Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption

Pediaditakis, Iosif; Kodella, Konstantia; Manatakis, Dimitris V.; Le, Christopher Y.; Hinojosa, Chris; Tien-Street, William; Μανωλάκος, Ηλίας Σ.; Vekrellis, Kostas; Hamilton, Geraldine A.; Ewart, Lorna; Rubin, Lee L.; Karalis, Katia

doi:10.1038/s41467-021-26066-5

Cited by 131 publications

(111 citation statements)

References 97 publications

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“…By leveraging next-generation sequencing data and information retrieved from wellcurated databases providing signature gene sets characteristic for the human cortex, we were able to show that the Brain-Chip exhibits higher transcriptomic similarity to the adult cortical tissue than the transwells, both models with the same cellular composition. These data complement previous reports on the advantages of the microfluidic organ-chip systems to provide a better tissue-relevant microenvironment compared to other commonly used conventional culture systems (Pediaditakis et al, 2021;Sances et al, 2018). Most importantly, our findings demonstrate the closeness of the Brain-Chip to the adult human cortex tissue and the cells' maturation state after seven days in culture.…”

Section: Discussionsupporting

confidence: 89%

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A Microengineered Brain-Chip to Model Neuroinflammation in Humans

Pediaditakis

Kodella

Manatakis

et al. 2022

Preprint

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Species differences in the brain and the blood-brain barrier (BBB) biology hamper the translation from animal models to humans and impede the development of specific therapeutics for brain diseases. Here we present a human Brain-Chip engineered to recapitulate critical aspects of the complex brain cell-cell interactions that mediate neuroinflammation development. Our human organotypic microphysiological system (MPS) includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels, providing a significant improvement in complexity and clinical mimicry compared to previous MPS models. This is the first report of a Brain-Chip with an RNA expression profile close to that of the adult human cortex and that demonstrates advantages over Transwell culture. Through perfusion of TNF-α, we recreated key inflammatory features, such as glia activation, the release of proinflammatory cytokines, and increased barrier permeability. Our model may provide a reliable tool for mechanistic studies in neuron-glial interactions and dysregulation of BBB function during neuroinflammation.

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Section: Discussionsupporting

confidence: 89%

“…Morphological Analysis. Immunocytochemistry was conducted as previously described (Pediaditakis et al, 2021). Cells were blocked on the Brain-Chip in phosphate-buffered saline (PBS) containing 10% donkey serum (Sigma) at 4°C overnight.…”

Section: Discussionmentioning

confidence: 99%

A Microengineered Brain-Chip to Model Neuroinflammation in Humans

Pediaditakis

Kodella

Manatakis

et al. 2022

Preprint

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“…Parkinson disease is a disorder of the substantia nigra region of the brain that is characterized by abnormal accumulation of α-synuclein aggregates, loss of dopaminergic neurons and proliferation of glial cells. A two-channel human brain chip representative of this region was created containing iPS-cell-derived dopaminergic neurons, astrocytes, microglia and pericytes interfaced with iPS cell-derived microvascular brain endothelium 84 . Transcriptomic analysis revealed that gene expression levels on-chip were much closer to those seen in the mature adult substantia nigra than in conventional culture systems.…”

Section: Clinical Mimicry In Organ Chipsmentioning

confidence: 99%

Human organs-on-chips for disease modelling, drug development and personalized medicine

2022

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The failure of animal models to predict therapeutic responses in humans is a major problem that also brings into question their use for basic research. Organ-on-a-chip (organ chip) microfluidic devices lined with living cells cultured under fluid flow can recapitulate organ-level physiology and pathophysiology with high fidelity. Here, I review how single and multiple human organ chip systems have been used to model complex diseases and rare genetic disorders, to study host–microbiome interactions, to recapitulate whole-body inter-organ physiology and to reproduce human clinical responses to drugs, radiation, toxins and infectious pathogens. I also address the challenges that must be overcome for organ chips to be accepted by the pharmaceutical industry and regulatory agencies, as well as discuss recent advances in the field. It is evident that the use of human organ chips instead of animal models for drug development and as living avatars for personalized medicine is ever closer to realization.

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“…Another example comes from PD where neurodegeneration is driven by progressive dysfunction of dopaminergic neurons in the substantia nigra -an area projecting to the cerebral cortex which was targeted by FUS+MB opening in a PD clinical trial [111] and in rat brain [112]. Recently, Pediaditakis et al developed a novel substantia-nigra human Brain-Chip in vitro model containing dopaminergic neurons, astrocytes, microglia, pericytes, and BMEC that could serve as a testing platform for validation of new drugs for PD [113]. Such multicellular brain-region specific BBB models, when combined with FUS+MB in vitro system, could become useful predictors of FUS-mediated therapeutic uptake in diseaseassociated brain structures.…”

Section: Human In Vitro Bbb Models Can Bridge the Gap Between Fus-med...mentioning

confidence: 99%

“Focused Ultrasound-mediated Drug Delivery in Humans – a Path Towards Translation in Neurodegenerative Diseases”

Wasielewska

White

2022

Pharm Res

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The blood-brain barrier (BBB) has a major protective function in preventing the entry of harmful molecules into the brain, but is simultaneously limiting the delivery of drugs, restricting their potential clinical application in neurodegenerative diseases. Recent preclinical evidence demonstrates that following application of focused ultrasound with microbubbles (FUS+MB), the BBB becomes reversibly accessible to compounds that normally are brain-impermeable, suggesting FUS+MB as a promising new platform for delivery of therapeutic agents into the central nervous system. As a step towards translation, small cohort clinical studies were performed demonstrating safe BBB opening in Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS) patients following FUS+MB, however improved drug delivery has not yet been achieved in human. Simultaneously, rapid progress in the human induced pluripotent stem cell (hiPSC) modeling technology allowed for development of novel Alzheimer’s disease patient-derived BBB in vitro model that reacts to FUS+MB with BBB opening and can be used to answer fundamental questions of human BBB responses to FUS+MB in health and disease. This review summarizes key features of the BBB that contribute to limited drug delivery, recapitulates recent advances in the FUS+MB mediated human BBB opening in vivo and in vitro in the context of neurodegenerative disorders, and highlights potential strategies for fast-track translation of the FUS+MB to improve bioavailability of drugs to the human brain. With safe and effective application, this innovative FUS+MB technology may open new avenues for therapeutic interventions in neurodegenerative diseases leading to improved clinical outcomes for patients.

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Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption

Cited by 131 publications

References 97 publications

A Microengineered Brain-Chip to Model Neuroinflammation in Humans

A Microengineered Brain-Chip to Model Neuroinflammation in Humans

Human organs-on-chips for disease modelling, drug development and personalized medicine

“Focused Ultrasound-mediated Drug Delivery in Humans – a Path Towards Translation in Neurodegenerative Diseases”

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