitor cells produce primarily oligodendrocytes whereas spinal cord progenitors produce similar numbers of astrocytes and oligodendrocytes [18,19]. So not all gliogenic zones are created alike and most are likely to serve specialized functions based on the territory they occupy. Before discussing components of the glial niche, it is important to understand that gliogenic zones are instructive and not a passive vessel for pre-programmed progenitors. When epidermal growth factor (EGF) is infused directly in the cortex, progenitor cells are re-directed from the rostral migratory stream and migrate into cortical layers [24,33]. Despite the fact that these progenitor cells have neurogenic capacity and do form neurons in the olfactory bulb, they do not form new neurons in the cortex when diverted. Similarly, the adult spinal cord contains progenitor cells that have neurogenic capacity in vitro but these cells do not spontaneously generate neurons when reintroduced in to the intact spinal cord [34]. Astrocyte cell division and the gliogenic niche So what are the progenitor cells of the gliogenic niche? First, it is important to note that traditional astrocytes divide in glial-restricted zones [28,29]. Acute mitotic labeling studies in the adult spinal cord indicate that astrocytes express S100b during S-phase and comprise , 5% of all dividing cells [19]. Although progenitors that
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produce both astrocytes and oligodendrocytes have been demonstrated in classic in vitro experiments [35,36], it is not clear how astrocytes are generated in vivo. Key questions remain. Do traditional astrocytes divide from immature progeny or are they themselves gliogenic progenitors or even stem cells (Figure 1)? As will be discussed, this question has been explored in neurogenic zones of the brain but has not to date been adequately addressed in the gliogenic brain. The most prominent component of the gliogenic niche is the common glial progenitor cell, which does not bear resemblance to an astrocyte. Glial progenitor cells express A2B5 antigen, platelet-derived growth factor (PDGF) receptor a and Nkx2.2 at early stages of commitment [1]. It has been thought that when glial progenitor cells become restricted to an oligodendrocyte fate they upregulate the markers NG2, proteolipid protein (PLP) and O4, among others [2,3]. Importantly, these glial progenitors continue to divide in the adult brain and spinal cord [3,19] and comprise as many as 70% of all dividing cells in the adult CNS. Within a month of undergoing S-phase, a small subset of the NG2 progenitors (, 2.5%) downregulate NG2 and begin to express mature oligodendrocyte proteins [37]; however, most NG2 cells remain as pre-oligodendrocytes [4,38]. Although cell division in the adult gliogenic niche is reduced when compared with the postnatal peak of myelination, the birth of new glia, including astrocytes, remains signicant. Traditional astrocytes and their instructive role in gliogenic niches What role then might traditional GFAP-positive astrocytes play within the glial progenitor niche? The adult glialinstructive microenvironment is still largely unexplored but there are clues from development and injury that might shed light on the adult niche and a potential instructive role for astrocytes, such as the temporal and spatial production of growth and/or trophic factors. Glial progenitors are produced by a sequence of events starting early in development. Sonic hedgehog (Shh) is initially necessary to prime stem cells to become competent to generate oligodendrocytes [39]. Later, leukemia inhibitory factor, ciliary neurotrophic factor and bone morphogen protein-4 (BMP4) become inducers of astrocytic fate, while broblast growth factor (FGF)-2 and thyroid hormone induce an oligodendrocyte fate [1]. Subsequently, the Shh responsiveness of glial progenitors diminishes and the oligodendrocyte progenitor becomes responsive to PDGF [40]. Concurrent signaling from neighboring neurons involves neuregulins (NRGs), which amplify the number and solidify the commitment of oligodendrocytes, depending upon the neuregulin-receptor components expressed by the progenitor [41]. For the glial progenitor, timing of cell division and commitment to myelinate is crucial for producing the appropriate number of myelinating cells. During development, this timing is programmed locally and varies from region to region [42]. Cell cycle and commitment encoding is directed by astrocytes through the release of PDGF during postnatal gliogenesis [35,43]. This developmental correlate suggests that astrocytes could play an important role in the gliogenic niche by

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Gliogenesis A

Neurogenesis Hippocampal granule cell layer

Stem cell astrocyte? Myelinating oligodendrocyte Oligodendrocyte progenitor cells

Subgranule zone progenitor cells

Newborn granule layer neurons

Factors iInfluencing the gliogenic niche FGF-2 Notch BMP PDGF Neuregulins Unyelinated axons

Ventricular zone stem and progenitor cells

Factors influencing the neurogenic niche FGF-2, EGF, TGF IGF-1 VEGF Shh BMP antagonists Activated astrocytes, endothelium
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Figure 1. Astrocytes of the adult CNS play two potential roles in the production of newborn glia and neurons. In a novel role for the astrocyte, cells that express the astrocytic marker glial brillary acidic protein can take on the role of the stem cell itself and produce both neurons and glia. Astrocytes do remain mitotically active and it is difcult to distinguish clearly between the stem cell astrocyte (purple) and the differentiated astrocytes (A), which play a more traditional role in bloodbrain barrier function and mediate a variety of local metabolic and neuronal signaling functions. Unlike most differentiated neural lineage cells, such as neurons and oligodendrocytes, the traditional astrocytes remain competent to divide. They also provide local instructive signals to resident stem and/or progenitor cells and can synthesize many ligands known to inuence oligodendrocyte or neuron proliferation and maturation. Thus, traditional astrocytes can actively control whether a local niche is neurogenic or gliogenic by organizing many of the signals that support neuronal or glial fate choices in stem cells. Neurogenic astrocytes are found in neurogenic regions, such as the granule cell layer of the hippocampus (green) where they promote maturation of the neuronal progenitor cells and immature neurons (blue). Astrocytes in gliogenic zones (gray) potentially suppress neurogenesis in favor of the recruitment and maturation of oligodendrocyte progenitors and immature oligodendrocyte (red). The exact lineage transitions between the putative astrocyte stem cell and the more committed progenitors are not well understood in vivo (dashed arrows). The exact instructive or selective molecules expressed by the astrocyte in the respective gliogenic or neurogenic niches also remain unknown but it is clear that signaling is regionally specialized and inuences location-specic stem cell fate. Commonly considered candidates for the molecular and cellular substrates of instructive niches are listed in the indicated boxes but there is much to be learned. Traditional astrocytes and astrocytes with stem cell qualities represent new players in these niches but there are many other contributors, including the immune system, that remain to be fully appreciated. Unraveling the components that control la vida local or the local environment of a neurogenic niche holds hope for deciphering the code of neural cell replacement in health and disease. Abbreviations: BMP, bone morphogenetic protein; EGF, epidermal growth factor; FGF-2, broblast growth factor 2; IGF-1, insulin-like growth factor 1; PDGF, platelet-derived growth factor; Shh, sonic hedgehog; TGFa, transforming growth factor a; VEGF, vascular endothelial growth factor.

adjusting the amplication of glial progenitor cells in correspondence with the local need. In the adult, it appears that neural stem cells remain responsive to Shh [44] but oligodendrocyte progenitors do not. This switch could be regulated in part by notch signaling [45]. Adult spinal cord progenitors retain this signaling pathway [46] and astrocytes are known to express notch ligands, particularly under conditions of injury or disease where local astrocytes become activated [47]. However, notch signaling plays different roles at different stages and can inhibit neurogenesis in favor of gliogenesis at one stage of cell development yet inhibit oligodendrocyte formation later in the cell lineage [47]. The specic developmental status of the progenitor cell, as well as the status of the local astrocyte, then becomes important in dening outcome. Astrocytes and the control of gliogenesis in pathology Injury or disease is one area where the traditional astrocyte could play a crucial role in altering the fate of
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a glial progenitor cell. Disease or injury induces traditional astrocytes to assume a new role in la vida de la lesion, releasing a barrage of cytokines including interleukin-6 (IL-6) [48,49]. IL-6 might not modulate only the immune response to injury but also the fate choice of immature progenitor cells to become astrocytes. Astrocytes also release NRGs in response to injury [50]. Depending on the erbB-receptor components of surrounding progenitors, astrocyte-derived NRG can signal proliferation or commitment in the oligodendrocyte lineages. Reactive astrocytes also increase expression of vascular endothelial growth factor (VEGF) and FGF-2, which are potent ampliers of progenitor proliferation [51,52]. Of course, the function of a single cytokine can be difcult to establish because their effects are pleiotropic and their appearance can resemble that of a mixed soup of injury-derived factors. However, the temporal nature of these cues, as well as the phenotype and capacity of endogenous progenitors to respond to these cues, will provide important insight into how astrocytes might orchestrate gliogenesis and neurogenesis following

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injury or following attempts to utilize stem and/or progenitor cell transplants for repair. Astrocytes and the neurogenic niche Gliogenesis and neurogenesis: intrinsic versus environmental control of stem cell fate Unlike the abundant and widespread production of oligodendrocytes, neurogenesis in the nave rodent brain is restricted to the hippocampus and olfactory bulb. The actively dividing precursors that produce glia are antigenically distinct from those that generate neurons and this lineage dichotomy is established well before stem cell progeny acquire the lineage-specic markers of myelin basic protein, GFAP or type III b-tubulin [14]. This suggests that commitment to an eventual fate begins before cells exit the cell cycle but, in spite of the phenotypic dichotomy, this early patterning in adult gliogenic regions can be reversible when cells are removed from the local environment [6 9]. Cells long thought to be glial or oligodendrocyte progenitors are readily converted to (or selected for) stem cells, which go on to make neurons in primary culture or following transplant into a neurogenic zone of the adult brain [34]. This suggests that there is a window of commitment in which local environment plays a larger role in determining cell fate than does the intrinsic expression patterning of the precursor genome. As an alternative to their stem cell role, GFAP-positive cells (presumably traditional astrocytes) participate in the creation of an instructive niche that inuences the fate of stem cell progeny. Astrocytes isolated from the hippocampus (but not those from spinal cord) promote stem-cell-mediated neurogenesis in culture, suggesting that astrocytes can take on region-specic instructive or selective roles in promoting neurogenesis or gliogenesis [53,54]. In addition, once immature neurons are produced, astrocytes further instruct newborn cells to form functional synapses [55]. Astrocytes are an important component of this instructive niche but are unlikely to act alone in this role. The architecture of the subventricular zone and hippocampus provide evidence that GFAP-positive cells are in intimate contact with the newly generated neuronal precursors [56,57] and, although astrocytes can provide a myriad of signals that could be instructive, it appears that simple cellular contact with an astrocyte (even with a dead astrocyte [54]) is sufcient to provide the neurogenesispromoting effects measured in stem cell cultures. This raises the concept that fate choice depends on a location-specic prole of soluble growth and/or trophic factors, as well as on an appropriate local environment consisting of extracellular matrix and/or cell-membrane-anchored ligands. Vasculature and the neurogenic niche Within the adult hippocampus, the neurogenic microenvironment takes on an intriguing format that suggests a specic role for astrocytes as well as vascular cells in the immediate locale of the dividing neural progenitor. Although the location of stem cells within the hippocampus is debatable [33,56,58], their progeny manifests as a transient amplifying pool of progenitor cells that divide in tight foci that form along the walls of small capillaries.
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Astrocytes and their vascular endfeet form a local niche that envelops the dividing precursors. After a brief expansion within this niche, the proliferative cells begin to express neuronal progenitor markers and subsequently migrate from the proliferative foci to take up residence as maturing neurons within the adjacent granule cell layer [59 61]. Coincidently, endothelial cells also proliferate at the site of focal progenitor recruitment, suggesting that an angiogenic stimulus accompanies the early proliferative stage of neurogenesis. Although not yet directly demonstrated in mammals, elegant data demonstrate a role for angiogenesis in the seasonal production of higher vocal center neurons in canaries [62], and infusion of the potent angiogenic factor VEGF upregulates neurogenesis in rodents [63]. Not only might an angiogenic factor stimulate a change in signaling within the vascular microenvironment but also neural progenitors might themselves proliferate in response to VEGF [63,64]. The role of cell status in dening the instructive inuence of a stem cell niche Astrocytes and vasculature cells are widespread in the adult brain, yet neurogenesis clearly does not occur in every instance where an astrocyte and blood vessels coincide. Just as developmental patterning regulates regional cell fate choice, the adult brain must also establish subtle distinctions in gene expression patterns within an otherwise ubiquitously distributed instructive cell population. When the potential role of astrocytes in the hippocampal neurogenic niche is considered with both adjacent granule cell layer and vascular signaling in mind, one derives several interesting possibilities suggesting that a conuence of events creates a uniquely activated population of cells within this instructive niche. Neural precursors within the subgranular zone reside in a niche that is rich in axonal projections from the adjacent granule cell layer. This zone is also rich in vascular proles that show an unusually high degree of endothelial cell division that correlates tightly with local precursor proliferation [59]. Finally, the subgranular zone and hilus are particularly rich in astrocytes that show subtle signs of activation (elevated levels of GFAP immunoreactivity). The imagination is led to the concept that a major part of the local lifestyle of stem cells in the hippocampus is the driving local rhythm of neuronal activity in the context of animated compatriots of activated astrocytes and vascular endothelium. Although fanciful, there could be a kernel of truth underlying the analogy that the demands placed on vasculature and astrocytes by local neuronal signaling stimulate a unique activated status for cells in the local microenvironment. Neuronal activity requires metabolic support and one mechanism for inducing a change in vascular function is via the activity-dependent action of hypoxia-inducible factor 1 [65]. Parallel activity-dependent activation of nitric oxide synthase in neurons, as well as in local glia and endothelium, leads to increased circulation. Included in the local glial and vascular response to nitric oxide is upregulated production of brain-derived neurotrophic factor (BDNF; a key element of angiogenesis-mediated avian neurogenesis [62]). When

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neuronal activity is articially increased (e.g. by seizures or electroshock therapy [66 68]) or if nitric oxide levels are directly manipulated [69], the result is a signicant increase in neurogenesis. Astrocytes are integral members of this activity-dependent signaling network and could provide the context-specic cues that dene where neurogenesis is to occur. The hypothetical stem cell niche in brain injury and repair Brain injury results in a coordinated reaction of neurons, astrocytes and vascular cells that, in some regions of the brain, is sufcient to stimulate an abortive neurogenesis. This intriguingly supports the activated cell status hypothesis but even this injury-induced response appears to be context specic. For example, focal ischemia in rats stimulates massive angiogenic and astrocytic responses in the affected striatum and overlying cortex, yet abortive neurogenesis is observed only within the striatum [23]. A more mild global insult has little effect in striatum and cortex but results in loss of hippocampal CA1 neurons. As in the cortical response to focal ischemia, the hippocampal CA1 region activates astrocytes and vasculature but does not natively replace neurons (although the neighboring granule cell layer does respond robustly with increased neurogenesis [70]. Amazingly, this failure can be overcome if the if recombinant FGF and EGF are infused into the ventricle following ischemia [22]. The role of these growth factors and their ability to convert a non-permissive activated niche into a permissive niche is unknown but it does indicate that there could be a balance of competing gliogenic versus neurogenic cues that might be easily swayed if their mechanisms were better understood. Does inammation antagonize the neurogenic niche? One clear difference between the native neurogenic niche of the hippocampus and that of the niche created by
Table 1. The astrocyte and neural cell genesisa
Role Stem cell Characteristics

activated astrocytes and vasculature of the injured brain is the inammatory response to injury. Although there is clear potential for inammatory cells and cytokines to inuence neural progenitor cell fate, only recently has the full extent of this inuence begun to be realized. For example, cranial radiation for the treatment of brain tumors results in a chronic and irreversible decline in hippocampal function. In rodents, this declining function is accompanied by a nearly complete and permanent loss of neurogenesis (even though fully functional stem cells remain in the hippocampus) [71]. The inammatory response within the hippocampus is robust and unusually persistent, and recent work indicates that the presence of activated microglia and pro-inammatory cytokines is a signicant impediment to normal signaling and survival of the newborn neuron within the neurogenic niche [71,72]. The same mechanisms appear to be involved in seizureinduced hippocampal injury (O. Lindvall, unpublished) and it seems that neuroinammation could be a general antagonist of the mammalian neurogenic niche [72]. Should this hold true, specic intervention in one or more components of neuroinammatory signaling might signicantly unmask the native neurogenic response to injury that is predicted by the activated status vascular cells and astrocytes. Summary Control by local stem and/or progenitor cells is inuenced by factors that are expressed by many cell types present within the niche consisting of progenitor cells, mature oligodendrocytes and neurons, as well as astrocytes and cells of the vasculature. Although factors provided by mature astrocytes are at least a part of the equation and glia are clearly involved in cell fate, the roles of the astrocyte in cell genesis are diverse (Table 1) and the exact role of astrocytes in the

Refs [12,17,56,57]

Astrocytes that have characteristics of traditional astrocytes, such as expression of glial brillary acidic protein, formation of vascular endfeet and astrocyte-like membrane potentials, are multipotent and self-renewing. Stem-cell-like astrocytes are localized to periventricular zones and have non-traditional astrocyte characteristics, such as nestin expression and formation of cilia. Astrocytes that express S-100b continue to divide in the adult CNS and following injury or pathology. Traditional astrocytes in the developing CNS and those from neurogenic regions of the adult CNS contain the necessary cues to support the formation and maturation of neurons from adult progenitor cells. Traditional astrocytes found outside of neurogenic zones support gliogenesis and potentially inhibit neurogenesis of adult progenitor cells. Following specic types of injury, astrocytes and local vasculature adopt an activated status similar to that seen in the intact neurogenic niche of the hippocampus. The astrocyte in this context can switch from gliogenic to neurogenic signaling, allowing neurons to be born in a normally non-neurogenic region. Traditional astrocytes outside of neurogenic zones can be capable of supporting neurogenesis following injury but this response reverts to gliogenic instruction, perhaps owing to local inammatory signaling. Suppression of the local inammatory response can disinhibit neurogenesis.

Astrocyte progenitor Organizer of neurogenic niches

[19,28,29] [53,54,55]

Organizer of gliogenic niches Component of injury-induced neurogenic niche

[35,36,52] [20,22,23]

Component of inammatory gliosis

[71,72]

Astrocytes can be heterogeneous in morphological and molecular characteristics and can serve unique functions that stretch beyond the traditional role of a neuronalsupport cell and inducer of the blood brain barrier. New observations suggest that astrocytes with traditional characteristics as well as those with previously undescribed features play key roles in neural cell genesis in the adult nervous system.

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instructive signaling that produces neurons and glia are not yet known (Figure 1). By sheer numbers and wide distribution, la vida local for the adult stem cell is one of oligodendrocyte production. However, under more stimulating conditions, la vida loca prevails and stem cells produce neurons. A prediction is that brain injury, such as ischemic stroke, should induce neurogenesis by virtue of recreating a neurogenic environment within the normally gliogenic parenchyma (e.g. with its massive glutamate stimulation, neuronal activity and robust ischemia-induced angiogenesis). However, neurogenesis is eeting at best and completely absent in many areas of injury [23,20]. Who or what plays the role of the local constabulary in quelling the party? Is there a role for local variation in astrocytes and their ability or inability to produce appropriate growth factors or substrates [22]? Or, is the failure of intrinsic replacement of both neurons and oligodendrocytes due to the intervention of an otherwise silent partner in CNS biology, such as neuroinammation? Finally, within each locale, which cell plays the role of the stem cell? If this cell is an astrocyte, is it from a unique subset of astrocytes or is the common astrocyte a stem cell with a mundane day job? Only the continuing exploration of la vida loca will provide insight into the various guises of the astrocyte in driving neural progenitor behavior within each local environment.
References
1 Rogister, B. et al. (1999) From neural stem cells to myelinating oligodendrocytes. Mol. Cell. Neurosci. 14, 287 300 2 Levine, J.M. and Nishiyama, A. (1996) The NG2 chondroitin sulfate proteoglycan: A multifunctional proteoglycan associated with immature cells. Perspect. Dev. Neurobiol. 3, 245 259 3 Levine, J.M. et al. (1993) Development and differentiation of glial precursor cells in the rat cerebellum. Glia 7, 307 321 4 Dawson, M.R.L. et al. (2000) NG2-expressing cells in the central nervous system: are they oligodendroglial progenitors? J. Neurosci. Res. 61, 471 479 5 Stallcup, W.B. and Beasley, L. (1987) Bipotential glial precursor cells of the optic-nerve express the NG2 proteoglycan. J. Neurosci. 7, 2737 2744 6 Palmer, T.D. et al. (1999) Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS. J. Neurosci. 19, 8487 8497 7 Kondo, T. and Raff, M. (2000) Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754 1757 8 Nunes, M.C. et al. (2003) Identication and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat. Med. 9, 439 447 9 Belachew, S. et al. (2003) Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J. Cell Biol. 161, 169 186 10 Miyata, T. et al. (2001) Asymmetric inheritance of radial glial bers by cortical neurons. Neuron 31, 727 741 11 Noctor, S.C. et al. (2002) Dividing precursor cells of the embryonic cortical ventricular zone have morphological and molecular characteristics of radial glia. J. Neurosci. 22, 3161 3173 12 Tramontin, A.D. et al. (2003) Postnatal development of radial glia and the ventricular zone (VZ): a continuum of the neural stem cell compartment. Cereb. Cortex 13, 580 587 13 Malatesta, P. et al. (2003) Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37, 751 764 14 Milosevic, A. and Goldman, J.E. (2002) Progenitors in the postnatal cerebellar white matter are antigenically heterogeneous. J. Comp. Neurol. 452, 192 203 15 Suzuki, S.O. and Goldman, J.E. (2003) Multiple cell populations in the
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early postnatal subventricular zone take distinct migratory pathways: a dynamic study of glial and neuronal progenitor migration. J. Neurosci. 23, 4240 4250 Marshall, C.A. et al. (2003) Gliogenic and neurogenic progenitors of the subventricular zone: who are they, where did they come from, and where are they going? Glia 43, 52 61 Filippov, V. et al. (2003) Subpopulation of nestin-expressing progenitor cells in the adult murine hippocampus shows electrophysiological and morphological characteristics of astrocytes. Mol. Cell. Neurosci. 23, 373 382 Levison, S.W. et al. (1999) Cycling cells in the adult rat neocortex preferentially generate oligodendroglia. J. Neurosci. Res. 57, 435 446 Horner, P.J. et al. (2000) Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J. Neurosci. 20, 2218 2228 Magavi, S.S. et al. (2000) Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951 955 Lim, D.A. et al. (2000) Noggin antagonizes BMP signaling to create a niche for adult neurogenesis. Neuron 28, 713 726 Nakatomi, H. et al. (2002) Regeneration of hippocampal pyramidal neurons after ischemic brain injury by recruitment of endogenous neural progenitors. Cell 110, 429 441 Arvidsson, A. et al. (2002) Neuronal replacement from endogenous precursors in the adult brain after stroke. Nat. Med. 8, 963 970 Doetsch, F. et al. (2002) EGF converts transit-amplifying neurogenic precursors in the adult brain into multipotent stem cells. Neuron 36, 1021 1034 Altman, J. (1963) Autoradiographic investigation of cell proliferation in the brains of rats and cats. Anat. Rec. 145, 573 591 Hommes, O.R. and Leblond, C.P. (1967) Mitotic division of neuroglia in the normal adult rat. J. Comp. Neurol. 129, 269 278 Mares, V. et al. (1975) An estimate of the number of cells arising by division in mouse cerebral hemispheres from age one to 12 months: an autoradiographic study of DNA synthesis. J. Comp. Neurol. 161, 471 482 McCarthy, G.F. and Leblond, C.P. (1988) Radioautographic evidence for slow astrocyte turnover and modest oligodendrocyte production in the corpus callosum of adult mice infused with 3H-thymidine. J. Comp. Neurol. 271, 589 603 Kaplan, M.S. and Hinds, J.W. (1980) Gliogenesis of astrocytes and oligodendrocytes in the neocortical grey and white matter of the adult rat: electron microscopic analysis of light radioautographs. J. Comp. Neurol. 193, 711 727 Wolswijk, G. and Noble, M. (1989) Identication of an adult-specic glial progenitor cell. Development 105, 387 400 Peters, A. (1996) Age-related changes in oligodendrocytes in monkey cerebral cortex. J. Comp. Neurol. 371, 153 163 Peters, A. and Sethares, C. (2003) Is there remyelination during aging of the primate central nervous system? J. Comp. Neurol. 460, 238 254 Kuhn, H.G. et al. (1997) Epidermal growth factor and broblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820 5829 Shihabuddin, L.S. et al. (2000) Adult spinal cord stem cells generate neurons after transplantation in the adult dentate gyrus. J. Neurosci. 20, 8727 8735 Raff, M.C. et al. (1988) Platelet-derived growth factor from astrocytes drives the clock that times oligodendrocyte development in culture. Nature 333, 562 565 Noble, M. and Wolswijk, G. (1992) Development and regeneration in the O-2A lineage: studies in vitro and in vivo. J. Neuroimmunol. 40, 287 293 Horner, P.J. et al. (2002) Dening the NG2 cell of the adult central nervous system. J. Neurocytol. 31, 469 480 Lipson, A.C. and Horner, P.J. (2002) Potent possibilities: endogenous stem cells in the adult spinal cord. Prog. Brain Res. 137, 283 297 Marigo, V. and Tabin, C.J. (1996) Regulation of patched by sonic hedgehog in the developing neural tube. Proc. Natl. Acad. Sci. U. S. A. 93, 9346 9351 Wolswijk, G. et al. (1991) Platelet-derived growth factor is mitogenic for O-2Aadult progenitor cells. Glia 4, 495 503 Canoll, P.D. et al. (1996) GGF/neuregulin is a neuronal signal that promotes the proliferation and survival and inhibits the differentiation of oligodendrocyte progenitors. Neuron 17, 229 243

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42 Power, J. et al. (2002) Oligodendrocyte precursor cells from different brain regions express divergent properties consistent with the differing time courses of myelination in these regions. Dev. Biol. 245, 362 375 43 Raff, M.C. et al. (1998) Cell number control and timing in animal development: the oligodendrocyte cell lineage. Int. J. Dev. Biol. 42, 263 267 44 Lai, K. et al. (2003) Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat. Neurosci. 6, 21 27 45 Wang, S. et al. (1998) Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63 75 46 Yamamoto, S. et al. (2001) Transcription factor expression and notchdependent regulation of neural progenitors in the adult rat spinal cord. J. Neurosci. 21, 9814 9823 47 John, G.R. et al. (2002) Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nat. Med. 8, 1115 1121 48 Dong, Y. and Benveniste, E.N. (2001) Immune function of astrocytes. Glia 36, 180 190 49 Ridet, J.L. et al. (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci. 20, 570 577 50 Tokita, Y. et al. (2001) Regulation of neuregulin expression in the injured rat brain and cultured astrocytes. J. Neurosci. 21, 1257 1264 51 Zhang, Z. and Chopp, M. (2002) Vascular endothelial growth factor and angiopoietins in focal cerebral ischemia. Trends Cardiovasc. Med. 12, 62 66 52 Reilly, J.F. and Kumari, V.G. (1996) Alterations in broblast growth factor receptor expression following brain injury. Exp. Neurol. 140, 139 150 53 Lim, D.A. and Alvarez-Buylla, A. (1999) Interaction between astrocytes and adult subventricular zone precursors stimulates neurogenesis. Proc. Natl. Acad. Sci. U. S. A. 96, 7526 7531 54 Song, H. et al. (2002) Astroglia induce neurogenesis from adult neural stem cells. Nature 417, 39 44 55 Ullian, E.M. et al. (2001) Control of synapse number by glia. Science 291, 657 661 56 Seri, B. et al. (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J. Neurosci. 21, 7153 7160

57 Doetsch, F. et al. (1999) Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703 716 58 Seaberg, R.M. and Van-Der-Kooy, K.D. (2002) Adult rodent neurogenic regions: the ventricular subependyma contains neural stem cells, but the dentate gyrus contains restricted progenitors. J. Neurosci. 22, 1784 1793 59 Palmer, T.D. et al. (2000) Vascular niche for adult hippocampal neurogenesis. J. Comp. Neurol. 425, 479 494 60 van Praag, H. et al. (2002) Functional neurogenesis in the adult hippocampus. Nature 415, 1030 1034 61 Kempermann, G. et al. (2003) Early determination and long-term persistence of adult-generated new neurons in the hippocampus of mice. Development 130, 391 399 62 Louissaint, A. Jr et al. (2002) Coordinated interaction of neurogenesis and angiogenesis in the adult songbird brain. Neuron 34, 945 960 63 Jin, K. et al. (2002) Vascular endothelial growth factor (VEGF) stimulates neurogenesis in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 99, 11946 11950 64 Maurer, M.H. et al. (2003) Expression of vascular endothelial growth factor and its receptors in rat neural stem cells. Neurosci. Lett. 344, 165 168 65 Guillemin, K. and Krasnow, M.A. (1997) The hypoxic response: hufng and HIFing. Cell 89, 9 12 66 Parent, J.M. (2002) The role of seizure-induced neurogenesis in epileptogenesis and brain repair. Epilepsy Res. 50, 179 189 67 Madsen, T.M. et al. (2000) Increased neurogenesis in a model of electroconvulsive therapy. Biol. Psychiatry 47, 1043 1049 68 Coyle, J.T. and Duman, R.S. (2003) Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157 160 69 Cheng, A. et al. (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev. Biol. 258, 319 333 70 Liu, J. et al. (1998) Increased neurogenesis in the dentate gyrus after transient global ischemia in gerbils. J. Neurosci. 18, 7768 7778 71 Monje, M.L. et al. (2002) Irradiation induces neural precursor-cell dysfunction. Nat. Med. 8, 955 962 72 Monje, M.L. et al. Inammatory blockade restores adult hippocampal neurogenesis. Science (in press)

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