Muscarinic acetylcholine receptors involved in the regulation of neural stem cell proliferation and differentiation in vitro

Neural stem cells (NSCs) are currently considered powerful candidates for cell therapy in neurodegenerative disorders such as Parkinson's disease. However, it is not known when and how NSCs begin to differentiate functionally. Recent reports suggest that classical neurotransmitters such as acetylcholine (Ach) are involved in the proliferation and differentiation of neural progenitor cells, suggesting that neurotransmitters play an important regulatory role in development of the central nervous system (CNS). We have shown by calcium imaging and immunochemistry that proliferation and differentiation are enhanced by M2 muscarinic Ach receptors (mAchR) expressed on the NSC surface and on their neural progeny. Moreover, atropine, an mAchR antagonist, blocks the enhancement and inhibits the subsequent differentiation of NSCs. Further understanding of this neural-nutrition role of Ach might elucidate fetal brain development, the brain's response to injury, and learning and memory.     

神经干细胞迁移的研究进展

神经干细胞的定向迁移是胚胎神经系统发育的先决条件,同时在成体组织的许多生理、病理过程中也起着重要作用;研究发现,许多神经退行性疾病都与神经干细胞迁移的缺陷相关。近年来,越来越多的证据表明,无论是内源性的还是移植的神经干细胞都有向大脑损伤部位迁移的特性,显示出神经干细胞用于神经再生及损伤修复治疗的潜能。该文着重在神经干细胞的基本特性以及神经干细胞定向迁移的细胞与分子机制研究等方面进行了综述。     

Stem cells in the embryonic cerebral cortex: Their role in histogenesis and patterning

The cytoarchitectural simplicity of the cerebral cortex makes it an attractive system to study central nervous system (CNS) histogenesis—the process whereby diverse cells are generated in the right numbers at the appropriate place and time. Recently, multipotent stem cells have been implicated in this process, as progenitor cells for diverse types of cortical neurons and glia. Continuous analysis of stem cell clone development reveals stereotyped division patterns within their lineage trees, highly reminiscent of neural lineage trees in arthropods and Caenorhabditis elegans. Given that these division patterns play a critical part in generating diverse neural types in invertebrates, we speculate that they play a similar role in the cortex. Because stereotyped lineage trees can be observed from cells growing at clonal density, cell-intrinsic factors are likely to have a key role in stem cell behavior. Cortical stem cells also respond to environmental signals to alter the types of cells they generate, providing the means for feedback regulation on the germinal zone. Evidence is accumulating that cortical stem cells, influenced by intrinsic programs and environmental signals, actually change with development—for example, by reducing the number and types of neurons they produce. Age-related changes in the stem cell population may have a critical role in orchestrating development; whether these cells truly self-renew is a point of discussion. In summary, we propose that cortical stem cells are the focus of regulatory mechanisms central to the development of the cortical cytoarchitecture. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 162–174, 1998     

Epigenetic mechanisms regulating fate specification of neural stem cells

Neural stem cells (NSCs) possess the ability to self-renew and to differentiate along neuronal and glial lineages. These processes are defined by the dynamic interplay between extracellular cues including cytokine signalling and intracellular programmes such as epigenetic modification. There is increasing evidence that epigenetic mechanisms involving, for example, changes in DNA methylation, histone modification and non-coding RNA expression are closely associated with fate specification of NSCs. These epigenetic alterations could provide coordinated systems for regulating gene expression at each step of neural cell differentiation. Here we review the roles of epigenetics in neural fate specification in the mammalian central nervous system.     

Epigenetic cues modulating the generation of cell‐type diversity in the cerebral cortex

The cerebral cortex is composed of a large variety of distinct cell‐types including projection neurons, interneurons, and glial cells which emerge from distinct neural stem cell lineages. The vast majority of cortical projection neurons and certain classes of glial cells are generated by radial glial progenitor cells in a highly orchestrated manner. Recent studies employing single cell analysis and clonal lineage tracing suggest that neural stem cell and radial glial progenitor lineage progression are regulated in a profound deterministic manner. In this review we focus on recent advances based mainly on correlative phenotypic data emerging from functional genetic studies in mice. We establish hypotheses to test in future research and outline a conceptual framework how epigenetic cues modulate the generation of cell‐type diversity during cortical development.     

Cell-intrinsic and cell-extrinsic cues regulating lineage decisions in multipotent neural crest-derived progenitor cells

Multipotent stem cells must generate various differentiated cell types in correct number and sequence during neural development. In the peripheral nervous system (PNS), this involves the formation of postmigratory progenitor cell types which maintain multipotency and are able to give rise to neural and non-neural cells in response to instructive growth factors. We propose that fate restrictions in such progenitor cells are controlled by the combinatorial interaction of different extracellular signals, including community effects in response to both neurogenic and gliogenic factors. In addition, distinct progenitor cell types display intrinsic differences which modulate their response to the extracellular environment. Thus, a progenitor cell is apparently able to integrate multiple intrinsic and extrinsic cues and thereby to choose fates appropriate for its location. Fate analysis of genetically modified progenitor cells will help to identify the molecules involved. This approach appears promising given the identification of multipotent progenitor cells from the mouse PNS and the availability of genetics in the mouse system.     

Context-dependent regulation of fate decisions in multipotent progenitor cells of the peripheral nervous system

A challenging problem in neural crest development is to understand how a migratory population of multipotent stem cells gives rise to a diverse array of differentiated cell types in the correct spatiotemporal manner. There is now ample evidence that this process involves the generation of postmigratory progenitor cells present in a variety of neural crest targets. When individual progenitors are challenged by instructive growth factors they are able to produce neural and non-neural cells, raising the question of how fate restrictions appropriate to a given embryonic location are regulated in multipotent postmigratory progenitor cells. Although some of the extracellular cues involved have been identified, it is likely that fate decisions in progenitor cells are controlled by the combinatorial action of multiple environmental signals. Moreover, cell type specificity is thought to be regulated by an interplay between extracellular and intracellular cues. We are just beginning to unravel some of the mechanisms that allow the context-dependent integration of cell-extrinsic and cell-intrinsic signals in multipotent progenitor cells.     

Embryonic and adult neural stem cell research in China

Neural stem cells(NSCs) are one specific type of multipotential stem cells that have the ability to proliferate for a long time and to differentiate into neural cells,including neurons,astrocytes and oligodendrocytes.These NSCs exist in both the embryonic and adult central nervous system(CNS) of all mammalian species.Progress has been made in the understanding of the developmental regulation of NSCs and their function in neurogenesis.This review discusses recent progress in this area,with emphasis on work d...     

Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits

ObjectiveMicroglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs.MethodsWe investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia‐specific Cx3cr1‐cre and Cx3cr1‐CreERT2 mice. RNA‐seq and ATAC‐seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours.ResultsIncreased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety‐like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions.ConclusionsOur study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system.

Microglia are thought to play an essential role in differentiation and maturation of neural precursor cells into neurons. As the prototypical innate immune cells of the central nervous system (CNS), the balance of microglial polarization is regulated by genetic or epigenetic modulators. Our study showed enhancement of chromatin accessibility by the chromatin remodelling gene Arid1a deletion led to abnormal development of microglia, which shows heightened M1 microglial polarization and weakened M2 polarization. In addition, irregular polarization led to abnormal neurogenesis with a significant decrease of neural stem/progenitor cell differentiation into neurons.     

The expression and functions of glycoconjugates in neural stem cells

The mammalian central nervous system is organized by a variety of cells such as neurons and glial cells. These cells are generated from a common progenitor, the neural stem cell (NSC). NSCs are defined as undifferentiated neural cells that are characterized by their high proliferative potential while retaining the capacity for self-renewal and multipotency. Glycoconjugates carrying carbohydrate antigens, including glycoproteins, glycolipids, and proteoglycans, are primarily localized on the plasma-membrane surface of cells and serve as excellent biomarkers at various stages of cellular differentiation. Moreover, they also play important functional roles in determining cell fate such as self-renewal, proliferation, and differentiation. In the present review, we discuss the expression pattern and possible functions of glycoconjugates and carbohydrate antigens in NSCs, with an emphasis on stage-specific embryonic antigen-1, human natural killer antigen-1, polysialic acid-neural cell-adhesion molecule, prominin-1, gp130, chondroitin sulfate proteoglycans, heparan sulfate proteoglycans, cystatin C, galectin-1, glycolipids, and Notch.     

Making and repairing the mammalian brain--signaling toward neurogenesis and gliogenesis

Neural stem cells (NSCs) are subscribed extraordinary potential in repair of the damaged nervous system. However, the molecular identity of NSCs has not been established. Most NSC cultures contain large numbers of multipotent, bipotent, and lineage restricted neural progenitors, the majority of which appear to lose neurogenic potential after expansion. This review first discusses the neurogenic to gliogenic switch that is characteristic of progenitor development in vivo and in NSC cultures, and then the cell intrinsic and extrinsic mechanisms regulating the sequential differentiation of neurons and glia. Finally, we discuss potential methods for maintaining the neurogenic potential of NSC cultures after expansion.     

Signalling mechanisms mediating neuronal responses to guidance cues

Several families of extracellular guidance cues have been implicated in guiding neurons and axons to their appropriate destinations in the nervous system. Their receptors include single- and seven-transmembrane receptors, and their signal transduction pathways converge onto the Rho family of small GTPases, which control the cytoskeleton. A single guidance protein can use different mechanisms to regulate different kinds of motility or the motilities of different cell types. There is crosstalk between the signalling pathways initiated by distinct guidance cues. Studies of neuronal guidance mechanisms have shed light not only on neural development, but also on other processes that involve the extracellular regulation of the cytoskeleton.     

神经干细胞在治疗脑损伤中的应用

神经干细胞（neural stem cells,NSCs）是中枢神经系统中既具有自我更新能力又能分化为神经系统各类细胞的细胞群。在体外一定条件下,NSCs能保持增殖能力,经定向诱导能分化为具有成熟神经细胞特征的各类细胞。NSCs移植治疗研究显示,植入的NSCs能分化为移植部位的神经细胞,并融入、整合该部位,重建受损神经网络,在一定程度上缓解病症。近年来,激活体内内源NSCs治疗神经损伤也逐渐得到广泛关注。因此,NSCs在治疗神经损伤中的应用研究已成为当前神经生物学基础理论和临床应用研究的热点。本文简要介绍了最近关于NSCs在治疗脑损伤中的应用研究进展。