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Control of Astrocytes Function and Phenotype: Role in Neuropathology
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Control of Astrocytes Function and Phenotype: Role in Neuropathology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 56726

Special Issue Editors

Dr. Graça Baltazar

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Guest Editor
CICS-UBI – Centro de Investigação em Ciências da Saúde (CICS-UBI) and Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal
Interests: glial cells; neuroprotection; Parkinson’s disease; ischemia; neurotrophic factors; neuroinflammation; electromagnetic stimulation; aging; G protein–coupled estrogen receptor 1 (GPER or GPR30); STEP
Dr. Cláudio Roque

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Guest Editor
CICS-UBI – Centro de Investigação em Ciências da Saúde (CICS-UBI) and Faculdade de Ciências da Saúde, Universidade da Beira Interior, Covilhã, Portugal
Interests: Astrocytes; G protein–coupled estrogen receptor 1; repetitive transcranial magnetic stimulation; ischemia; neurite degeneration; neurons; oxygen and glucose deprivation; primary cortical cultures; synaptic plasticity

Special Issue Information

Dear colleagues,

Until a couple of decades ago, astrocytes were underrated cells, with experimental studies relying on neurocentric approaches. However, over recent years, more functions and interactions between astrocytes and other cells have been revealed. Through an amazing multiplicity of functions encompassing trophic and energy support, maintenance of synapses, or control of neurogenesis, among others, astrocytes perform key functions in the maintenance and protection of the CNS. On the other hand, increasing data suggest that the dysregulation of astrocytes, or their senescence, may also have a significant contribution to pathological situations. Moreover, during the last few years, it has been shown that these multitasking cells display distinctive functional, morphological, and phenotypical heterogeneity across and within the regions of the CNS. Although the control of astrocyte diversity as well as its contribution to neuropathology is still poorly characterized, it seems increasingly evident that the modulation of astrocyte properties is a promising strategy to induce neuroprotection and neurorepair. However, to achieve this purpose, it is crucial to continue unveiling the cellular and molecular mechanisms that control astrocyte diversity.

This Special Issue on “Control of astrocytes function and phenotype: role in neuropathology” from the International Journal of Molecular Sciences aims to provide a summary of the ultimate advances in this area, with special emphasis on the molecular mechanisms through which it may be possible to modulate astrocytes' protective or deleterious effects on brain disorders. This Special Issue will publish original research articles as well as comprehensive reviews, including current understanding of molecular mechanisms involved in astrocytes modulation.

Dr. Graça Baltazar
Dr. Cláudio Roque
Guest Editors

Manuscript Submission Information

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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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • Astrocyte diversity
  • Astrocyte modulation
  • Astrocyte-microglia interplay
  • Gliotransmitters
  • Metabolism
  • Neurodegeneration
  • Neurologic and Neuropsychiatric disorders
  • Neuron–astrocyte interactions Neurorepair

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Published Papers (9 papers)

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Research

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18 pages, 2127 KiB  
Article
Differential Proteomic Analysis of Astrocytes and Astrocytes-Derived Extracellular Vesicles from Control and Rai Knockout Mice: Insights into the Mechanisms of Neuroprotection
by Tommaso Montecchi, Enxhi Shaba, Domiziana De Tommaso, Fabrizio Di Giuseppe, Stefania Angelucci, Luca Bini, Claudia Landi, Cosima Tatiana Baldari and Cristina Ulivieri
Int. J. Mol. Sci. 2021, 22(15), 7933; https://doi.org/10.3390/ijms22157933 - 25 Jul 2021
Cited by 10 | Viewed by 3451
Abstract
Reactive astrocytes are a hallmark of neurodegenerative disease including multiple sclerosis. It is widely accepted that astrocytes may adopt alternative phenotypes depending on a combination of environmental cues and intrinsic features in a highly plastic and heterogeneous manner. However, we still lack a [...] Read more.
Reactive astrocytes are a hallmark of neurodegenerative disease including multiple sclerosis. It is widely accepted that astrocytes may adopt alternative phenotypes depending on a combination of environmental cues and intrinsic features in a highly plastic and heterogeneous manner. However, we still lack a full understanding of signals and associated signaling pathways driving astrocyte reaction and of the mechanisms by which they drive disease. We have previously shown in the experimental autoimmune encephalomyelitis mouse model that deficiency of the molecular adaptor Rai reduces disease severity and demyelination. Moreover, using primary mouse astrocytes, we showed that Rai contributes to the generation of a pro-inflammatory central nervous system (CNS) microenvironment through the production of nitric oxide and IL-6 and by impairing CD39 activity in response to soluble factors released by encephalitogenic T cells. Here, we investigated the impact of Rai expression on astrocyte function both under basal conditions and in response to IL-17 treatment using a proteomic approach. We found that astrocytes and astrocyte-derived extracellular vesicles contain a set of proteins, to which Rai contributes, that are involved in the regulation of oligodendrocyte differentiation and myelination, nitrogen metabolism, and oxidative stress. The HIF-1α pathway and cellular energetic metabolism were the most statistically relevant molecular pathways and were related to ENOA and HSP70 dysregulation. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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22 pages, 6624 KiB  
Article
Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model
by Roberto Stella, Raphael Severino Bonadio, Stefano Cagnin, Maria Lina Massimino, Alessandro Bertoli and Caterina Peggion
Int. J. Mol. Sci. 2021, 22(13), 7028; https://doi.org/10.3390/ijms22137028 - 29 Jun 2021
Cited by 10 | Viewed by 3279
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN [...] Read more.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways and molecules in ALS astrocytes were unveiled by investigating the proteomic profile and the secreted metabolome of primary spinal cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein in comparison with the transgenic counterpart expressing hSOD1(WT) protein. Here we show that ALS primary astrocytes are depleted of proteins—and of secreted metabolites—involved in glutathione metabolism and signaling. The observed increased activation of Nf-kB, Ebf1, and Plag1 transcription factors may account for the augmented expression of proteins involved in the proteolytic routes mediated by proteasome or endosome–lysosome systems. Moreover, hSOD1(G93A) primary astrocytes also display altered lipid metabolism. Our results provide novel insights into the altered molecular pathways that may underlie astrocyte dysfunctionalities and altered astrocyte–MN crosstalk in ALS, representing potential therapeutic targets to abrogate or slow down MN demise in disease pathogenesis. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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18 pages, 3690 KiB  
Article
Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming
by Rubén Tovar, Antonio Vargas, Jesús Aranda, Lourdes Sánchez-Salido, Laura González-González, Julie A. Chowen, Fernando Rodríguez de Fonseca, Juan Suárez and Patricia Rivera
Int. J. Mol. Sci. 2021, 22(12), 6292; https://doi.org/10.3390/ijms22126292 - 11 Jun 2021
Cited by 2 | Viewed by 2792
Abstract
Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, [...] Read more.
Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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19 pages, 3415 KiB  
Article
Neuromodulation of Astrocytic K+ Clearance
by Alba Bellot-Saez, Rebecca Stevenson, Orsolya Kékesi, Evgeniia Samokhina, Yuval Ben-Abu, John W. Morley and Yossi Buskila
Int. J. Mol. Sci. 2021, 22(5), 2520; https://doi.org/10.3390/ijms22052520 - 3 Mar 2021
Cited by 15 | Viewed by 3886
Abstract
Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and [...] Read more.
Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]o) or impairments of the astrocytic clearance mechanism affect the resonance and oscillatory behavior of both the individual and networks of neurons. These results indicate that astrocytes have the potential to modulate neuronal network activity, however, the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behavior, on the astrocytic clearance process. Our results suggest that while some neuromodulators (5-HT; NA) might affect astrocytic spatial buffering via gap-junctions, others (DA; Histamine) primarily affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to maximize the synchronous network activity. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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16 pages, 2091 KiB  
Article
Fibrinogen Interaction with Astrocyte ICAM-1 and PrPC Results in the Generation of ROS and Neuronal Death
by Nurul Sulimai, Jason Brown and David Lominadze
Int. J. Mol. Sci. 2021, 22(5), 2391; https://doi.org/10.3390/ijms22052391 - 27 Feb 2021
Cited by 18 | Viewed by 2946
Abstract
Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of [...] Read more.
Many neuroinflammatory diseases, like traumatic brain injury (TBI), are associated with an elevated level of fibrinogen and short-term memory (STM) impairment. We found that during TBI, extravasated fibrinogen deposited in vasculo-astrocyte interfaces, which was associated with neurodegeneration and STM reduction. The mechanisms of this fibrinogen-astrocyte interaction and its functional role in neurodegeneration are still unclear. Cultured mouse brain astrocytes were treated with fibrinogen in the presence or absence of function-blocking antibody or peptide against its astrocyte receptors intercellular adhesion molecule-1 (ICAM-1) or cellular prion protein (PrPC), respectively. Fibrinogen interactions with astrocytic ICAM-1 and PrPC were characterized. The expression of pro-inflammatory markers, generations of reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, and neuronal death caused by astrocyte-conditioned medium were assessed. Data showed a strong association between fibrinogen and astrocytic ICAM-1 or PrPC, overexpression of pro-inflammatory cytokines and overproduction of ROS and NO, resulting in neuronal apoptosis and death. These effects were reduced by blocking the function of astrocytic ICAM-1 and PrPC, suggesting that fibrinogen association with its astrocytic receptors induce the release of pro-inflammatory cytokines, resulting in oxidative stress, and ultimately neuronal death. This can be a mechanism of neurodegeneration and the resultant STM reduction seen during TBI. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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Review

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20 pages, 29374 KiB  
Review
The Glymphatic System (En)during Inflammation
by Frida Lind-Holm Mogensen, Christine Delle and Maiken Nedergaard
Int. J. Mol. Sci. 2021, 22(14), 7491; https://doi.org/10.3390/ijms22147491 - 13 Jul 2021
Cited by 94 | Viewed by 24988
Abstract
The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels [...] Read more.
The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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17 pages, 1642 KiB  
Review
Different Flavors of Astrocytes: Revising the Origins of Astrocyte Diversity and Epigenetic Signatures to Understand Heterogeneity after Injury
by Alejandro Villarreal and Tanja Vogel
Int. J. Mol. Sci. 2021, 22(13), 6867; https://doi.org/10.3390/ijms22136867 - 26 Jun 2021
Cited by 15 | Viewed by 4496
Abstract
Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in [...] Read more.
Astrocytes are a specific type of neuroglial cells that confer metabolic and structural support to neurons. Astrocytes populate all regions of the nervous system and adopt a variety of phenotypes depending on their location and their respective functions, which are also pleiotropic in nature. For example, astrocytes adapt to pathological conditions with a specific cellular response known as reactive astrogliosis, which includes extensive phenotypic and transcriptional changes. Reactive astrocytes may lose some of their homeostatic functions and gain protective or detrimental properties with great impact on damage propagation. Different astrocyte subpopulations seemingly coexist in reactive astrogliosis, however, the source of such heterogeneity is not completely understood. Altered cellular signaling in pathological compared to healthy conditions might be one source fueling astrocyte heterogeneity. Moreover, diversity might also be encoded cell-autonomously, for example as a result of astrocyte subtype specification during development. We hypothesize and propose here that elucidating the epigenetic signature underlying the phenotype of each astrocyte subtype is of high relevance to understand another regulative layer of astrocyte heterogeneity, in general as well as after injury or as a result of other pathological conditions. High resolution methods should allow enlightening diverse cell states and subtypes of astrocyte, their adaptation to pathological conditions and ultimately allow controlling and manipulating astrocyte functions in disease states. Here, we review novel literature reporting on astrocyte diversity from a developmental perspective and we focus on epigenetic signatures that might account for cell type specification. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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21 pages, 6380 KiB  
Review
Astrocytes in Multiple Sclerosis—Essential Constituents with Diverse Multifaceted Functions
by Rina Aharoni, Raya Eilam and Ruth Arnon
Int. J. Mol. Sci. 2021, 22(11), 5904; https://doi.org/10.3390/ijms22115904 - 31 May 2021
Cited by 36 | Viewed by 5447
Abstract
In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), [...] Read more.
In multiple sclerosis (MS), astrocytes respond to the inflammatory stimulation with an early robust process of morphological, transcriptional, biochemical, and functional remodeling. Recent studies utilizing novel technologies in samples from MS patients, and in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), exposed the detrimental and the beneficial, in part contradictory, functions of this heterogeneous cell population. In this review, we summarize the various roles of astrocytes in recruiting immune cells to lesion sites, engendering the inflammatory loop, and inflicting tissue damage. The roles of astrocytes in suppressing excessive inflammation and promoting neuroprotection and repair processes is also discussed. The pivotal roles played by astrocytes make them an attractive therapeutic target. Improved understanding of astrocyte function and diversity, and the mechanisms by which they are regulated may lead to the development of novel approaches to selectively block astrocytic detrimental responses and/or enhance their protective properties. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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16 pages, 486 KiB  
Review
Modeling Neurodevelopmental and Neuropsychiatric Diseases with Astrocytes Derived from Human-Induced Pluripotent Stem Cells
by Baiyan Ren and Anna Dunaevsky
Int. J. Mol. Sci. 2021, 22(4), 1692; https://doi.org/10.3390/ijms22041692 - 8 Feb 2021
Cited by 8 | Viewed by 4174
Abstract
Accumulating studies demonstrate the morphological and functional diversity of astrocytes, a subtype of glial cells in the central nervous system. Animal models are instrumental in advancing our understanding of the role of astrocytes in brain development and their contribution to neurological disease; however, [...] Read more.
Accumulating studies demonstrate the morphological and functional diversity of astrocytes, a subtype of glial cells in the central nervous system. Animal models are instrumental in advancing our understanding of the role of astrocytes in brain development and their contribution to neurological disease; however, substantial interspecies differences exist between rodent and human astrocytes, underscoring the importance of studying human astrocytes. Human pluripotent stem cell differentiation approaches allow the study of patient-specific astrocytes in the etiology of neurological disorders. In this review, we summarize the structural and functional properties of astrocytes, including the unique features of human astrocytes; demonstrate the necessity of the stem cell platform; and discuss how this platform has been applied to the research of neurodevelopmental and neuropsychiatric diseases. Full article
(This article belongs to the Special Issue Control of Astrocytes Function and Phenotype: Role in Neuropathology)
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