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Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

ABSTRACT: High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer's disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes in vitro. Here, a three-dimensional Alzheimer's disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network of the human blood-brain barrier with neurospheres derived from Alzheimer's disease-specific neural progenitor cells. To shorten microfluidic co-culture times, neurospheres were pre-differentiated for 21 days to express Alzheimer's disease-specific pathological phenotypes prior to the introduction into the microfluidic device. In agreement with post-mortem studies and Alzheimer's disease in vivo models, after 7 days of co-culture with pre-differentiated Alzheimer's disease-specific neurospheres, the three-dimensional blood-brain barrier network exhibited significant changes in barrier permeability and morphology. Furthermore, vascular networks in co-culture with Alzheimer's disease-specific microtissues displayed localized β-amyloid deposition. Thus, by interconnecting a microvascular network of the blood-brain barrier with pre-differentiated neurospheres the presented model holds immense potential for replicating key neurovascular phenotypes of neurodegenerative disorders in vitro.

SUBMITTER: Ko EC

PROVIDER: S-EPMC10600382 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

Ko Eunkyung Clare EC Spitz Sarah S Pramotton Francesca Michela FM Barr Olivia M OM Xu Ciana C Pavlou Georgios G Zhang Shun S Tsai Alice A Maaser-Hecker Anna A Jorfi Mehdi M Choi Se Hoon SH Tanzi Rudolph E RE Kamm Roger D RD

Frontiers in bioengineering and biotechnology 20231009

High failure rates in clinical trials for neurodegenerative disorders such as Alzheimer's disease have been linked to an insufficient predictive validity of current animal-based disease models. This has created an increasing demand for alternative, human-based models capable of emulating key pathological phenotypes <i>in vitro</i>. Here, a three-dimensional Alzheimer's disease model was developed using a compartmentalized microfluidic device that combines a self-assembled microvascular network o ...[more]

PMID: 37901842

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Project description:BackgroundThree dimensional (3D) cell cultures have been an area of increasing interest and relevance across several research fields including drug discovery, developmental biology and stem cell-based therapies. However, handling 3D structures can be difficult. In particular, the replacement of liquid media and reagents in which liquid is removed using pipettes is difficult to perform as the 3D spheroids can be easily aspirated into the pipette tip.ResultsWe have developed the 3D-tip, a novel tool that facilitates media change and washing procedures of 3D-spheroid cultures. The 3D-tip contains a mesh with 40-μm pores allowing the aspiration of liquids including media, drugs, buffers and reagents, with the mesh acting as a barrier preventing the spheroids being aspirated into the pipette tip. After aspiration of liquids, the spheroids are gently deposited back into the culture vessel. Our results demonstrate that the 3D-tips offer superior handling of 3D-spheroid cultures in comparison to commonly used methods. We showed that the 3D-tips can easily be used on both fixed and unfixed spheroids and on cancer cell, stem cell and glial cell spheroids.In contrast with the 50/50 media exchange method, the 3D-tips allow a complete media change with minimal loss of spheroids and without damaging their morphology. Our results showed that 86.0% of spheroids remained in the chamber after changing the media using the 3D-tips. In contrast, only 45.0% of spheroids remained using the 50/50 media exchange strategy.In comparison with the centrifugation technique, the 3D-tips preserved spheroids whereas centrifugation led to the loss of spheroids and/or the alteration of the size and shape of the 3D cellular structures. We observed that 87.6 and 84.6% of the fixed and unfixed spheroids remained using the 3D-tip, respectively. In contrast, only 66.3% of the fixed spheroids and 36.4% of the unfixed spheroids were left using the centrifugation method. From a time perspective, the 3D-tips dramatically reduce the time taken for replacing media.ConclusionsThis novel pipette tip is suitable for high throughput screening and automation and will revolutionise the techniques used for the production and analysis of 3D spheroids.

Dataset Information

Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

Publications

Accelerating the in vitro emulation of Alzheimer's disease-associated phenotypes using a novel 3D blood-brain barrier neurosphere co-culture model.

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