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Cells
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Neural Differentiation and Development
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Neural Differentiation and Development

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (15 February 2023) | Viewed by 19670

Special Issue Editors

Prof. Dr. Simona Candiani

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Guest Editor
Dipartimento di Scienze della Terra, dell’Ambiente e della Vita (DISTAV), Università degli Studi di Genova, 16132 Genoa, Italy
Interests: developmental neurobiology; evolutionary biology; non-coding RNAs; neurodegenerative diseases; in vivo model organisms; natural killer cells and immune checkpoint
Special Issues, Collections and Topics in MDPI journals
Dr. Matteo Bozzo

E-Mail Website
Guest Editor
Dipartimento di Scienze della Terra, dell’Ambiente e della Vita (DISTAV), Università degli Studi di Genova, 16132 Genoa, Italy
Interests: developmental neurobiology; evo-devo; invertebrate chordates; neurodevelopmental disorders; innate immunity
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The building of the nervous system requires an integrated series of developmental steps, starting with the specification of neural progenitors from a subset of ectodermal cells. The spatial arrangement of neural progenitors and their patterns of division and migration determine the architecture of the mature organ. Changes in the unfolding of these developmental events can produce variability for natural selection to act upon or cause a malfunction. Studying the mechanisms of neural development is thus not only intrinsically interesting but also crucial for understanding animal evolution and the pathogenesis of many neural disorders.

This Special Issue will accept original articles, reviews, and state-of-art technical notes in the field of neural differentiation and developmental neurobiology. We welcome studies employing morphological, biophysical, cellular, molecular, pharmacological, or physiological methods to investigate the differentiation and maturation of neural cells during both normal development and regeneration or disease as well as nervous system morphogenesis across the various branches of the animal tree. Manuscripts focusing on the neural development of non-conventional model species or applying a comparative approach to address the evolution of developmental processes will be particularly appreciated.

We look forward to your manuscript submissions.

Prof. Dr. Simona Candiani
Dr. Matteo Bozzo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neural precursors
  • neurogenesis
  • gliogenesis
  • invertebrate nervous system
  • evolution of neurodevelopment

Published Papers (10 papers)

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Research

16 pages, 2313 KiB  
Article
Serotonin Receptors and Their Involvement in Melanization of Sensory Cells in Ciona intestinalis
by Silvia Mercurio, Matteo Bozzo, Alessandro Pennati, Simona Candiani and Roberta Pennati
Cells 2023, 12(8), 1150; https://doi.org/10.3390/cells12081150 - 13 Apr 2023
Cited by 2 | Viewed by 1534
Abstract
Serotonin (5-hydroxytryptamine (5-HT)) is a biogenic monoamine with pleiotropic functions. It exerts its roles by binding to specific 5-HT receptors (5HTRs) classified into different families and subtypes. Homologs of 5HTRs are widely present in invertebrates, but their expression and pharmacological characterization have been [...] Read more.
Serotonin (5-hydroxytryptamine (5-HT)) is a biogenic monoamine with pleiotropic functions. It exerts its roles by binding to specific 5-HT receptors (5HTRs) classified into different families and subtypes. Homologs of 5HTRs are widely present in invertebrates, but their expression and pharmacological characterization have been scarcely investigated. In particular, 5-HT has been localized in many tunicate species but only a few studies have investigated its physiological functions. Tunicates, including ascidians, are the sister group of vertebrates, and data about the role of 5-HTRs in these organisms are thus important for understanding 5-HT evolution among animals. In the present study, we identified and described 5HTRs in the ascidian Ciona intestinalis. During development, they showed broad expression patterns that appeared consistent with those reported in other species. Then, we investigated 5-HT roles in ascidian embryogenesis exposing C. intestinalis embryos to WAY-100635, an antagonist of the 5HT1A receptor, and explored the affected pathways in neural development and melanogenesis. Our results contribute to unraveling the multifaceted functions of 5-HT, revealing its involvement in sensory cell differentiation in ascidians. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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26 pages, 4250 KiB  
Article
Multiple Forms of Neural Cell Death in the Cyclical Brain Degeneration of A Colonial Chordate
by Chiara Anselmi, Federico Caicci, Tommaso Bocci, Matteo Guidetti, Alberto Priori, Veronica Giusti, Tom Levy, Tal Raveh, Ayelet Voskoboynik, Irving L. Weissman and Lucia Manni
Cells 2023, 12(7), 1041; https://doi.org/10.3390/cells12071041 - 29 Mar 2023
Cited by 1 | Viewed by 2641
Abstract
Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in B. schlosseri, a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously [...] Read more.
Human neuronal loss occurs through different cellular mechanisms, mainly studied in vitro. Here, we characterized neuronal death in B. schlosseri, a marine colonial tunicate that shares substantial genomic homology with mammals and has a life history in which controlled neurodegeneration happens simultaneously in the brains of adult zooids during a cyclical phase named takeover. Using an ultrastructural and transcriptomic approach, we described neuronal death forms in adult zooids before and during the takeover phase while comparing adult zooids in takeover with their buds where brains are refining their structure. At takeover, we found in neurons clear morphologic signs of apoptosis (i.e., chromatin condensation, lobed nuclei), necrosis (swollen cytoplasm) and autophagy (autophagosomes, autolysosomes and degradative multilamellar bodies). These results were confirmed by transcriptomic analyses that highlighted the specific genes involved in these cell death pathways. Moreover, the presence of tubulovesicular structures in the brain medulla alongside the over-expression of prion disease genes in late cycle suggested a cell-to-cell, prion-like propagation recalling the conformational disorders typical of some human neurodegenerative diseases. We suggest that improved understanding of how neuronal alterations are regulated in the repeated degeneration–regeneration program of B. schlosseri may yield mechanistic insights relevant to the study of human neurodegenerative diseases. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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19 pages, 21431 KiB  
Article
Chromatin Remodeling Enzyme Snf2h Is Essential for Retinal Cell Proliferation and Photoreceptor Maintenance
by Andrea Kuzelova, Naoko Dupacova, Barbora Antosova, Sweetu Susan Sunny, Zbynek Kozmik, Jr., Jan Paces, Arthur I. Skoultchi, Tomas Stopka and Zbynek Kozmik
Cells 2023, 12(7), 1035; https://doi.org/10.3390/cells12071035 - 28 Mar 2023
Viewed by 1539
Abstract
Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the [...] Read more.
Chromatin remodeling complexes are required for many distinct nuclear processes such as transcription, DNA replication, and DNA repair. However, the contribution of these complexes to the development of complex tissues within an organism is poorly characterized. Imitation switch (ISWI) proteins are among the most evolutionarily conserved ATP-dependent chromatin remodeling factors and are represented by yeast Isw1/Isw2, and their vertebrate counterparts Snf2h (Smarca5) and Snf2l (Smarca1). In this study, we focused on the role of the Snf2h gene during the development of the mammalian retina. We show that Snf2h is expressed in both retinal progenitors and post-mitotic retinal cells. Using Snf2h conditional knockout mice (Snf2h cKO), we found that when Snf2h is deleted, the laminar structure of the adult retina is not retained, the overall thickness of the retina is significantly reduced compared with controls, and the outer nuclear layer (ONL) is completely missing. The depletion of Snf2h did not influence the ability of retinal progenitors to generate all the differentiated retinal cell types. Instead, the Snf2h function is critical for the proliferation of retinal progenitor cells. Cells lacking Snf2h have a defective S-phase, leading to the entire cell division process impairments. Although all retinal cell types appear to be specified in the absence of the Snf2h function, cell-cycle defects and concomitantly increased apoptosis in Snf2h cKO result in abnormal retina lamination, complete destruction of the photoreceptor layer, and consequently, a physiologically non-functional retina. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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23 pages, 6604 KiB  
Article
The Combined Effects of Topography and Stiffness on Neuronal Differentiation and Maturation Using a Hydrogel Platform
by Sabrina Mattiassi, Abigail A. Conner, Fan Feng, Eyleen L. K. Goh and Evelyn K. F. Yim
Cells 2023, 12(6), 934; https://doi.org/10.3390/cells12060934 - 18 Mar 2023
Cited by 1 | Viewed by 1678
Abstract
Biophysical parameters such as substrate topography and stiffness have been shown independently to elicit profound effects on neuronal differentiation and maturation from neural progenitor cells (NPCs) yet have not been investigated in combination. Here, the effects of various micrograting and stiffness combinations on [...] Read more.
Biophysical parameters such as substrate topography and stiffness have been shown independently to elicit profound effects on neuronal differentiation and maturation from neural progenitor cells (NPCs) yet have not been investigated in combination. Here, the effects of various micrograting and stiffness combinations on neuronal differentiation and maturation were investigated using a polyacrylamide and N-acryloyl-6-aminocaproic acid copolymer (PAA-ACA) hydrogel with tunable stiffness. Whole laminin was conjugated onto the PAA-ACA surface indirectly or directly to facilitate long-term mouse and human NPC-derived neuron attachment. Three micrograting dimensions (2–10 µm) were patterned onto gels with varying stiffness (6.1–110.5 kPa) to evaluate the effects of topography, stiffness, and their interaction. The results demonstrate that the extracellular matrix (ECM)-modified PAA-ACA gels support mouse and human neuronal cell attachment throughout the differentiation and maturation stages (14 and 28 days, respectively). The interaction between topography and stiffness is shown to significantly increase the proportion of β-tubulin III (TUJ1) positive neurons and microtubule associated protein-2 (MAP2) positive neurite branching and length. Thus, the effects of topography and stiffness cannot be imparted. These results provide a novel platform for neural mechanobiology studies and emphasize the utility of optimizing numerous biophysical cues for improved neuronal yield in vitro. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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21 pages, 3680 KiB  
Article
Retinoic Acid and POU Genes in Developing Amphioxus: A Focus on Neural Development
by Matteo Bozzo, Deianira Bellitto, Andrea Amaroli, Sara Ferrando, Michael Schubert and Simona Candiani
Cells 2023, 12(4), 614; https://doi.org/10.3390/cells12040614 - 14 Feb 2023
Cited by 1 | Viewed by 1981
Abstract
POU genes are a family of evolutionarily conserved transcription factors with key functions in cell type specification and neurogenesis. In vitro experiments have indicated that the expression of some POU genes is controlled by the intercellular signaling molecule retinoic acid (RA). In this [...] Read more.
POU genes are a family of evolutionarily conserved transcription factors with key functions in cell type specification and neurogenesis. In vitro experiments have indicated that the expression of some POU genes is controlled by the intercellular signaling molecule retinoic acid (RA). In this work, we aimed to characterize the roles of RA signaling in the regulation of POU genes in vivo. To do so, we studied POU genes during the development of the cephalochordate amphioxus, an animal model crucial for understanding the evolutionary origins of vertebrates. The expression patterns of amphioxus POU genes were assessed at different developmental stages by chromogenic in situ hybridization and hybridization chain reaction. Expression was further assessed in embryos subjected to pharmacological manipulation of endogenous RA signaling activity. In addition to a detailed description of the effects of these treatments on amphioxus POU gene expression, our survey included the first description of Pou2 and Pou6 expression in amphioxus embryos. We found that Pit-1, Pou2, Pou3l, and Pou6 expression are not affected by alterations of endogenous RA signaling levels. In contrast, our experiments indicated that Brn1/2/4 and Pou4 expression are regulated by RA signaling in the endoderm and the nerve cord, respectively. The effects of the treatments on Pou4 expression in the nerve cord revealed that, in developing amphioxus, RA signaling plays a dual role by (1) providing anteroposterior patterning information to neural cells and (2) specifying neural cell types. This finding is coherent with a terminal selector function of Pou4 for GABAergic neurons in amphioxus and represents the first description of RA-induced changes in POU gene expression in vivo. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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18 pages, 12615 KiB  
Article
Increased Nuclear FOXP2 Is Related to Reduced Neural Stem Cell Number and Increased Neurogenesis in the Dorsal Telencephalon of Embryos of Diabetic Rats through Histamine H1 Receptors
by Diana Sarahi De la Merced-García, Ángel Sánchez-Barrera, Juan Hernández-Yonca, Ismael Mancilla, Guadalupe García-López, Néstor Fabián Díaz, Luis Ignacio Terrazas and Anayansi Molina-Hernández
Cells 2023, 12(3), 510; https://doi.org/10.3390/cells12030510 - 03 Feb 2023
Viewed by 1695
Abstract
Diabetic rat embryos have increased cortical neurogenesis and neuron maturation, and their offspring presented altered neuron polarity, lamination, and diminished neuron excitability. The FOXP2 overexpression results in higher cortical neurogenesis by increasing the transition of radial glia to the intermediate progenitor. Similarly, histamine [...] Read more.
Diabetic rat embryos have increased cortical neurogenesis and neuron maturation, and their offspring presented altered neuron polarity, lamination, and diminished neuron excitability. The FOXP2 overexpression results in higher cortical neurogenesis by increasing the transition of radial glia to the intermediate progenitor. Similarly, histamine through H1-receptor activation increases cortical neuron differentiation. Indeed, blocking the H1-receptor by the systemic administration of chlorpheniramine to diabetic pregnant rats prevents increased neurogenesis. Here, we explore the relationship between the H1-receptor and FOXP2 on embryo neurogenesis from diabetic dams. Through qRT-PCR, Western blot, immunohistofluorescence, and flow cytometry, we showed an increased FOXP2 expression and nuclear localization, a reduced Nestin expression and -positive cells number, and a higher PKCα expression in the cortical neuroepithelium of fourteen-day-old embryos from diabetic rats. Interestingly, this scenario was prevented by the chlorpheniramine systemic administration to diabetic pregnant rats at embryo day twelve. These data, together with the bioinformatic analysis, suggest that higher H1-receptor activity in embryos under high glucose increases FOXP2 nuclear translocation, presumably through PKCα phosphorylation, impairing the transition of radial glia to intermediate progenitor and increasing neuron differentiation in embryos of diabetic rats. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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20 pages, 8611 KiB  
Article
Selective Menin Deletion in the Hippocampal CA1 Region Leads to Disruption of Contextual Memory in the MEN1 Conditional Knockout Mouse: Behavioral Restoration and Gain of Function following the Reintroduction of MEN1 Gene
by Anosha Kiran Ulfat, Shadab Batool, Fahad Iqbal and Naweed I. Syed
Cells 2022, 11(24), 4019; https://doi.org/10.3390/cells11244019 - 12 Dec 2022
Viewed by 1500
Abstract
Cholinergic neuronal networks in the hippocampus play a key role in the regulation of learning and memory in mammals. Perturbations of these networks, in turn, underlie neurodegenerative diseases. However, the mechanisms remain largely undefined. We have recently demonstrated that an in vitro MEN1 [...] Read more.
Cholinergic neuronal networks in the hippocampus play a key role in the regulation of learning and memory in mammals. Perturbations of these networks, in turn, underlie neurodegenerative diseases. However, the mechanisms remain largely undefined. We have recently demonstrated that an in vitro MEN1 gene deletion perturbs nicotinic cholinergic plasticity at the hippocampal glutamatergic synapses. Furthermore, MEN1 neuronal conditional knockout in freely behaving animals has also been shown to result in learning and memory deficits, though the evidence remains equivocal. In this study, using an AVV viral vector transcription approach, we provide direct evidence that MEN1 gene deletion in the CA1 region of the hippocampus indeed leads to contextual fear conditioning deficits in conditional knockout animals. This loss of function was, however, recovered when the same animals were re-injected to overexpress MEN1. This study provides the first direct evidence for the sufficiency and necessity of MEN1 in fear conditioning, and further endorses the role of menin in the regulation of cholinergic synaptic machinery in the hippocampus. These data underscore the importance of further exploring and revisiting the cholinergic hypothesis that underlies neurodegenerative diseases that affect learning and memory. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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28 pages, 3542 KiB  
Article
Synapsin III Regulates Dopaminergic Neuron Development in Vertebrates
by Gaia Faustini, Francesca Longhena, Alessia Muscò, Federica Bono, Edoardo Parrella, Luca La Via, Alessandro Barbon, Marina Pizzi, Franco Onofri, Fabio Benfenati, Cristina Missale, Maurizio Memo, Daniela Zizioli and Arianna Bellucci
Cells 2022, 11(23), 3902; https://doi.org/10.3390/cells11233902 - 02 Dec 2022
Cited by 2 | Viewed by 1783
Abstract
Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard [...] Read more.
Attention deficit and hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by alterations in the mesocorticolimbic and nigrostriatal dopaminergic pathways. Polymorphisms in the Synapsin III (Syn III) gene can associate with ADHD onset and even affect the therapeutic response to the gold standard ADHD medication, methylphenidate (MPH), a monoamine transporter inhibitor whose efficacy appears related with the stimulation of brain-derived neurotrophic factor (BDNF). Interestingly, we previously showed that MPH can bind Syn III, which can regulate neuronal development. These observations suggest that Syn III polymorphism may impinge on ADHD onset and response to therapy by affecting BDNF-dependent dopaminergic neuron development. Here, by studying zebrafish embryos exposed to Syn III gene knock-down (KD), Syn III knock-out (ko) mice and human induced pluripotent stem cells (iPSCs)-derived neurons subjected to Syn III RNA interference, we found that Syn III governs the earliest stages of dopaminergic neurons development and that this function is conserved in vertebrates. We also observed that in mammals Syn III exerts this function acting upstream of brain-derived neurotrophic factor (BDNF)- and cAMP-dependent protein kinase 5 (Cdk5)-stimulated dendrite development. Collectively, these findings own significant implications for deciphering the biological basis of ADHD. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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22 pages, 4596 KiB  
Article
Stemness Activity Underlying Whole Brain Regeneration in a Basal Chordate
by Tal Gordon, Tal Zaquin, Mark Alec Kowarsky, Yotam Voskoboynik, Noam Hendin, Omri Wurtzel, Federico Caicci, Lucia Manni, Ayelet Voskoboynik and Noa Shenkar
Cells 2022, 11(23), 3727; https://doi.org/10.3390/cells11233727 - 22 Nov 2022
Cited by 3 | Viewed by 1801
Abstract
Understanding how neurons regenerate following injury remains a central challenge in regenerative medicine. Adult mammals have a very limited ability to regenerate new neurons in the central nervous system (CNS). In contrast, the basal chordate Polycarpa mytiligera can regenerate its entire CNS within [...] Read more.
Understanding how neurons regenerate following injury remains a central challenge in regenerative medicine. Adult mammals have a very limited ability to regenerate new neurons in the central nervous system (CNS). In contrast, the basal chordate Polycarpa mytiligera can regenerate its entire CNS within seven days of complete removal. Transcriptome sequencing, cellular labeling, and proliferation in vivo essays revealed that CNS regeneration is mediated by a newly formed neural progeny and the activation of neurodevelopmental pathways that are associated with enhanced stem-cell activity. Analyzing the expression of 239 activated pathways enabled a quantitative understanding of gene-set enrichment patterns at key regeneration stages. The molecular and cellular mechanisms controlling the regenerative ability that this study reveals can be used to develop innovative approaches to enhancing neurogenesis in closely-related chordate species, including humans. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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22 pages, 6760 KiB  
Article
Enhancement of Neuroglial Extracellular Matrix Formation and Physiological Activity of Dopaminergic Neural Cocultures by Macromolecular Crowding
by Andy N. Vo, Srikanya Kundu, Caroline Strong, Olive Jung, Emily Lee, Min Jae Song, Molly E. Boutin, Michael Raghunath and Marc Ferrer
Cells 2022, 11(14), 2131; https://doi.org/10.3390/cells11142131 - 06 Jul 2022
Cited by 2 | Viewed by 2721
Abstract
The neuroglial extracellular matrix (ECM) provides critical support and physiological cues for the proper growth, differentiation, and function of neuronal cells in the brain. However, in most in vitro settings that study neural physiology, cells are grown as monolayers on stiff surfaces that [...] Read more.
The neuroglial extracellular matrix (ECM) provides critical support and physiological cues for the proper growth, differentiation, and function of neuronal cells in the brain. However, in most in vitro settings that study neural physiology, cells are grown as monolayers on stiff surfaces that maximize adhesion and proliferation, and, therefore, they lack the physiological cues that ECM in native neuronal tissues provides. Macromolecular crowding (MMC) is a biophysical phenomenon based on the principle of excluded volume that can be harnessed to induce native ECM deposition by cells in culture. Here, we show that MMC using two species of Ficoll with vitamin C supplementation significantly boosts deposition of relevant brain ECM by cultured human astrocytes. Dopaminergic neurons cocultured on this astrocyte–ECM bed prepared under MMC treatment showed longer and denser neuronal extensions, a higher number of pre ad post synaptic contacts, and increased physiological activity, as evidenced by higher frequency calcium oscillation, compared to standard coculture conditions. When the pharmacological activity of various compounds was tested on MMC-treated cocultures, their responses were enhanced, and for apomorphine, a D2-receptor agonist, it was inverted in comparison to control cell culture conditions, thus emulating responses observed in in vivo settings. These results indicate that macromolecular crowding can harness the ECM-building potential of human astrocytes in vitro forming an ultra-flat 3D microenvironment that makes neural cultures more physiological and pharmacological relevant. Full article
(This article belongs to the Special Issue Neural Differentiation and Development)
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