Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation

Watson, Patricia M.; Kavanagh, Edel; Allenby, Gary; Vassey, Matthew

doi:10.1177/2472555217691450

Cited by 58 publications

(42 citation statements)

References 180 publications

(359 reference statements)

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“…Although 2D cultures provide clear visualization of cell interactions, 3D models can better reflect in vivo cell interactions (Hopkins, DeSimone, Chwalek, & Kaplan, ; Watson, Kavanagh, Allenby, & Vassey, ). We therefore examined the OEC–astrocyte and SC–astrocyte interactions using a 3D liquid marble culturing system we have recently developed (Vadivelu et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…We found that after 2 weeks in culture, OECs and DRG Schwann cells interacted with astrocytes in a similar manner ( Figure 6). The OECs and SCs maintained a largely bipolar morphology, whereas the astrocytes Although 2D cultures provide clear visualization of cell interactions, 3D models can better reflect in vivo cell interactions (Hopkins, DeSimone, Chwalek, & Kaplan, 2015;Watson, Kavanagh, Allenby, & Vassey, 2017). We therefore examined the OEC-astrocyte and SCastrocyte interactions using a 3D liquid marble culturing system we have recently developed (Vadivelu et al, 2015).…”

Section: Both Oecs and Schwann Cells Can Interact With Astrocytes Imentioning

confidence: 99%

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Novel insights into the glia limitans of the olfactory nervous system

Nazareth

Chen

Shelper

et al. 2019

J of Comparative Neurology

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Olfactory ensheathing cells (OECs) are often described as being present in both the peripheral and the central nervous systems (PNS and CNS). Furthermore, the olfactory nervous system glia limitans (the glial layer defining the PNS–CNS border) is considered unique as it consists of intermingling OECs and astrocytes. In contrast, the glia limitans of the rest of the nervous system consists solely of astrocytes which create a distinct barrier to Schwann cells (peripheral glia). The ability of OECs to interact with astrocytes is one reason why OECs are believed to be superior to Schwann cells for transplantation therapies to treat CNS injuries. We have used transgenic reporter mice in which glial cells express DsRed fluorescent protein to study the cellular constituents of the glia limitans. We found that the glia limitans layer of the olfactory nervous system is morphologically similar to elsewhere in the nervous system, with a similar low degree of intermingling between peripheral glia and astrocytes. We found that the astrocytic layer of the olfactory bulb is a distinct barrier to bacterial infection, suggesting that this layer constitutes the PNS–CNS immunological barrier. We also found that OECs interact with astrocytes in a similar fashion as Schwann cells in vitro. When cultured in three dimensions, however, there were subtle differences between OECs and Schwann cells in their interactions with astrocytes. We therefore suggest that glial fibrillary acidic protein–reactive astrocyte layer of the olfactory bulb constitutes the glia limitans of the olfactory nervous system and that OECs are primarily “PNS glia.”

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Section: Resultsmentioning

confidence: 99%

Section: Both Oecs and Schwann Cells Can Interact With Astrocytes Imentioning

confidence: 99%

Novel insights into the glia limitans of the olfactory nervous system

Nazareth

Chen

Shelper

et al. 2019

J of Comparative Neurology

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“…There has been a growing interest in the use of in vitro 3D brain-like tissue systems for the study of neurological diseases using patient-derived stem cells (Lancaster et al, 2017; S. P. Pasca, 2016; Quadrato et al, 2016; Watson, Kavanagh, Allenby, & Vassey, 2017). Some of the limitations of these systems include inconsistent and slow co-differentiation of the cells towards neurons and supporting cells, such as astrocytes.…”

Section: Discussionmentioning

confidence: 99%

Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix

Kaplan

Sood

Cairns

et al. 2019

Preprint

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15Brain extracellular matrix (ECM) is often overlooked in vitro brain tissue models, despite its 16 instructive roles during development. Using developmental stage-sourced brain ECM in reproducible 3D 17 bioengineered culture systems, we demonstrate enhanced functional differentiation of human induced 18 neural stem cells (hiNSCs) into healthy neurons and astrocytes. Particularly, fetal brain tissue-derived 19 ECM supported long-term maintenance of differentiated neurons, demonstrated by morphology, gene 20 expression and secretome profiling. Astrocytes were evident within the second month of differentiation, 21 and reactive astrogliosis was inhibited in brain ECM-enriched cultures when compared to unsupplemented 22cultures. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was 23 confirmed by calcium signaling and unsupervised cluster analysis. Additionally, the study identified 24 native biochemical cues in decellularized ECM with notable comparisons between fetal and adult brain-25 derived ECMs. The development of novel brain-specific biomaterials for generating mature in vitro brain 26 models provides an important path forward for interrogation of neuron-glia interactions. 27

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“…Cell-cell connections between different components of the CNS, including neurons and microglia, in 3D may contribute to generate a more physiological milieu, to the increase the integrity and the function of the BBB endothelium and reciprocally affect the phenotype of the other cells actively implicated in the interaction with particulate matter. [47] The transport of nanomaterials across the BBB endothelium is usually by transcytosis and is initiated by endocytosis, for which the size should be ≤200 nm. [48] Depending on the shape and surface properties, particles as large at 500 nm could be transported to a more limited extent.…”

Section: Interaction Of Nanoparticles With 5-cell Organoidsmentioning

confidence: 99%

Multicellular Organoids of the Neurovascular Blood-Brain Barrier: A New Platform for Precision Neuronanomedicine

Kumarasamy

Sosnik

2020

Preprint

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The treatment of neurological disorders (NDs) is challenged by low dug permeability from the systemic circulation into the central nervous system (CNS) owing to the presence of the blood brain barrier (BBB). Neuronanomedicine investigates nanotechnology strategies to target the brain and improve the therapeutic outcome in NDs. 2D adherent cell BBB models show substantial phenogenomic heterogeneity and their ability to predict the permeability of molecules and nanoparticles into the brain is extremely limited. Thus, the high throughput screening of CNS nanomedicines relies on the use of animal models. To address this dearth, 3D organoids that mimic the in vivo physiology are under development. Still, there exist concerns about the standardization and scaleup of the production process, their proper characterisation, and their industrial application. In this work, we report on a novel multicellular organoid of the neurovascular blood brain barrier that recapitulates the regulated syncytium of human endothelial cells and the function of the human BBB. For this, an advanced organoid comprising human brain microvascular endothelial cells, brain vascular pericytes and human astrocytes combined with primary neurons and microglia isolated from neonate rats is biofabricated without the use of an extracellular matrix. The structure and function are fully characterized by confocal laser scanning fluorescence microscopy, light sheet fluorescence microscopy, scanning transmission electron microscopy, cryogenic scanning electron microscopy, western blotting, RNA sequencing and quantitative gene expression by quantitative polymerase chain reaction analysis. The bulk of this self assembloids is comprised of neural cells and microglia and the surface covered by endothelial cells that act as a biological barrier that resembles the BBB endothelium. In addition, the formation of neuron microglia morphofunctional communication sites is confirmed. Analysis of key transcriptomic expressions show the up-regulation of selected BBB genes including tight junction proteins, solute carriers, transporters of the ATP-binding cassette superfamily, metabolic enzymes, and prominent basement membrane signatures. Results confirmed the more efficient intercellular communications in 3D organoids made of multiple neural-tissue cells than in 2D endothelial cell monocultures. These multicellular organoids are utilized to screen the permeability of different polymeric, metallic, and ceramic nanoparticles. Results reveal penetration through different mechanisms such as clathrin mediated endocytosis and distribution patterns in the organoid that depend on the nanoparticle type, highlighting the promise of this simple, reproducible and scalable multicellular organoid platform to investigate the BBB permeability of different nanomaterials in nanomedicine, nanosafety, and nanotoxicology.

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Bioengineered 3D Glial Cell Culture Systems and Applications for Neurodegeneration and Neuroinflammation

Cited by 58 publications

References 180 publications

Novel insights into the glia limitans of the olfactory nervous system

Novel insights into the glia limitans of the olfactory nervous system

Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix

Multicellular Organoids of the Neurovascular Blood-Brain Barrier: A New Platform for Precision Neuronanomedicine

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