Function and therapeutic value of astrocytes in neurological diseases

Lee, Hong-Gyun; Wheeler, Michael A.; Quintana, Francisco J.

doi:10.1038/s41573-022-00390-x

Cited by 287 publications

(213 citation statements)

References 318 publications

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“…We observed phenotypic profiles between single neuron spheroids that were more distinctly unique when they contained astrocytes. Given the vital role astrocytes play in synaptic connections and neurological disease (Chung et al, 2015; Lee et al, 2022; Ota et al, 2013), we generated all neuronal spheroids with a ratio of 90% neurons and 10% astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Strong

Kundu

Boutin

et al. 2022

Preprint

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SUMMARY3D spheroids have emerged as powerful drug discovery tools given their high-throughput screening (HTS) compatibility. Here, we established a method for generating functional neural spheroids with differentiated human induced pluripotent stem cell (hiPSC)-derived neurons and astrocytes at cell type compositions mimicking specific regions of the human brain. Recordings of intracellular calcium oscillations were used as functional assays, and the utility of this spheroids system was shown through disease modelling, drug testing, and formation of assembloids to model neurocircuitry. We developed disease models for Alzheimer’s and Parkinson’s Disease through incorporating genetically engineered cells into spheroids, and Opioid Use Disorder by chronically treating spheroids with DAMGO. We reversed baseline functional deficits in each disease model with clinically approved treatments and showed that assembloid activity can be chemogenetically manipulated. Here, we lay the groundwork for brain region-specific spheroids as a robust functional assay platform for HTS studies.

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Section: Discussionmentioning

confidence: 99%

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Strong

Kundu

Boutin

et al. 2022

Preprint

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“…One of the most contributive factors to developing an ND is the dysregulation of glial cells, being astrocytes one of the most important players in these pathologies [ 10 ]. Among other functions, astrocytes are essential for CNS homeostasis by modulation of synaptogenesis and synaptic transmission, maintaining the blood-brain barrier, neurotransmitter recycling, and ionic balance [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis

Vesga-Jiménez¹,

Martin-Jimenez²,

Grismaldo

et al. 2022

IJMS

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Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

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“…Given that one astrocyte may contact tens of thousands of synapses simultaneously (Bushong et al, 2002) via these fine processes, local and fast Ca 2+ signals might enable the astrocyte to powerfully yet precisely control the flow of information through synaptic circuits. Importantly, reactive astrocytes, hallmark of brain diseases, display aberrant amplitude, duration, frequency and spatial spread of Ca 2+ signals (Shigetomi et al, 2019; Nedergaard et al, 2010; Lee et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, reactive astrocytes, hallmark of brain diseases, display aberrant amplitude, duration, frequency and spatial spread of Ca 2+ signals Shigetomi et al (2019); Nedergaard et al (2010); Lee et al (2022).…”

Section: Introductionmentioning

confidence: 99%

Control of Ca²⁺signals by astrocyte nanoscale morphology at tripartite synapses

Denizot

Arizono

et al. 2021

Preprint

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Ca2+ signals in astrocytes can trigger the modulation of neuronal activity. Recent developments in Ca2+ imaging and super-resolution microscopy have allowed to characterize the complex morphology of astrocyte branchlets that communicate with neurons and the associated Ca2+ microdomains. Here, we use computational tools to investigate the causal relationship between branchlet morphology and spatio-temporal profile of Ca2+ signals. 3D reticular branchlet geometries were designed, alternating between large (nodes) and thinner cellular compartments (shafts). Simulations confirm experimental observations that a decreased shaft width is associated with a decreased diffusion flux from nodes, enhancing local Ca2+ activity. Upon successive neuronal stimuli, a decreased shaft width facilitates signal propagation in astrocyte branchlets. We further identify parameters that decrease local Ca2+ activity, such as a discontinuous ER geometry and an increased Ca2+ buffering. Overall, this study proposes key parameters that regulate Ca2+ activity locally, potentially favoring neuron-astrocyte communication at tripartite synapses.

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Function and therapeutic value of astrocytes in neurological diseases

Cited by 287 publications

References 318 publications

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis

Control of Ca²⁺signals by astrocyte nanoscale morphology at tripartite synapses

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Function and therapeutic value of astrocytes in neurological diseases

Cited by 287 publications

References 318 publications

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Functional brain region-specific neural spheroids for modeling neurological diseases and therapeutics screening

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis

Control of Ca2+signals by astrocyte nanoscale morphology at tripartite synapses

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Control of Ca²⁺signals by astrocyte nanoscale morphology at tripartite synapses