Modelling neurodegenerative diseases &lt;em&gt;in vitro&lt;/em&gt;: Recent advances in 3D iPSC technologies

Siney, Elodie J.; Kurbatskaya, Ksenia; Chatterjee, Shreyasi; Prasannan, Preeti; Mudher, Amritpal; Willaime‐Morawek, Sandrine

doi:10.3934/celltissue.2018.1.1

Cited by 8 publications

(7 citation statements)

References 123 publications

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“…3D AD models have begun to be used to model the human cellular aspects that mouse models inherently cannot. [28][29][30][31] . Some of these 3D models have even used iPSCs taken from an AD patient and differentiated them into neurons that produced A β and eventually tau tangles [30][31][32] .…”

Section: Introductionmentioning

confidence: 99%

Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects

et al. 2020

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Alzheimer's disease (AD) is the most common form of dementia and is associated with the accumulation of amyloid-β (A β), a peptide whose aggregation has been associated with neurotoxicity. Drugs targeting A β have shown great promise in 2D in vitro models and mouse models, yet preclinical and clinical trials for AD have been highly disappointing. We propose that current in vitro culture systems for discovering and developing AD drugs have significant limitations; specifically, that A β aggregation is vastly different in these 2D cultures carried out on flat plastic or glass substrates vs. in a 3D environment, such as brain tissue, where A β confinement alters aggregation kinetics and thermodynamics. In this work, we identified attenuation of A β cytotoxicity in 3D hydrogel culture compared to 2D cell culture. We investigated A β structure and aggregation in solution vs. hydrogel using Transmission Electron Microscopy (TEM), Fluorescence Correlation Spectroscopy (FCS), and Thioflavin T (ThT) assays. Our results reveal that the equilibrium is shifted to stable extended β-sheet (ThT positive) aggregates in hydrogels and away from the relatively unstable/unstructured presumed toxic oligomeric A β species in solution. Volume exclusion imparted by hydrogel confinement stabilizes unfolded, presumably toxic species, promoting stable extended β-sheet fibrils. Statement of Significance Alzheimer's disease (AD) is a devastating disease and has been studied for over 100 years. Yet, no cure exists and only 5 prescription drugs are FDA-approved to temporarily treat the AD symptoms of declining brain functions related to thinking and memory. Why don't we have more effective treatments to cure AD or relieve AD symptoms? We propose that current culture methods based upon cells cultured on flat, stiff substrates have significant limitations for discovering and developing AD drugs. This study provides strong evidence that AD drugs should be tested in 3D culture systems as a step along the development pathway towards new, more effective drugs to treat AD.

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Section: Introductionmentioning

confidence: 99%

Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects

et al. 2020

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“…Since then, other examples of 3D cultures analyzed the role of Aβ secretion and accumulation (Papadimitriou et al., 2018; Pavoni et al., 2018). Advantages and limitations of these 3D models are reviewed elsewhere (Siney et al, 2018). Nonetheless, combining these powerful 3D models with microfluidic platforms allows new opportunities to model aspects of the disease beyond a neurocentric viewpoint.…”

Section: Microfluidic Models Of Neurological Diseasesmentioning

confidence: 99%

Advances in microfluidic in vitro systems for neurological disease modeling

Holloway

Willaime‐Morawek

Siow

et al. 2021

J of Neuroscience Research

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“…Moreover, biological differences appear to be problematic as well, since several studies have identified that drug testing results on cells acquired from animal models are poorly relevant when compared with the results of human clinical trial (Dauer and Przedborski, 2003;Choi et al, 2017;Kankala et al, 2018). To obtain a more reliable research system, closer to the human brain, scientists have recently started to integrate human-derived cells into microfluidic devices for the study of CNS or PNS physiology and of NDD pathologies (Ohtani-Kaneko et al, 2017;J;Siney et al, 2018;Sances et al, 2018). Human induced-pluripotent stem cells (hiPSCs) can be differentiated into cell types of interest while maintaining the endogenous genomic background (Choi et al, 2017;J;Siney et al, 2018;Kankala et al, 2018).…”

Section: Cell Culture Interactions In Microfluidic Devicesmentioning

confidence: 99%

Modeling Neurodegenerative Diseases Using In Vitro Compartmentalized Microfluidic Devices

Miny

Maisonneuve²,

Quadrio

et al. 2022

Front. Bioeng. Biotechnol.

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The human brain is a complex organ composed of many different types of cells interconnected to create an organized system able to efficiently process information. Dysregulation of this delicately balanced system can lead to the development of neurological disorders, such as neurodegenerative diseases (NDD). To investigate the functionality of human brain physiology and pathophysiology, the scientific community has been generated various research models, from genetically modified animals to two- and three-dimensional cell culture for several decades. These models have, however, certain limitations that impede the precise study of pathophysiological features of neurodegeneration, thus hindering therapeutical research and drug development. Compartmentalized microfluidic devices provide in vitro minimalistic environments to accurately reproduce neural circuits allowing the characterization of the human central nervous system. Brain-on-chip (BoC) is allowing our capability to improve neurodegeneration models on the molecular and cellular mechanism aspects behind the progression of these troubles. This review aims to summarize and discuss the latest advancements of microfluidic models for the investigations of common neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.

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Modelling neurodegenerative diseases <em>in vitro</em>: Recent advances in 3D iPSC technologies

Cited by 8 publications

References 123 publications

Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects

Collagen hydrogel confinement of Amyloid-β (Aβ) accelerates aggregation and reduces cytotoxic effects

Advances in microfluidic in vitro systems for neurological disease modeling

Modeling Neurodegenerative Diseases Using In Vitro Compartmentalized Microfluidic Devices

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