Neurogenesis in the adult mammalian brain

The concept of the CNS cell composition stability has recently undergone significant changes. It was earlier believed that neurogenesis in the mammalian CNS took place only during embryonic and early postnatal development. New approaches make it possible to obtain new results overriding the dogma that neurogenesis is impossible in the adult brain. The present review summarizes the information about the neural stem cell. It has been demonstrated that new neurons are constantly formed in adult mammals, including man. In two brain zones, subventricular zone and denate gyrus, neurogenesis appears proceed throughout the entire life of mammals, including man. The newly arising neurons are essential for some important processes, such as memory and learning. Stem cells were found in the subependymal and/or ependymal layer. They express nestin, and have a low mitotic activity. During embryogenesis, the stem cell divides asymmetrically: one daughter cell resides as the stem cell in the ependymal layer and another migrates to the subventricular zone. There it gives rise very fast to a pool of dividing precursors, from which neural and glial cells differentiate and migrate to the sites of final localization. The epidermal and fibroblast growth factors act as mitogens for the neural stem cell. The neural stem cell gives rise to the cells of all germ layers in vitro and has a wide potential for differentiation in the adult organism. Hence, it can be used as a source of various cell types of the nervous tissue necessary for cellular transplantation therapy.     

Development of neural stem cell in the adult brain

New neurons are continuously generated in the dentate gyrus of the mammalian hippocampus and in the subventricular zone of the lateral ventricles throughout life. The origin of these new neurons is believed to be from multipotent adult neural stem cells. Aided by new methodologies, significant progress has been made in the characterization of neural stem cells and their development in the adult brain. Recent studies have also begun to reveal essential extrinsic and intrinsic molecular mechanisms that govern sequential steps of adult neurogenesis in the hippocampus and subventricular zone/olfactory bulb, from proliferation and fate specification of neural progenitors to maturation, navigation, and synaptic integration of the neuronal progeny. Future identification of molecular mechanisms and physiological functions of adult neurogenesis will provide further insight into the plasticity and regenerative capacity of the mature central nervous system.     

Adult neurogenesis in the mammalian brain: significant answers and significant questions

Adult neurogenesis, a process of generating functional neurons from adult neural precursors, occurs throughout life in restricted brain regions in mammals. The past decade has witnessed tremendous progress in addressing questions related to almost every aspect of adult neurogenesis in the mammalian brain. Here we review major advances in our understanding of adult mammalian neurogenesis in the dentate gyrus of the hippocampus and from the subventricular zone of the lateral ventricle, the rostral migratory stream to the olfactory bulb. We highlight emerging principles that have significant implications for stem cell biology, developmental neurobiology, neural plasticity, and disease mechanisms. We also discuss remaining questions related to adult neural stem cells and their niches, underlying regulatory mechanisms, and potential functions of newborn neurons in the adult brain. Building upon the recent progress and aided by new technologies, the adult neurogenesis field is poised to leap forward in the next decade.     

Neurogenesis in the Adult Mammalian Brain

The concept of the CNS cell composition stability has recently undergone significant changes. It was earlier believed that neurogenesis in the mammalian CNS took place only during embryonic and early postnatal development. New approaches make it possible to prove that neurogenesis takes part even in the adult brain. The present review summarizes the data about the neural stem cell. It has been demonstrated that new neurons are constantly formed in adult mammals, including man. In two brain zones, subventricular zone and dentate gyrus, neurogenesis appears to proceed throughout the entire life of mammals, including man. The newly arising neurons are essential for some important processes, such as memory and learning. Stem cells were found in the subependymal and/or ependymal layer. They express nestin and have a low mitotic activity. During embryogenesis, the stem cell divides asymmetrically: one daughter cell resides as the stem cell in the ependymal layer and another migrates to the subventricular zone. There it gives rise to a pool of dividing precursors, from which neural and glial cells differentiate and migrate to the sites of final localization. The epidermal and fibroblast growth factors act as mitogens for the neural stem cell. The neural stem cell gives rise to the cells of all germ layers in vitro and has a wide potential for differentiation in the adult organism. Hence, it can be used as a source of various cell types of the nervous tissue necessary for cellular transplantation therapy.     

TRIM32-dependent transcription in adult neural progenitor cells regulates neuronal differentiation

In the adult mammalian brain, neural stem cells in the subventricular zone continuously generate new neurons for the olfactory bulb. Cell fate commitment in these adult neural stem cells is regulated by cell fate-determining proteins. Here, we show that the cell fate-determinant TRIM32 is upregulated during differentiation of adult neural stem cells into olfactory bulb neurons. We further demonstrate that TRIM32 is necessary for the correct induction of neuronal differentiation in these cells. In the absence of TRIM32, neuroblasts differentiate slower and show gene expression profiles that are characteristic of immature cells. Interestingly, TRIM32 deficiency induces more neural progenitor cell proliferation and less cell death. Both effects accumulate in an overproduction of adult-generated olfactory bulb neurons of TRIM32 knockout mice. These results highlight the function of the cell fate-determinant TRIM32 for a balanced activity of the adult neurogenesis process.     

Long-Term Fate Mapping Using Conditional Lentiviral Vectors Reveals a Continuous Contribution of Radial Glia-Like Cells to Adult Hippocampal Neurogenesis in Mice

Newborn neurons are generated throughout life in two neurogenic regions, the subventricular zone and the hippocampal dentate gyrus. Stimulation of adult neurogenesis is considered as an attractive endogenous repair mechanism to treat different neurological disorders. Although tremendous progress has been made in our understanding of adult hippocampal neurogenesis, important questions remain unanswered, regarding the identity and the behavior of neural stem cells in the dentate gyrus. We previously showed that conditional Cre-Flex lentiviral vectors can be used to label neural stem cells in the subventricular zone and to track the migration of their progeny with non-invasive bioluminescence imaging. Here, we applied these Cre-Flex lentiviral vectors to study neurogenesis in the dentate gyrus with bioluminescence imaging and histological techniques. Stereotactic injection of the Cre-Flex vectors into the dentate gyrus of transgenic Nestin-Cre mice resulted in specific labeling of the nestin-positive neural stem cells. The labeled cell population could be detected with bioluminescence imaging until 9 months post injection, but no significant increase in the number of labeled cells over time was observed with this imaging technique. Nevertheless, the specific labeling of the nestin-positive neural stem cells, combined with histological analysis at different time points, allowed detailed analysis of their neurogenic potential. This long-term fate mapping revealed that a stable pool of labeled nestin-positive neural stem cells continuously contributes to the generation of newborn neurons in the mouse brain until 9 months post injection. In conclusion, the Cre-Flex technology is a valuable tool to address remaining questions regarding neural stem cell identity and behavior in the dentate gyrus.     

Olfactory bulb neurogenesis and its neurological impact

Contrary to the long-held dogma according to which the adult mammalian brain does not produce neurons anymore, neuronal turnover has been reported in two discrete areas of the adult brain: the hippocampus and the olfactory bulb. Adult-generated neurons are produced from neural stem cells located in the hippocampal subgranular zone and the subventricular zone of the lateral ventricles. Recently, number of genetic and epigenetic factors that modulate proliferation of stem cells, migration, differentiation and survival of newborn neurons have been characterized. We know that neurogenesis increases in the diseased brain, after stroke or after traumatic brain injury. Importantly, progenitors from the subventricular zone, but not from the subgranular zone, are incorporated at the sites of injury, where they replace some of the degenerated neurons. Thus, the central nervous system has the capacity to regenerate itself after injury and, today, researchers develop strategies aimed at promoting neurogenesis in diseased areas. This basic research is attracting a lot of attention because of the hope that it will lead to regeneration and reconstruction therapy for the damaged brain. In this review, we discuss major findings concerning the organization of the neurogenic niche located in the subventricular zone and examine both intrinsic and extrinsic factors that regulate adult neurogenesis. Then, we present evidences for the intrinsic capability of the adult brain for cell replacement, and shed light on recent works demonstrating that one can greatly enhance appropriate brain cell replacement by using molecular cues known to endogenously control proliferation, migration, differentiation and/or survival of subventricular zone progenitors. Finally, we review some of the advantages and limits of strategies aimed at using endogenous progenitors and their relevance to human clinics.     

成年哺乳动物皮质区神经发生的研究进展

神经发生是神经干细胞在适当的条件下分化成功能性整合神经元的过程,主要包括细胞的增殖、迁移、分化和存活。成年神经发生区以前脑室管膜下区(Subventricular zones,SVZ)和海马齿状回颗粒层下区(Subgranular zones,SGZ)为主,但皮质作为神经元和神经胶质细胞数量最多、分布最广,同时也是哺乳动物高度发展的脑区,是否有成年神经元新生,已成为近年来神经科学领域的研究热点[1,2]。现本文就未成熟神经元在皮质区的研究方法、分布、来源与转归、病理生理功能影响等方面探讨成年哺乳动物皮质神经发生现象。     

侧脑室室管膜下区神经再生的研究进展

神经再生(Neurogenesis)是指具有自我更新能力的神经干细胞(Neural Stem Cells,NSCs)经过迁移、增殖,最终分化为具有特定功能的神经细胞的过程。以往人们认为,神经再生只存在于胚胎期或外周神经系统,近几年发现,在成年动物的中枢神经系统也存在神经再生,研究发现侧脑室室管膜下区(SVZ)是神经再生发生的主要区域之一,产生新的神经元和神经胶质细胞通过RMS通路运输至嗅球进而对嗅觉损伤部分进行修复。本文主要从成年神经再生的发展、神经再生与疾病的关系、神经再生的过程等方面进行综述。     

Effects of neuroinflammation on the regenerative capacity of brain stem cells

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 lipopolysaccharide-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.     

Gene profiles within the adult subventricular zone niche: proliferation, differentiation and migration of neural progenitor cells in the ischemic brain

Focal cerebral ischemia induces neurogenesis in the subventricular zone (SVZ) of the adult human brain. Neurogenesis is controlled by proliferation, differentiation, and migration of neural progenitor cells. This article reviews emerging data that changes of cell cycle kinetics of neural progenitor cells induced by stroke contribute to increased neural progenitor cell proliferation and that gene profiles control proliferation, differentiation, and migration of neural progenitor cells within the SVZ niche. A better understanding of gene profiles that control the biological function of adult SVZ neural progenitor cells could lead to more selective and effective treatments to enhance neurogenesis during stroke recovery.     

Purinergic signaling regulates neural progenitor cell expansion and neurogenesis

Neural stem and progenitor cells typically exhibit a density-dependent survival and expansion, such that critical densities are required below which clonogenic progenitors are lost. This suggests that short-range autocrine factors may be critical for progenitor cell maintenance. We report here that purines drive the expansion of ventricular zone neural stem and progenitor cells, and that purine receptor activation is required for progenitor cells to be maintained as such. Neural progenitors expressed P2Y purinergic receptors and mobilized intracellular calcium in response to agonist. Receptor antagonists suppressed proliferation and permitted differentiation into neurons and glia in vitro, while subsequent removal of purinergic inhibition restored progenitor cell expansion. Real-time bioluminescence imaging of extracellular ATP revealed that the source of extracellular nucleotides are the progenitor cells themselves, which appear to release ATP in episodic burst events. Enzyme histochemistry of the adult rat brain for ectonucleotidase activity revealed that NTDPase, which acts to degrade active ATP and thereby clears it from areas of active purinergic transmission, was selectively localized to the subventricular zone and the dentate gyrus, regions in which neuronal differentiation proceeds from the progenitor cell pool. These data suggest that purine nucleotides act as proliferation signals for neural progenitor cells, and thereby serve as negative regulators of terminal neuronal differentiation. As a result, progenitor cell-derived neurogenesis is thus associated with regions of both active purinergic signaling and modulation thereof.     

Brain micro-ecologies: neural stem cell niches in the adult mammalian brain

Neurogenesis persists in two germinal regions in the adult mammalian brain, the subventricular zone of the lateral ventricles and the subgranular zone in the hippocampal formation. Within these two neurogenic niches, specialized astrocytes are neural stem cells, capable of self-renewing and generating neurons and glia. Cues within the niche, from cell-cell interactions to diffusible factors, are spatially and temporally coordinated to regulate proliferation and neurogenesis, ultimately affecting stem cell fate choices. Here, we review the components of adult neural stem cell niches and how they act to regulate neurogenesis in these regions.     

室管膜下区神经干细胞与神经发生的研究进展

室管膜下区(subventricular zone,SVZ)存在着神经干细胞(nueral stem cells,NSCs),是成年哺乳动物脑内重要的神经发生区域。神经发生过程极为复杂,包括一系列的生物学事件。在病理状态下,SVZ区的细胞增殖,新生的神经细胞迁移到病灶处,取代或修复受损的细胞,起到保护脑组织的作用。该文就SVZ区的神经干细胞、神经发生过程及病理状态下神经发生的相关研究做一综述。     

For the long run: maintaining germinal niches in the adult brain

The adult mammalian brain retains neural stem cells that continually generate new neurons within two restricted regions: the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus subgranular zone (SGZ) of the hippocampus. Though these cellular populations are spatially isolated and subserve different brain systems, common themes begin to define adult neurogenic niches: (1) astrocytes serve as both stem cell and niche cell, (2) a basal lamina and concomitant vasculogenesis may be essential components of the niche, and (3) "embryonic" molecular morphogens and signals persist in these niches and play critical roles for adult neurogenesis. The adult neurogenic niches can be viewed as "displaced" neuroepithelium, pockets of cells and local signals that preserve enough embryonic character to maintain neurogenesis for life.     

Adult neural stem cells: plasticity and developmental potential.

Stem cells play an essential role during the processes of embryonic tissue formation and development and in the maintenance of tissue integrity and renewal throughout adulthood. The differentiation potential of stem cells in adult tissues has been thought to be limited to cell lineages present in the organ from which they derive, but there is evidence that somatic stem cells may display a broader differentiation repertoire. This has been documented for bone marrow stem cells (which can give rise to muscle, hepatic and brain cells) and for muscle precursors, which can turn into blood cells. The adult central nervous system (CNS) has long been considered incapable of cell renewal and structural remodeling. Recent findings indicate that, even in postnatal and adult mammals, neurogenesis does occur in different brain regions and that these regions actually contain adult stem cells. These cells can be expanded both in vivo and ex vivo by exposure to different combinations of growth factors and subsequently give rise to a differentiated progeny comprising the major cell types of the CNS. Almost paradoxically, adult neural stem cells display a multipotency much broader than expected, since they can differentiate into non-CNS mesodermal-derivatives, such as blood cells and skeletal muscle cells. We review the recent findings documenting this unforeseen plasticity and unexpected developmental potential of somatic stem cells in general and of neural stem cells in particular. To better introduce these concepts, some basic notions on the functional properties of adult neural stem cells will also be discussed, particularly focusing on the emerging role of the microenvironment in determining and maintaining their peculiar characteristics.     

Neural stem cells and the regulation of adult neurogenesis

Presumably, the 'hard-wired' neuronal circuitry of the adult brain dissuades addition of new neurons, which could potentially disrupt existing circuits. This is borne out by the fact that, in general, new neurons are not produced in the mature brain. However, recent studies have established that the adult brain does maintain discrete regions of neurogenesis from which new neurons migrate and become incorporated into the functional circuitry of the brain. These neurogenic zones appear to be vestiges of the original developmental program that initiates brain formation. The largest of these germinal regions in the adult brain is the subventricular zone (SVZ), which lines the lateral walls of the lateral ventricles. Neural stem cells produce neuroblasts that migrate from the SVZ along a discrete pathway, the rostral migratory stream, into the olfactory bulb where they form mature neurons involved in the sense of smell. The subgranular layer (SGL) of the hippocampal dentate gyrus is another neurogenic region; new SGL neurons migrate only a short distance and differentiate into hippocampal granule cells. Here, we discuss the surprising finding of neural stem cells in the adult brain and the molecular mechanisms that regulate adult neurogenesis.     

Locating and labeling neural stem cells in the brain

The phenomenon of adult neurogenesis has been demonstrated in most mammals including humans. At least two regions of the adult brain maintain stem cells throughout life; the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subventricular zone (SVZ) of the lateral ventricle wall. Both regions continuously produce neurons that mature and become integrated into functional networks that are involved in learning and memory and odor discrimination, respectively. Apart from these well‐studied regions neurogenesis has been reported in a number of other brain regions, such as amygdala and cortex. However, these studies have been contested and there is currently no well‐postulated function for non‐SVZ/SGZ neurogenesis. The studies of the regional localization of neurogenesis in the brain have been made possible due to several methods for detecting adult neurogenesis including; bromodeoxyuridine labeling (BrdU) together with markers of mature neurons, genetic labeling, by mouse transgenesis, or with the use of viral vectors. These techniques are already put to creative use and will be essential for the discovery of the nature of the adult neural stem cells. In this mini‐review, we will discuss the localization of neural stem/progenitor cells in the brain and their implications as well as discussing the pro's and con's of stem cell labeling techniques. J. Cell. Physiol. 226: 1–7, 2010. © 2010 Wiley‐Liss, Inc.     

Functional evaluation of neural stem cell differentiation by single cell calcium imaging

Neurogenesis in the adult mammalian brain occurs in two specific brain areas, the subventricular zone (SVZ) bordering the lateral ventricles and the subgranular zone (SGZ) of the hippocampus. Although these regions are prone to produce new neurons, cultured cells from these neurogenic niches tend to be mixed cultures, containing both neurons and glial cells. Several reports highlight the potential of the self-healing capacity of the brain following injury. Even though much knowledge has been produced on the neurogenesis itself, brain repairing strategies are still far away from patients cure. Here we review general concepts in the neurogenesis field, also addressing the methods available to study neural stem cell differentiation. A major problem faced by research groups and companies dedicated to brain regenerative medicine resides on the lack of good methods to functionally identify neural stem cell differentiation and novel drug targets. To address this issue, we developed a unique single cell calcium imaging-based method to functionally discriminate different cell types derived from SVZ neural stem cell cultures. The unique functional profile of each SVZ cell type was correlated at the single cell level with the immunodetection of specific phenotypic markers. This platform was raised on the basis of the functional response of neurons, oligodendrocytes and immature cells to depolarising agents, to thrombin and to histamine, respectively. We also outline key studies in which our new platform was extremely relevant in the context of drug discovery and development in the area of brain regenerative medicine.     

Akhirin regulates the proliferation and differentiation of neural stem cells/progenitor cells at neurogenic niches in mouse brain

Specialized microenvironment, or neurogenic niche, in embryonic and postnatal mouse brain plays critical roles during neurogenesis throughout adulthood. The subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus in the mouse brain are two major neurogenic niches where neurogenesis is directed by numerous regulatory factors. Now, we report Akhirin (AKH), a stem cell maintenance factor in mouse spinal cord, plays a pivotal regulatory role in the SVZ and in the DG. AKH showed specific distribution during development in embryonic and postnatal neurogenic niches. Loss of AKH led to abnormal development of the ventricular zone and the DG along with reduction of cellular proliferation in both regions. In AKH knockout mice (AKH^−/−), quiescent neural stem cells (NSCs) increased, while proliferative NSCs or neural progenitor cells decreased at both neurogenic niches. In vitro NSC culture assay showed increased number of neurospheres and reduced neurogenesis in AKH^−/−. These results indicate that AKH, at the neurogenic niche, exerts dynamic regulatory role on NSC self-renewal, proliferation and differentiation during SVZ and hippocampal neurogenesis.