3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

Bolognin, Silvia; Fossépré, Marie; Qing, Xiaobing; Jarazo, Javier; Ščančar, Janez; Moreno, Edinson Lucumi; Nickels, Sarah Louise; Wasner, Kobi; Ouzren, Nassima; Walter, Jonas; Grünewald, Anne; Glaab, Enrico; Salamanca, Luis; Fleming, Ronan M. T.; Antony, Paul; Schwamborn, Jens Christian

doi:10.1002/advs.201800927

Cited by 108 publications

(101 citation statements)

References 69 publications

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“…Yet, there are still serious hurdles to overcome, including the reduced long-term viability of such systems due to lack of sufficient oxygenation within the 3D core and the large variability observed [ 133 ]. In a first attempt within the PD field, the culture of patient neurons derived from hiPSCs carrying the LRRK2-G2019S mutation was optimized in 3D microfluidics [ 134 ]. Automated high-content imaging revealed decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in the absence of external stressors.…”

Section: Looking Into the Future: Optimization Of Hipsc-based Modementioning

confidence: 99%

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

Kouroupi

Antoniou

Prodromidou

et al. 2020

IJMS

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Parkinson’s disease (PD) is a common progressive neurodegenerative disorder characterized by loss of striatal-projecting dopaminergic neurons of the ventral forebrain, resulting in motor and cognitive deficits. Despite extensive efforts in understanding PD pathogenesis, no disease-modifying drugs exist. Recent advances in cell reprogramming technologies have facilitated the generation of patient-derived models for sporadic or familial PD and the identification of early, potentially triggering, pathological phenotypes while they provide amenable systems for drug discovery. Emerging developments highlight the enhanced potential of using more sophisticated cellular systems, including neuronal and glial co-cultures as well as three-dimensional systems that better simulate the human pathophysiology. In combination with high-throughput high-content screening technologies, these approaches open new perspectives for the identification of disease-modifying compounds. In this review, we discuss current advances and the challenges ahead in the use of patient-derived induced pluripotent stem cells for drug discovery in PD. We address new concepts implicating non-neuronal cells in disease pathogenesis and highlight the necessity for functional assays, such as calcium imaging and multi-electrode array recordings, to predict drug efficacy. Finally, we argue that artificial intelligence technologies will be pivotal for analysis of the large and complex data sets obtained, becoming game-changers in the process of drug discovery.

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Section: Looking Into the Future: Optimization Of Hipsc-based Modementioning

confidence: 99%

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

Kouroupi

Antoniou

Prodromidou

et al. 2020

IJMS

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show abstract

“…In contrast to 2D culture, 3D approaches reveal robust endophenotypes affecting only dopaminergic neurons. This model has the potential to develop patient-specific therapeutic drugs against the disease [79]. In a recent study, 3D co-culture and compartmentalization of mouse embryonic stem cells (mESCs)-derived motor neurons and skeletal muscle cells within an ECM were utilized to create NMJs [80].…”

Section: Microfluidic Neurological Disorder Modelmentioning

confidence: 99%

“…Reproduced with permission from[75] copyright 2017, The Royal Society of Chemistry (RSC). (d) Neural outgrowth and formation of a human motor unit along with NMJ in a 3D ALS motor unit model and NMJs in microfluidic devices reproduced with permission from[79]. Copyright 2018, AAAS.…”

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confidence: 99%

In Vitro Blood–Brain Barrier-Integrated Neurological Disorder Models Using a Microfluidic Device

2019

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The blood–brain barrier (BBB) plays critical role in the human physiological system such as protection of the central nervous system (CNS) from external materials in the blood vessel, including toxicants and drugs for several neurological disorders, a critical type of human disease. Therefore, suitable in vitro BBB models with fluidic flow to mimic the shear stress and supply of nutrients have been developed. Neurological disorder has also been investigated for developing realistic models that allow advance fundamental and translational research and effective therapeutic strategy design. Here, we discuss introduction of the blood–brain barrier in neurological disorder models by leveraging a recently developed microfluidic system and human organ-on-a-chip system. Such models could provide an effective drug screening platform and facilitate personalized therapy of several neurological diseases.

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“…The image analysis was performed using MatLab, The MatWorks Inc. as previously described (Arias-Fuenzalida et al, 2019;Bolognin et al, 2018).…”

Section: Image Analysismentioning

confidence: 99%

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

Jarazo

Barmpa

Rosety

et al. 2019

Preprint

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The etiology of Parkinson's disease (PD) is only partially understood despite the fact that environmental causes, risk factors, and specific gene mutations are contributors to the disease. Biallelic mutations in the PTEN-induced putative kinase 1 (PINK1) gene involved in mitochondrial homeostasis, vesicle trafficking, and autophagy, are sufficient to cause PD. By comparing PD patient-derived cells, we show differences in their energetic profile, imbalanced proliferation, apoptosis, mitophagy, and a reduced differentiation efficiency to dopaminergic neurons compared to control cells. Using CRISPR/Cas9 gene editing, correction of a patient's point mutation ameliorated the metabolic properties and neuronal firing rates but without reversing the differentiation phenotype. However, treatment with 2-Hydroxypropyl-β-Cyclodextrin (HP-β-CD) increased the mitophagy capacity of neurons leading to an improved dopaminergic differentiation of patient specific neurons in midbrain organoids. In conclusion, we show that treatment with a repurposed compound is sufficient for restoring dopaminergic differentiation of PD patient-derived cells.

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3D Cultures of Parkinson's Disease‐Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing

Cited by 108 publications

References 69 publications

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

Patient-Derived Induced Pluripotent Stem Cell-Based Models in Parkinson’s Disease for Drug Identification

In Vitro Blood–Brain Barrier-Integrated Neurological Disorder Models Using a Microfluidic Device

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

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