Abstract
Adult neurogenesis is a process that generates new and functional neurons from neural stem cells (NSCs) in a specialized neurogenic niche throughout life. Misregulated neurogenesis is detrimental to normal brain functions. To ensure proper neurogenesis, the niche cells must respond to extrinsic cues while fulfilling the intrinsic requirements of the neurogenic program and adapting their roles accordingly to influence NSC behavior. Understanding how the neurogenic niche executes its functions may guide strategies to maintain its integrative process and provide a permissive milieu for neurogenesis. In this review, we summarize the recent discoveries of interactive regulation of NSCs and neurogenesis by neurogenic niche and its implications in functional integrity of adult brain and neurological disorders.
Introduction
In 1978, Schofield first postulated stem cell and defined local milieu required for the maintenance of stem cells (Schofield 1978). Since then, an increasing amount of study has focused on defining stem cell niche in embryonic and adult organisms. The stem cell niche is defined by its ability to anatomically house stem cells and functionally control their development in vivo. In the central nerve system, neural stem cells (NSCs) is precisely controlled in their local niche by a tempospatial regulatory manner. Adult neurogenesis was discovered and described by Joseph Altman in 1962 (Altman 1962). So far, it is well accepted that neurogenesis mainly occurs in the two neurogenic niches in the adult mammalian brain: the subgranular zone (SGZ) in the dentate gyrus of hippocampus and the subventricular zone (SVZ) lining the lateral ventricle (Bond and others 2015; Box 1). In adult neurogenic niches, newborn neurons are generated from NSCs throughout life, which is required for brain homeostasis and is implicated in information processing, associated with cognitive outcomes and affective behaviors (Goncalves and others 2016). Maintenance of neurogenesis in adult neurogenic niche is achieved by the reciprocal regulation between NSCs and niche cells (Vicidomini and others 2020). The interaction and functional coordination of the cellular components as well as the heterogeneity and complexity of neurogenic niches become more and more important to understand adult neurogenesis. Therefore, enhanced understanding of the contribution of biological processes, key signaling, and factors related to neurogenic niche and neurogenesis will not only shed light on the processes that govern the functional integrity of the adult brain but also provide valuable insights into neurological disorders. In this review, we mainly discuss the recent discoveries describing cellular components in the neurogenic niches and the mechanisms underlying the regulation of adult neurogenesis by neurogenic niche factors in physiological and pathological conditions.
The Features of Adult Neural Stem Cell Niche
The adult neural stem cell (NSC) niche defines a microenvironment in which NSCs are retained after embryonic development for the production of new cells in adult brain. There are many distinct features of the niche in adult brain.
Heterologous cell-cell interactions are invariably exhibit complex signaling that is dependent on tight regulation and often cell-cell contact. Fox example, vascular endothelial cell and astrocyte regulate NSC proliferation and differentiation by physical cell-cell contact.
Secreted and membrane-bound factors from the niche cells such as EGF, Noggin, and Ephs directly bind surface receptors on NSCs to regulate their self-renewal and cell fate.
Long-range and local axonal inputs are richly innervated in the niche, where the neurotransmitters and other factors are released by afferent inputs to regulate NSC quiescence and activation.
The extracellular matrix and associated molecules are integral components of NSC niche creating a favorable microenvironment and architecture to sustain NSCs and neurogenesis.
The immune cell microglia shape neurogenesis by clearance of cell corps, provide trophic supports for NSCs, and dynamically regulate the niche and NSCs to response to inflammation and brain damage.
Physical parameters such as stiffness and blood flow direct NSC maintenance, proliferation and differentiation.
Adult Neurogenesis in the Neural Stem Cell Niches
Neurogenesis and the Cytoarchitecture of Adult Neurogenic Niches
In adult SVZ, quiescent radial glial cells (type B cells, also known as NSCs) are activated and give rise to intermediate progenitor cells (IPCs, also known as type C cells), which in turn generate neuroblasts (Type A cells). These neuroblasts migrate through a migratory chain called rostral migratory stream (RMS) toward the olfactory bulb, where they differentiate into mature neurons and integrate into existent neuronal networks (Bond and others 2015). Except for NSCs and their lineages, there are several cellular components in the SVZ (Table 1, Fig. 1). The choroid plexus produces cerebral-spinal fluid in lateral ventricle (Johanson and others 2011), where NSCs with primary cilia protruding into the ventricle and sense the ventricle stimuli (Lee and others 2019). The ciliated ependymal cells that face the ventricle provide a barrier and filtration system for cerebrospinal fluid (Del Bigio 1995). Ependymal cells, surrounding NSCs, form pinwheel-like structures along the ventricular surface (Mirzadeh and others 2008). NSCs have a long basal process (known as end-foot), which is ending on the blood endothelial cells (Shen and others 2008). Astrocytes are in close contact with NSCs and modulates NSCs and neurogenesis in SVZ. Microglia are recognized as the resident brain immune cells and are an essential component of the SVZ neurogenic niche (Matarredona and others 2018). Recently, thin unmyelinated suprapendymal axons have been found to be tightly bound to the ependymal surface of SVZ (Tong and others 2014).
Cytoarchitecture in Adult Neurogenic Niches.
SGZ = subgranular zone; SVZ = subventricular zone.
Cell types and anatomy in the adult SVZ niche. Coronal schema showing V/SVZ adjacent to the lateral ventricles. Box is expanded to right and shows compartments and cell types in the V/SVZ niche. SVZ neural stem cells (NSCs, B, purple) generate migrating neuroblasts (A, light green) destined for the olfactory bulb via a rapidly dividing transit-amplifying cell (C, dark green). Multi-ciliated ependymal cells (orange) line the walls of the lateral ventricle. Supraependymal axons (light green), on the apical surface of NSCs, form desmosome-like contacts with ependymal cells (orange). The choroid plexus (CP, light brown) secretes factors into the CSF that are important for the regulation of NSCs. NSCs contact blood vessels (BV) with the end foot of their basal process, which allows cell-cell interaction with endothelial cells (red). Astrocytes, microglia, and the basal lamina are all likely key components of the niche.
In the adult SGZ, radial glial cells (type 1 cells, also known as NSCs) are activated from quiescence and proliferate into nonradial cells, both of which give rise to IPCs (also known as type 2 cells) that are transient amplifying cells. IPCs give rise to neuronal lineage-committed proliferating progenitors or neuroblasts (type 3 cells), which in turn give rise to immature neurons. Immature neurons migrate to inner granule cell layer and differentiate into mature granule neurons in dentate gyrus, where they form synaptic integration into hippocampal neuronal networks (Sun and others 2015). In contrast to the SVZ, the SGZ neurogenic niche lies deep within dentate gyrus of the hippocampal parenchyma, where it displays quite distinct cytoarchitectures (Table 1, Fig. 2). In the SGZ, NSCs are in close contact with blood vessels (Licht and Keshet 2015; Palmer 2002) and astrocytes (Casse and others 2018). The granule neurons, interneurons, and mossy cells surrounding NSCs also serve as niche components to regulate NSCs and neurogenesis. Microglia not only eliminate apoptotic cells generated during neurogenesis (Sierra and others 2010) but also provide trophic support for NSCs in the SGZ (Gemma and Bachstetter 2013).
Cell types and anatomy in the adult SGZ niche. Coronal schema showing SGZ at the interface between the hilus and the granule cell layer of the dentate gyrus. SGZ NSCs (Type 1, light yellow) divide to generate intermediate progenitor cells (Type 2, green), which give rise to neuroblasts (Type 3, purple) and progressively differentiate into immature neurons (light blue) and mature neurons (red). Neurogenesis occurs in pockets adjacent to blood vessels (BV). The vascular basal lamina, endothelial cells, mossy cells, astrocytes, microglia, and local inhibitory interneurons project to the SGZ likely plays an important role in the niche.
Regulation of Neurogenesis in the SVZ Niche (Table 2, Fig. 3)
The Alternations and Influences of Niche Factors Derived from Cellular Components to Neurogenesis in SVZ.
Representative scheme illustrating the niche cells regulate adult neurogenesis in SVZ.
In each ventricle of the adult brain, the choroid plexus, a highly vascularized tissue, secretes cerebrospinal fluid (CSF). CSF is a rich source of proteins, lipids, hormones, cholesterol, glucose, microRNAs, and many other molecules and metabolites that influence multiple aspects of brain functions (Lehtinen and others 2013). Several key morphogens that influence neurogenesis in the adult SVZ are known to be synthesized by the choroid plexus, including fibroblast growth factor 2 (FGF-2), bone morphogenetic proteins (BMPs), and insulin-like growth factor 2 (IGF2; Redzic and others 2005). Interestingly, the choroid plexus has been found to release microRNA (miR-204) and thereby regulates NSC numbers (Lepko and others 2019). Mature ependymal cells generate a unidirectional CSF flow through oriented cilia beating and formation of gradient guidance cues to promote neuroblasts migration along the RMS (Sawamoto and others 2006). Ependymal cells actively regulate NSC expansion and neuronal fate specification of NCSs through release of Noggin (Lim and others 2000) and ependyma-derived matricellular protein cellular communication network factor 1 (CCN1; Wu and others 2020). Astrocytes derived from SVZ promote proliferation and neuronal fate commitment of NSCs (Gengatharan and others 2016). In addition, astrocytes express Robo receptors and respond to the repulsive activity of the neuron-secreted Slit by forming and maintaining glial tubes, which is needed to enable the rapid and directional migration of neuroblasts in adult brain (Kaneko and others 2010), as well as release glutamate to regulate the survival of neuroblasts (Platel and others 2010). The vasculature comprises an extensive network of planar interconnected blood vessels in the SVZ (Tavazoie and others 2008). Vascular endothelial cells maintain the quiescence of NSCs in the SVZ thought Efnb2 and Jag1 by a direct cell-cell manner (Ottone and others 2014). Contacts between NSCs and blood vessels are unconventionally permeable and frequently devoid of astrocyte and pericyte interferences in the SVZ (Ottone and Parrinello 2015), suggesting that NSCs might be directly exposed to blood-borne molecules. Then systemic factors have been found to influence the SVZ neurogenesis through the cerebral vasculature. The systemic chemokine, CCL11, from young mice has been shown to improve SVZ neurogenesis and olfactory discrimination (Katsimpardi and others 2014). Neurotransmitter system in adult brain plays important roles in neurogenesis (Hagg 2009). The GABA neurotransmitter released from neuroblasts provides a feedback mechanism to control the proliferation of NSCs by activating GABAA receptors (Liu and others 2005). Serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on the ventricular walls, where they directly interact with NSCs to regulate neurogenesis via 5HT2C (Tong and others 2014). Microglia in the SVZ modulate neurogenesis through releasing soluble factors, extracellular vesicles, and gap junctions (Matarredona and others 2018).
Regulation of Neurogenesis in SGZ Niches (Table 3, Fig. 4)
The Alternations and Influences of Niche Factors Derived from Cellular Components to Neurogenesis in SGZ.
Representative scheme illustrating the niche cells regulate adult neurogenesis in SGZ.
In the SGZ, neurogenesis is known to be particularly sensitive to the surrounding neuronal activity. Mature granule neurons near the neurogenic site are suited to function as niche cells, providing spatiotemporal regulation of adult neurogenesis in response to neuronal activity. Excitation of hippocampal dentate granule cells regulates quiescence of NSCs through direct GC-NSC interaction in the local niche, which is through down-regulated ephrin-B3, and attenuate transcellular EphB2 kinase-dependent signaling in the adjacent NSCs (Dong and others 2019). Mossy cells, a major population of excitatory neurons in adult dentate gyrus control NSC quiescence and maintenance through a dynamic balance between direct glutamatergic and indirect GABAergic pathways (Yeh and others 2018). The GABA neurotransmitter, released by a specific population of parvalbumin interneurons, regulates NSC quiescence and neuronal cell fate decisions (Song and others 2012). Noggin endogenously produced by NSCs and granule neurons have been shown to be important for proliferation and fate specification of NSCs in the SGZ, where Noggin mRNA levels are under the control of the RNA-binding protein FXR2 (Guo and others 2011). Astrocytes not only assist maturation and integration of newborn neurons through vesicular release of D-serine (Sultan and others 2015) but also guide NSCs for neurogenic fate though secretive factor and signaling molecules (Casse and others 2018). Proliferating NSCs in the SGZ are in close physical proximity to blood vessels (Palmer and others 2000). The vasculature-related factors such as insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) have been found to regulate hippocampal neurogenesis (Licht and Keshet 2015). Hippocampus-engaged exploration elevates microvascular hyperemia, which is critical to exploration-induced hippocampal neurogenesis through nitric oxide signaling in parvalbumin neurons (Shen and others 2019). Interestingly, brain vascular endothelial cells have been found to regulate neurogenesis through maintenance of lactate homeostasis in the SGZ niche (Wang and others 2019). Under homeostatic conditions, microglia not only phagocytose NSC-differentiated newborn neurons that have undergone apoptosis (Sierra and others 2010) but also provide trophic support for adult hippocampal neurogenesis (Gemma and Bachstetter 2013).
Interactive Regulation of Niche Cells by NSCs (Fig. 5)
Representative scheme illustrating reciprocal regulation between NSCs and niche cells.
To ensure sustained neurogenesis, the niche cells must respond to extrinsic cues while fulfilling the intrinsic requirements of the neurogenic program and adapting their roles accordingly to influence NSC behavior. However, the maintenance of brain homeostasis is achieved, to some extent, by the reciprocal regulation between adult NSCs and niche cells (Fuentealba and others 2012). Except fulfilling their neurogenic role, NSCs also perform their nonneurogenic role to maintain brain homeostasis. NSCs have been found to serve as phagocytes and their phagocytic activity critically contributes to neurogenesis in the adult brain (Lu and others 2011). NSCs regulate the structural organization of the ependymal cell pinwheel architecture through the NSC-apical end-foot molecule VCAM-1 (Kokovay and others 2012). Under homeostatic conditions, NSCs are able to modulate microglial activities by secreting vascular endothelial growth factor (VEGF; Mosher and others 2012). Recently, it has been demonstrated that NSCs behave as a functional niche for the maturation of newborn neurons through the secretion of pleiotrophin (Tang and others 2019). Therefore, understanding the mechanisms underlying the reciprocal interactive regulation between NSCs and niche cells could provide us a complex picture of the neurogenic niche as a whole.
Neurogenic Niches in Neurodegenerative Disorders
Neurogenic niche regulates neurogenesis and synapse turnover, integration of newly formed cells into neuronal ensembles, modifies epigenetic mechanisms controlling resistance to cellular stress, modulates production of neurotransmitters and molecules with neurotrophic activity, prevents apoptosis, suppresses neuroinflammation, affects neuron-glia interactions, thereby enhancing cognition, learning, and social communications in animals or humans with or without brain pathology function and cognition. Alterations of adult neurogenesis have been found in neurodegenerative diseases (Winner and Winkler 2015). In this section, we will summarize how the neurogenic niche is affected in animal models and human brains of Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease (Table 4).
The Alterations of Neurogenic Niches in the Neurodegenerative Diseases.
Alzheimer’s Disease
Alzheimer’s disease (AD) is a chronic, progressive, multifarious, neurodegenerative disorder of aging characterized by cognitive dysfunction due to hyperphosphorylated tau proteins and deposition of amyloid-β (Aβ) protein in the brain including hippocampus (Boese and others 2020). Phospho-tau accumulation has been found in GABAergic interneurons, which disrupt adult hippocampal neurogenesis by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche (Zheng and others 2020). Pharmacological strengthening of GABAergic tempo rescues the tau-induced adult hippocampal neurogenesis deficits and improves hippocampus-dependent cognition, which suggests modulation of GABAergic signal will lead to a cell therapy for AD (Zheng and others 2020). Amyloid precursor protein (APP) is a substrate of γ-secretase and misregulated cleavage of APP in the amyloidogenic pathway is implicated in AD. The vascular-derived soluble APP has been found to be functional as a niche signal to regulate NSC proliferation and neurogenesis (Sato and others 2017). Microglia derived from PSEN1 mutated mice inhibit NSC proliferation and neuronal lineage commitment (Choi and others 2008). In addition, an increase in gliosis and vascular-associated changes have been found in presenile AD human hippocampus (Boekhoorn and others 2006). Based on multifactorial and complex pathophysiological cascades in multiple AD stages, effective AD therapies need to focus on targeting early AD pathology. In particular, NSC niches participate extensively in mammalian brain homeostasis and repair and exhibit pleiotropic intrinsic properties that likely make them attractive candidates for the treatment of AD.
Huntington’s Disease
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG trinucleotide repeat expansion within the huntingtin (HD/IT15) gene, affecting a range of cellular and molecular functions in the brain (Morton and others 2019). The pathophysiology of HD manifests primarily in the brain with progressive symptomology that includes cognitive, psychiatric, and motor dysfunction (Morton and others 2019). Huntingtin aggregates were found in mature neurons in the neurogenic niche but not in NSCs (Kohl and others 2010), suggesting that there is a non-cell-autonomous mechanism of aggregated huntingtin on adult neurogenesis. NSC quiescence in the hippocampal neurogenic niche is associated with elevated transforming growth factor-beta signaling in an animal model of HD (Kandasamy and others 2010). The thickening of the SVZ has been displayed in the human brain of HD, where it exhibits a distinct lipid signature (Hunter and others 2018). Therefore, a detail analysis of stem cell-autonomous versus non–cell-autonomous actions may help us better understand contribution of adult neurogenesis to the pathology of HD.
Parkinson’s Disease
Parkinson’s disease (PD) is a movement disorder with frequent psychiatric complications as well as a high prevalence of cognitive impairment. Pathological hallmarks of PD are the loss of dopaminergic neurons and the accumulation of α-synuclein (Balestrino and Schapira 2020). A loss of serotonergic nerve terminals has been found to innervate into the dentate gyrus, which subsequently impair serotonergic system in neurogenic niche and attenuate adult neurogenesis in a BAC α-synuclein rat (Kohl and others 2016), suggesting that a dysfunction of the serotonergic system projecting to the hippocampus have an impact on adult neurogenesis and subsequently contribute to early nonmotor symptoms of PD, such as anxiety and depression. In addition, the dopaminergic neurons from the ventral tegmental area (VTA) innervate to SVZ neurogenic region, while the dopaminergic neurons from both VTA and the substantial nigra pars compacta innervate to the SGZ niches (Hoglinger and others 2014). Therefore, understanding the role of the long-range DAergic inputs in NSCs and adult neurogenesis may help us better understand the pathogenic progress of PD.
Conclusions and Future Perspectives
The works discussed in this review briefly illustrate the complexity of neurogenesis and NSC niche in the adult mammals. Deciphering the interactive regulation between NSCs neurogenic niche and their implications in functional integrity of adult brain will help us understanding of the functional integrity of adult brain by considering the complex picture of the neurogenic niche as a whole. So far, how niche cell and their cellular components in both neurogenic niches influence the process of neurogenesis and whether their dysfunctions underlying the etiology of the neurological disorders are still not fully illustrated yet. Recently, proteomic analyses has been utilized to define the adult NSC niche, characterize the niche-specific features, and identify key regulators of adult neurogenesis, which provide a powerful resource and clear direction to unravel the unique compositions of neurogenic niches (Kjell and others 2020). Thus, further studies focused on cellular and molecular mechanism underlying niche regulation of NSCs and neurogenesis and niche responses to physiological and pathological stimuli would help us take the therapeutic promise of adult NSC closer to its potential. Finally, deeper analysis of communication, cross talk, and signal integration in the neurogenic niche will inspire novel approaches to understand the integrative capacity of adult brain, further increase our current knowledge on the generative and regenerative potential of the niche not only as active participants in pathophysiological events, but as pharmacological targets or even as therapeutics for neurological illness.
Footnotes
Acknowledgements
We apologize for not being able to cite many original papers because of space constrains. We thank Xia Hao for figure illustration.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research was supported by grants from Matching Funds of Tianjin University of Traditional Chinese Medicine (60106/YL18020259 to YL); Tianjin Municipal Education Commission Scientific Research Project (Natural Science, Grant No. 2019ZD11 to YL); the National Key Research and Development Program of China (2019YFA080200 to WG); the Chinese Academy of Science (CAS) Key Research Program of Frontier Sciences (QYZDB-SSW-SMC046 to WG); the National Science Foundation of China (81571099 and 31771123 to WG); and Beijing Brain Project (Z16110000266004 to WG).
