The incredible elastic brain: how neural stem cells expand our minds

The Incredible Elastic Brain:How Neural Stem Cells Expand Our Minds Erzsebet Kokovay,Qin and Sally 1New York Neural Stem Cell Institute, 1 Discovery Drive, Rensselaer, NY 12144, USA*Correspondence: DOI 10.1016/j.neuron.2008.10.025 Brain development was thought to be largely hardwired and accomplished by birth, and the brain wasthought to have essentially no regenerative capacity. The remarkable discovery of adult neurogenesis andneural stem cells (NSCs) existing in the mature CNS changed that, allowing us to think optimistically aboutCNS repair. These discoveries helped to generate a robust field of neural progenitor cell biology, with rele-vance to CNS development, pathogenesis, the search for novel neurological therapies, as well as our under-standing of how the brain works.
Studies of neurodevelopment over the past two decades have covery of NSCs in the adult was a paradigm shift. Although the produced a rich understanding of molecules important for pro- main idea of brain stability holds true in large part, we have ducing specific CNS cell types in vivo. This knowledge base come to accept that NSCs in the CNS proliferate and give rise has impacted NSC studies in two major ways: providing an un- to new neurons throughout life. In this section we discuss the derstanding of how developmental factors specify regional and major discoveries that led to acceptance of adult neurogenesis, temporal differences to create diverse NSCs and offspring and some of the surprises that were encountered along the way, and a rationale for applying developmental mechanisms to stimulate the implications of the existence of endogenous neural stem self-repair and to create an abundant supply of specific CNS cells ex vivo. Information on NSCs is dovetailing with studies of This shift in thinking did not come easily. The history is told in the ESC/IPSC-to-NSC transition, accelerating utilization of plu- detail in more comprehensive reviews (for example, ripotent cells for neural applications. Goal-oriented research is ) so it will be described only briefly here. In the 1960s, essential to translate these findings for patient benefit-we Joseph Altman and Gopal Das published a string of papers have the capacity to make patient-matched motor neurons for using [3H]-thymidine to label proliferating cells, which revealed spinal cord injury or retinal cells to restore vision and to identify production of ''microneurones'' or granule neurons in the hippo- factors that inhibit self-renewal to prevent brain cancer growth, campal dentate gyrus (DG) and proliferating cells in the sube- and it is imperative to do so. However, we must acknowledge pendymal layer of the lateral ventricle (also known as the sub- that these goals were made achievable in large part through ventricular zone [SVZ]) that ran in a band to the olfactory bulb basic studies in developmental neuroscience and plasticity, by ''as if streaming in it,'' thus first describing adult progenitor approaching questions such as: ''Why do male birds sing in the cell proliferation and migration of new olfactory neurons in the springtime?'' or ''What are the signals that make a hydra head or rostral migratory stream. However, the technology wasn't avail- a fly with four wings instead of two?'' As we look to the future of able to distinguish between glial cells and small granule neu- NSC applications, inspired by what is now possible, we must re- rons, so perhaps understandably, this early work was not imme- main grounded in those sustaining questions of how the nervous diately embraced. In the late 1970s, Michael Kaplan and James system forms and changes, providing a fertile ground for discov- Hinds confirmed Altman and Das's findings using electron mi- ery by investigating a variety of progenitor cell systems, a variety croscopy of thin sections and autoradiography to show that of organisms (including humans), and keeping an open mind for ultrastructurally new cells in the olfactory bulb and dentate gyrus serendipity and surprises. Here we highlight some of the major were granule neurons with synapses from neighboring cells, advances in the CNS NSC and neurogenesis field and identify suggesting functional integration. However, skepticism per- sisted as there was no agreement about what characteristicsconstitute neuronal identity, and it was unknown if synapses could form on adult glia or if [3H]thymidine could be taken up during DNA repair in mature cells. Kaplan proposed to look for neurogenesis in humans who had been given [3H]thymidine as Twenty years ago, it was generally thought that, unlike other or- a cancer treatment, but unfortunately, these experiments were gans with regenerative capacity, the brain had little, being unable viewed as too much for a young postdoc to handle ( to produce new neurons after development. The concept of ma- ture brain stability made intuitive sense: being a complex tissue Major advances were made by Fernando Nottebohm and col- with millions of intricate connections, if new neurons were leagues in the 1980s, who were using adult songbirds as a model added, the stability necessary for long-term storage of memories system for vocal learning (). Female song birds and experience seemed impossible. On this backdrop, the dis- have smaller song nuclei than males, and females sing very little 420 Neuron 60, November 6, 2008 ª2008 Elsevier Inc.
and have simpler songs than males. Nottebohm injected female canaries with testosterone and noticed that this induced them to While there is general acceptance of endogenous neurogenic sing more like males, accompanied by growth of two song con- stem cells and continued neuron generation in the murine DG trol nuclei, the high vocal center (HVC), and the robust nucleus of and the olfactory system, from the SVZ and into the olfactory the archipallium (RA). Furthermore, seasonal changes in the size bulb itself, there are still important claims of other neurogenic lo- of the nuclei were observed in male canaries. Part of this plastic- cations that need to be resolved. Areas with reported lower ity could be explained by increased dendritic arborization in the levels of proliferation, such as hypothalamus and amygdala, RA. But what accounted for growth in the HVC: were new cells are being explored (In humans, neurogenic added? To answer this question, Steve Goldman injected stem cells can be isolated from the SVZ, but the evidence that [3H]thymidine into testosterone-treated female canaries and ob- they make new neurons in vivo is in dispute. And the notion served that new cells appeared in the HVC after 30 days. At ear- that in any species, neurogenesis occurs in the neocortex, ob- lier time points labeled cells were observed on the wall of the served by both Altman and Kaplan in the original studies along lateral ventricle. This led them to conclude that, as in develop- with neurogenesis in the SVZ and DG, is still not widely held.
ment, new neurons were born near the lateral ventricle and The low level of cortical neurogenesis and the fact that the neo- migrate up to the HVC to differentiate. The newborn cells resem- cortex is conceptually the bastion of brain stability generated bled neurons at the electron microscope level. However, familiar resistance. More recent studies that employed multiple immuno- with the skepticism encountered by Altman and Kaplan, Notte- markers have reported neurogenesis in rat and primate neocor- bohm expanded on these findings with John Paton in a series of tex; however, these findings remain controversial, the debate brilliant experiments. A daily dose of [3H]thymidine was used to centering on clear identification of these cells as neurons rather label a large number of cells in the HVC, and then birds were than glia. Some cells that proliferate locally express the glial pro- anesthetized and a hollow electrode was advanced into the genitor marker, NG2, have small glia-like nuclei and are nestled HVC and into a cell. Once a cell was penetrated, the bird re- close to larger pyramidal nuclei, leading some to conclude they ceived auditory stimulation and some cells underwent an action are satellite glia. However, colabeling of BrdU and multiple potential in response to the sound. These cells were then filled neuronal markers such as NeuN, GABA, GAD, calbindin, and with horseradish peroxidase via the electrode. When the brains calretinin has lead others to identify these cells as small inhibitory of these birds were analyzed, some of cells that had exhibited an action potential (and were HRP labeled) were also labeled with Intriguingly, cells with features of NSCs can be isolated and [3H]-thymidine after autoradiography, and thus were newly cultured from regions outside the two main neurogenic zones, born cells. The labeled cells had numerous dendrites and den- the DG and SVZ, including cortical parenchyma and spinal dritic spines and were functionally integrated into the surround- ing circuitry. Despite this supremely elegant proof, much of this spread throughout the mature CNS but are largely dormant, con- work was viewed as not significant to mammals but, rather, spe- tributing to low level neuro- or gliogenesis, or perhaps rare cells can revert to this state. Establishing sites of stem cell potential In the early 1990s, Elizabeth Gould, then a postdoc in Bruce in vivo is important because the strategy chosen to encourage McEwen's lab, was investigating the effects of adrenal hor- CNS repair will be quite different based on whether we need to mones on the hippocampus when they observed serendipitously direct progenitor cell migration from remote zones such as the numerous cells with neuronal morphologies being born in the DG or SVZ or whether we can activate local progenitor cells.
rat hippocampus. Coincidently, the remarkable discovery was Both approaches show promise: newborn cells move out of neu- made that neural cells from the adult brain could be stimulated rogenic zones toward sites of ischemic injury, attracted by che- to proliferate in vitro and differentiate into neurons and glia mokines, such as CXCL12, and infusion of growth factors, such ). This evidence for a neuropotent progen- as BDNF, providing a means of targeting NSCs to deliver cells itor in the adult added impetus to search for similar cells in vivo and their cargo. And after cortical injury or infusion of growth fac- and helped renewed observations of neurogenesis in the SVZ tors such as BDNF, CNTF, and Shh, new neurons appear in the and DG of early postnatal and adult animals gain acceptance parenchyma of cerebral cortex, adult striatum, septum, thala- mus, and hypothalamus, some of which are thought to come nologies, in particular, the use of bromodeoxyuridine (BrdU) to The hope is that with time, methods will be devel- label proliferating cells without autoradiography, the availability oped that allow precise control over this regenerative potential, of cell type specific markers, and confocal microscopy, making to direct cells to locations of cell loss or injury, to replace appro- birthdating and cell identification easier. Finally, using brain sam- priate cell populations, and to recreate functionality. Although ples from cancer patients that had received BrdU to label tumor many of these hurdles, in particular the connectivity problems, proliferation, Fred Gage and colleagues demonstrated that neu- are significant, we must remind ourselves that any element of en- rogenesis occurs in the human hippocampus ( dogenous regenerative capacity was completely unanticipated suggesting functional significance in humans. This was a turning point for the field of adult neurogenesis, leading notonly to acceptance of the phenomenon, but to a great deal of en- The Functional Impact of Adult Neurogenesis thusiasm and curiosity about what it could mean for brain func- One day we predict there will be a new franchise, NewBrain Inc., that caters to promoting brain enhancement. It turns out that Neuron 60, November 6, 2008 ª2008 Elsevier Inc. 421 exercise, playing with toys, avoiding stress, eating curry, and be- of neurogenesis, to an appreciation of how drugs impact the sys- coming pregnant are all proneurogenic, which should lead to an tem. The cognitive impairment resulting from chemotherapy, for interesting business model. That neurogenesis persists to adult- example, may result in part from killing endogenous progenitor hood was exciting enough, but the discovery of environmental cells, and screening for agents that attack this system minimally impact on the process was thrilling-neurogenesis was not just a constitutive phenomenon. It exhibited plasticity, and with this, crease neurogenesis, and studies of the impact of a variety of neuroactive drugs are just beginning. The future for this area of Neurogenesis encompasses cell birth, fate determination, sur- research is fodder for fascinating speculation. Will we be able vival, integration, and acquisition of functional properties, as de- to eliminate age-related memory loss, boost brain power, com- scribed in the elegant studies of Hongjun Song and colleagues bat depression, or perhaps develop an exquisite sense of smell? working in adult hippocampal neurogenesis by following retrovir-ally labeled cells through their stages of development ). Environmental signals can impact this process at and Production of Neurons and Glia in the Dish a variety of stages. More neurons are born than survive in both An important point of debate among developmental neuroscien- the SVZ and DG, leading to a readily available pool of cells that tists in the 1980s, which had been reverberating in embryology can be selected. In her groundbreaking studies, Elizabeth Gould circles for about a century, was whether there was a common demonstrated that the level of newborn cells being added to the progenitor for neurons and glial cells. To resolve this and other DG could be manipulated by stress and hormone levels in the fundamental questions of progenitor biology, prior to retroviral adult rat, likely due to increases in glucocorticoids, which reduce lineage tracing, some researchers, including a pioneer in the progenitor cell division ). It would later field, Martin Raff, decided to take a reductionist approach to be shown that both age and environment have an impact on neu- characterize progenitor cell types isolated from the brain in vitro to determine their developmental potential (the types of Exercise and exposure to an enriched environment cells they can produce), proliferative potential, response to ex- can increase survival of newborn neurons in the hippocampus ogenous growth factors, and how fate choices are made. The and may help counter the decreases observed during aging.
dogma at the time, however, was that neuronal progenitor cells Environmental responsiveness suggested that adult neurogene- would simply stop dividing and differentiate once they were sis is functionally important and led to inquiry into the functional placed in tissue culture (TC). Then, there were few resources for neural cell culture, it was a rather precarious process-prac- Neurogenesis increases plasticity on multiple levels by addi- tically a culinary art-and we have to acknowledge the TC pio- tion of new cells and structural remodeling of neural circuits, syn- neers who defined media for neural cells and enabled in vitro aptogenesis, and changes in synaptic strength. Addition of new studies to go forward. As ex vivo growth of NSCs and their prog- cells to the olfactory bulb and hippocampus results in functional eny, derived either from the nervous system or from pluripotent integration of cells with unique characteristics. For example, new stem cells, is necessary to produce the large numbers of animal dentate granule cells exhibit a lower LTP threshold than older and human cells anticipated for a variety of neuroscience and granule cells and are insensitive to inhibition by GABA. This plas- neurotherapeutic applications, the development of specialized ticity is thought to be important for adapting to experience, in stem cell culture media and reagents will continue to be an im- particular for learning and memory. In general, contextual and spatial learning tasks that are hippocampal dependent enhance Extracting progenitor cells from the nervous system and pro- the survival of newborn neurons in the DG, whereas hippocam- viding them with growth factors in vitro established a controlled pal independent learning does not. However, experiments that system to approach important questions about their fundamen- ablate neurogenesis have had different outcomes on hippocam- tal characteristics. Clonal culture studies of progenitors from the pal-dependent learning tasks with some researchers observing embryonic mouse basal forebrain showed that the nervous sys- deficits and others reporting no difference from controls tem contained highly prolific, multipotent, self-renewing cells ). Likewise, in the olfactory bulb, neurogenesis and learning are increased by an enriched odor environment, and the discovery that multipotent progenitor cells can be cultured odor deprivation decreases neurogenesis. However, again, ab- from adult brain as floating multicellular spheres called neuro- lation studies of bulbar neurogenesis have reported mixed ef- fects on olfactory discrimination and learning ( that the CNS contained stem cells. Although this review is fo- cused on the CNS, studies in the PNS, where neural crest plained by differences in species, strain, ablation techniques, stem cells were discovered early and continuing neurogenesis and the behavioral paradigm used (In addition, was recognized in the olfactory epithelium, helped pave the broad ablation techniques that impact both olfactory and hippo- way to acceptance of the central phenomenon.
campal regions confound: in the future, precise ablation of neu- In vitro studies have become a staple method for investigating rogenesis in specific regions should help elucidate the roles of mechanisms of NSC self-renewal and differentiation. Establish- each neurogenic system to behavioral adaptation.
ment of human neural lines has provided a much-needed re- Deducing the functional impact of neurogenesis has wide- source for translational studies More complex ranging implications, from placement of Wiis in retirement coculture systems allow us to ask questions about cell-cell inter- homes, aiming to increase exercise and maintain a healthy level actions, which is leading to development of 3D TC systems for 422 Neuron 60, November 6, 2008 ª2008 Elsevier Inc.
modeling aspects of neural diseases and as a surrogate for drug A further surprise concerned the identity of adult NSCs. In the screening on CNS tissue, for testing toxicity, and for efficacy.
adult avian brain, a radial glial-like cell in the ventricular zone di- Some of the most exciting advances in NSC research will likely vides to give rise to a neuroblast that then uses the radial fiber to come from involvement of bioengineers who bring new technol- migrate to the HVC and throughout the telencephalon. Pursuing ogies to the TC realm. Self-assembling nanofibers for scaffolding this question in mammals, Fiona Doetsch, then a graduate stu- cell growth, hydrogels, and artificial microenvironments func- dent in Arturo Alvarez-Buylla's lab, performed an elegant series tionalized with bioactive molecules such as laminin fragments, of experiments that included ultrastructural studies and lineage are just a few of the projects that foreshadow what is likely to tracing, leading to the conclusion that adult brain progenitor cells be an explosion in methods to grow and manipulate NSCs, were GFAP+ and thus related to astrocytes ). A controversy arose as to whether some ependymal cells, multiciliate cells which abut the ventricle, were stem cells in the The neurosphere assay has been widely adopted as a facile adult forebrain, a dispute that was actually highlighted in the measure of NSC activity. While important questions concerning New York Times in a science editorial in 1999 (underscoring the origin of neurosphere-forming cells remain-for example, ex- the well-known erudition of New Yorkers) and an idea that con- actly which cells they correspond to in vivo-the discovery of tinues to find support. However, it appears that SVZ astrocytes a nontransformed cell that can grow in nonadherent conditions, are intercalated frequently with ependymal cells in the germinal from the brain no less, led to a veritable sphere-fest, with a similar zone and can proliferate to regenerate the ependymal lining if approach yielding floating multicell growths from a variety of damaged, e.g., in aging (). Thus, while multicilate tissues. It will be intriguing to figure out what engenders ependymal cells in the germinal region, when viewed at the EM sphere-forming ability in diverse progenitor cell subtypes and whether this will expose properties of normal cells that predis- pose to oncogenesis. The neurosphere assay is still being im- proliferative NSCs ), providing a possible proved in order to distinguish progenitor cells from self-renewing coherence between the two ideas. As the cells lining the ventricle stem cells and to ensure clonality. It also forms the basis of novel in other regions, such as spinal cord, are indicated to have pro- directions such as creating arrays of patterned neurosphere genitor properties that are activated upon injury ( cultures for high-throughput screening for factors impacting ), it will be important to perform in depth ultrastructural anal- ysis with multiple immunomarkers to identify the proliferating cell The fact that neurospheres are almost as easy to grow types within it. Importantly, two types of ciliated ependymal cells as sea monkeys has enabled many new researchers entrance have been identified in the adult SVZ, E1 cells with 32-73 cilia to the NSC field to provide valuable comparative information and E2 cells with only two cilia and a complex basal body ( with other stem cell types as well as innovative interdisciplinary Consequently, it is plausible that the ventricular lining will be regionally varied, with different populations of multi-ciliate ependymal cells and possibly other admixed cell types.
This highlights how NSC studies are leading us to a fuller under- standing of CNS cell biology and to question our established in- Demonstrating a subpopulation of progenitors with stem cell terpretation of cell classes and cell function.
characteristics begs the question as to the identity of these cells Unequivocal identification of NSCs will depend on establish- in vivo. Twenty years ago, we understood the embryonic CNS ing new markers. Identifying some of the genes expressed in germinal zone to contain neuroepithelial ventricular zone pro- stem cells-including GFAP, Nestin, GLAST, Sox2, CD133, Mu- genitor cells as neuronal precursors, which migrated along radial sashi, and LeX-has allowed enrichment of acutely isolated glial as guiding cells, and SVZ progenitors as largely glial precur- cells, and gene array analysis of these cells can be used to gen- sors. Where might stem cells fit into this picture? With the advent erate an understanding of unique markers or combinations that of immunomarkers for major subpopulations of CNS cells and can generate secure identification for NSCs. Comparison of fluorescent reporters enabling visualization of live cells, these these cells to mature populations, including astrocytes, will be cardinal viewpoints were changed. Unexpectedly, radial glial highly valuable to identify biological functions that are unique cells were identified as the principle progenitor cell in embryonic to NSCs and could underlie their critical functions of self-renewal germinal zones, producing neurons and neuroblasts that fre- and fate determination. Recent single-cell gene expression stud- quently underwent their terminal division in the SVZ, as well as ies are an exciting advance that should help to further define glia (reviewed in That radial glia included the stem cell population was underscored by lineage tracing ofthese cells into the adult SVZ ). Presently, it Moving Through: Adult NSC Lineage Progression is not possible to point to which specific radial glial cells are stem cells; however, we are beginning to describe subpopula- In the adult SVZ, a relatively quiescent GFAP-positive stem cell tions, for example, those that respond to Notch signaling via (a Type B cell) gives rise to a more rapidly proliferative transit am- plifying cell (Type C cell) that expands the progenitor pool and based on transcriptome analysis ). Refinement produces Type A neuroblasts that divide and migrate in the ros- of functional and expression markers will produce a fuller under- tral migratory stream toward the olfactory bulb. There they differ- standing of radial glia subtypes during development.
entiate into granule neurons that integrate into the granule layer Neuron 60, November 6, 2008 ª2008 Elsevier Inc. 423 or periglomerular neurons in the glomerular layer Much of the foregoing work on adult NSC lineage progression ). SVZ Type B cells also produce oligodendrocytes has been deduced from genetic lineage tracing methods and destined for the overlying corpus callosum, the striatum, and fim- static images. The dynamic nature of the process, including bria fornix (). In the hippocampus, two popula- cell division mode and regulation, changes in cell morphology tions of progenitor cells exist in the subgranular zone. Type 1 and position, and migratory behavior of cell subclasses, is an cells are Sox2+, relatively quiescent cells that resemble radial exciting new area of exploration. Imaging wholemounts of SVZ glia in that they are GFAP-positive and send a long process is beginning to provide real-time information about regulatory through the granule layer into the overlying molecular layer.
molecules that impact this dynamic process Type 2 cells also express Sox2 but are GFAP-negative and lack radial processes and proliferate more readily. The lineagerelationship between Type 1 and Type 2 cells is being elucidated.
Both cells appear to give rise to neuroblasts which migrate into Within the adult neurogenic niches, neural stem cells proliferate the granule cell layer and mature into glutamatergic granule neu- and produce neurons appropriate for their destination. However rons that project to the CA3 and hilar regions ).
when removed from their niche and plated in culture or trans- In the future, we anticipate more detailed lineage trees, as planted into another region, NSCs from the SVZ generate largely studies are improving our understanding of the subtypes of pro- glial progeny (Conversely, stem cells de- genitor cells in these zones. For example, Cre-mediated lineage rived from nonneurogenic regions such as spinal cord, when tracing of adult SVZ progenitor cells reveals different embryonic transplanted into the adult hippocampus, generate granule neu- regional origins, each contributing to different subtypes of inter- neurons in the olfactory bulb (reviewed in ).
have shown that extrinsic factors in the neurogenic stem cell These studies suggest there is an intrinsic heterogeneity within niche play a critical role in regulating stem cell behavior and the SVZ progenitor cells. Indeed, transcription factors including act in an instructive manner. Interestingly, adult SVZ cells can Pax6, Mash1, Olig2, ER81, Dlx1/2, Dlx5/6, and Emx1 are differ- make hippocampal neurons when placed into the hippocampus, entially expressed in subpopulations of cells in the SVZ ( and hippocampus-derived stem cells can make olfactory neu- rons after transplantation into the RMS (in- ), playing roles in determining diversity of neuronal dicating molecular signals may be niche-specific. Given these subtypes in the olfactory bulb. With more characterization, we findings, it is crucial to understand the nature of the adult NSC expect that different types of adult SVZ progenitor cells can be niche and the tissue-specific extracellular signals in order to un- defined by combinatorial expression of cell surface markers derstand how stem cell self-renewal and neurogenesis are regu- and transcription factors, which will further our understanding lated during normal aging and in the diseased brain.
of the lineage relationships and specific outcomes of adult Stem cell niches have been well characterized in a variety of tissues and across different species. In the relatively simple Maintenance of and transition between these basic compart- invertebrate stem cell systems, such as those of Drosophila ments is regulated by exogenous growth factors (see niche sec- melanogaster and Caenorhabditis elegans, individual stem cells tion) and also cell-intrinsic regulatory factors. A timely review are countable and can be identified by genetic tags, allowing summarizes the impact of epigenetic factors such as regulatory components of stem cell niches to be characterized precisely RNAs and histone-modifying enzymes on stem cell self-renewal at the single-cell level. It is more difficult in mammals, especially for the nervous system, to definitively identify individual stem the progenitor pool by increasing self-renewal, such as Notch cells in vivo due to lack of highly specific markers. Nevertheless, signaling or the polycomb protein Bmi-1 ( based on ultrastructural properties and basic cell-type markers, may act in part via regulating the incidence of symmetric a clearer picture of the structure and properties of adult neural proliferative versus asymmetric cell divisions from NSCs, a con- niches is beginning to emerge. Recent studies provide a better cept for which there is good evidence in embryonic germinal understanding of the direct physical interaction and molecular in the adult. The fate of progenitor cells can be altered by manip- ulating gene expression. For example, in the adult SVZ, enforced work is revealed using 3D wholemount imaging ( expression of Pax6 enhances neurogenesis, while expression of Olig2 or reduction of Smad4 in NSC promotes oligogenesis ( as observed in hippocampus and songbird neurogenic zones regulated in this manner, but cell fate can be reprogrammed- where NSCs and their progeny contact the vasculature, the for example, expression of Ascl1/Mash1 in the hippocampal blood-brain barrier lacks astrocyte endfeet and pericyte cover- dentate gyrus can make these cells differentiate into oligoden- drocytes in vivo, a fate that they would normally rarely acquire suggesting SVZ cells may have easier access to blood-borne signals. A subset of GFAP-expressing cells, the stem cell- in astrocytes can induce the appearance of cells with NSC fea- containing population, is intercalated within the ependymal tures ). As we learn more about the essential layer in a honeycomb-like pattern (), some form- genes needed to reprogram cells into specific phenotypes, this ing a unique pinwheel organization specific to regions of adult approach could extend the potential of adult NSCs enormously.
neurogenesis (). These cells are in close 424 Neuron 60, November 6, 2008 ª2008 Elsevier Inc.
proximity to blood vessels either via their somas or basal pro- cell types more or less autonomously. It was shown that regional cesses and are thus in a distinct position to receive signals information is encoded in NSCs and that while it can be changed from both the CSF and the SVZ blood vessels.
to some limited extent by environmental factors, e.g., upon het- It is perhaps not surprising that some of the central signaling erotopic transplantation, it is a fundamental and characteristic pathways that function during development of the nervous sys- tem such as Notch, Wnt, BMP, and Shh signaling pathways In addition to regional specification, studies also demon- also play significant roles in adult neurogenesis (see reviews strated that NSCs and progenitors isolated from a variety or neu- ral regions, for example from retina and cortex, become increas- gins and targets of these signaling molecules are an active ingly specialized over time. Thus, early cells can produce most of area of research. Moreover, the same factor can have different the cell types in that region and do so in the correct temporal effects, for example, Noggin, expressed in the dentate gyrus order, while later cells become gradually restricted and the ependymal cells in the SVZ, promotes neurogenesis ). Remarkably, the timing mechanism is intrinsi- through inhibition of BMP signaling (while cally stored in individual cells, which can recapitulate the order directed knockout of the BMP effector Smad4 in adult SVZ NSCs even in clonal culture NSCs generate neurons can inhibit neurogenesis ), indicating a com- by undergoing a series of asymmetric cell divisions, and they can plexity of action that might vary based on how factors are pre- produce different cell types at each division, followed by a dra- sented, at what level, and to which targets. Besides these usual matic asymmetric cell division that changes their output from suspects, other factors have been identified as players in the neuronal to glial generation. The timing of the switch from neuro- adult niche that are less well recognized as morphogenic signals genesis to gliogenesis is intrinsically programmed; for example, in brain development. For example, PEDF, a secreted factor the COUP-TFI/II genes are required for ES-derived NSCs and expressed by endothelial cells and ependymal cells in the adult embryonic forebrain NSCs to respond to gliogenic signals SVZ, promotes NSC self-renewal in vitro and in vivo ( (similar to the role of NF1A in the developing ). We anticipate many more regulatory fac- spinal cord ), but is also dependent on envi- tors will be uncovered, some unique to the adult niche where ronmental factors, such as release of cardiotrophin-1 from corti- proximity to CSF, choroid plexus, subventricular zone vascular plexus, and locally somewhat leaky vessels ( Overall, the picture that is emerging is of a vast variety of NSC provide a complex molecular environment.
types that are regionally and temporally specified as an essential Understanding the niche signals will make it possible to create step in the production of specific types of neurons and glia dur- a microenvironment that encourages neurogenesis, which will ing development. This knowledge is helping us design strategies be a crucial factor for designing new strategies to activate en- to produce specific types of CNS cell from ESCs and iPSCs.
dogenous NSCs and to facilitate neurogenesis from trans- ESCs produce an early neural lineage progenitor, recognized as planted cells. Notably, if Noggin, BDNF, or FGF2 are ectopically a rosette-forming cell that can be regionally patterned expressed in the striatal parenchyma, a nonneurogenic region, Growth of ESCs in conditions that yield forebrain and NSCs are transplanted into this site, the transplanted cells progeny also results in temporally ordered appearance of corti- from cortical NSCs, emphasizing the inherent fundamental tem- the parenchyma that are inhibitory to neurogenesis, such as poral programs. Characterizing this heterogeneity and under- Ephrin expression (will also help advance this standing the molecular basis of regional and temporal patterning aim. These findings will guide in vitro construction of artificial in- is one of the most important goals of NSC biology. This is the in- structive microniches to help determine growth of stem cells in formation that will be needed to reprogram cells to a specified culture or after implantation into the injured CNS. And they pro- vide information that can be used to combat stem-like cells in Many of the specific applied goals for utilizing NSCs require brain cancers; for example, application of BMP can stimulate dif- the production of a homogenous population of cells for experi- ferentiation in some gliomas, thus inhibiting tumor growth ( mental drug testing or to produce a select cell subtype, such ). Importantly, we need to understand how these as nigral dopaminergic cells for cell-replacement therapies.
various extracellular signals are chaperoned and coordinated in Methods to generate large numbers of single cell types from neu- the 3D stem cell niche, which is a relatively unexplored frontier, ral precursors will have to take into account the natural tendency and how the effects of multiple factors are integrated by the re- of these cells to diversify when left to their own devices. Even di- rected reprogramming of NSCs or expanded neural progenitorpopulations toward a single cell class might be difficult to attain, Making CNS Cells to Order: Dendrites with That? given their inherent heterogeneity. It might be easier, at least the- Over the past 20 years, the field of developmental neurobiology oretically, to take a more homogenous cell type, such as fibro- has made great strides. Advances in molecular biology and the blasts, and imprint them to instill specific aspects of a desired ability to generate mutant and transgenic animals have resolved neural phenotype, a possibility that once seemed unimaginable, fundamental problems concerning regional patterning and pro- but with the extraordinary discovery of induced pluripotency, genitor behavior. Once basic CNS regional compartments are now seems attainable. However, in the more immediate future, established via signal gradients, the progenitor cells within traditional approaches are being pursued, such as developing them proliferate and differentiate into regionally appropriate culture conditions and selection methods to enrich for neural Neuron 60, November 6, 2008 ª2008 Elsevier Inc. 425 Table 1. Summary of Factors Used to Manipulate NSC Behavior type B cell proliferation, Oligodendrocytes This is not an exhaustive list, but serves to identify the various types of factors that have been used to change NSC fate. In the future, we anticipatedevelopment of families of small molecules that will mimic environmental and intrinsic factors, allowing reprogramming of NSCs to specific neural fateswith enhanced potential to repair even in the adult injured environment, summoning the advent of NSCs as cell medicines. AHP, Adult HippocampalProgenitor in vitro; HC, Hippocampus.
cell subtypes derived from NSCs. While ESCs and iPSCs allow areas. Consequently, we can approach questions in stem cell production of vast numbers of progeny, the unlimited prolifera- science that can't be asked or just aren't as meaningful in other tive potential of these pluripotent cells is a double-edged sword, systems. For example, the question of fine spatial placement is and utilization in vivo will require a high bar of assurance against difficult to rationalize in gut or skin, but identifying stem cells in tumor formation. In contrast, NSC-derived cells have a lower a particular region of the nervous system automatically has in- proliferative potential and, in some regards, are closer to clinical cumbent implications: are the cells in a memory-forming region applications; for example, the first clinical trial for lysosomal stor- or an area involved in motor programs or visual processing? Sim- age disease is ongoing. The use of NSCs in clinical therapies is ilarly, we can approach questions of cell niche or context with more layers of understanding-identifying the cell types and that we are now at the point of discussing the hurdles involved in signaling molecules involved, the molecules that pass from using these cells illustrates the remarkable progress we have neurons, glia, microglia, or blood cells to NSCs have deep impli- cations, given the wealth of background information on nervoussystem physiology. Thus, we can ask nuanced questions about stem cell biology within the nervous system, for example, The nervous system is a most provocative and complex organ.
regarding the relative role of stem cells during development There is a wealth of knowledge about cell types and disposition, and into adulthood; the molecular basis of self-renewal the function of specific parts, and the interactions between and how this is regulated depending on NSC sub-type; how 426 Neuron 60, November 6, 2008 ª2008 Elsevier Inc.
developmental potential is encoded, programmed, and changed Chmielnicki, E., Benraiss, A., Economides, A.N., and Goldman, S.A. (2004).
to generate the vast diversity of neural cells; and the structure Adenovirally expressed noggin and brain-derived neurotrophic factor cooper-ate to induce new medium spiny neurons from resident progenitor cells in the and role of the niche. Pursuit of these questions should bring adult striatal ventricular zone. J. Neurosci. 24, 2133-2142.
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