Midbrain Organoids: A New Tool to Investigate Parkinson’s Disease

Smits, Lisa M.; Schwamborn, Jens Christian

doi:10.3389/fcell.2020.00359

Cited by 56 publications

(44 citation statements)

References 124 publications

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“…The 3DMEAs highlighted in this review present similar opportunities for in vitro analysis of brain organoids, such as the potential to record, say, dopaminergic neurons in both a substantia nigra-like region and ventral tegmental area-like region of a midbrain organoid to study Parkinson’s disease. These areas are differentially effected in Parkinson’s disease ( Smits and Schwamborn, 2020 ), representing a clear application for brain organoid modeling.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

Passaro

Stice

2021

Front. Neurosci.

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Brain organoids, or cerebral organoids, have become widely used to study the human brain in vitro. As pluripotent stem cell-derived structures capable of self-organization and recapitulation of physiological cell types and architecture, brain organoids bridge the gap between relatively simple two-dimensional human cell cultures and non-human animal models. This allows for high complexity and physiological relevance in a controlled in vitro setting, opening the door for a variety of applications including development and disease modeling and high-throughput screening. While technologies such as single cell sequencing have led to significant advances in brain organoid characterization and understanding, improved functional analysis (especially electrophysiology) is needed to realize the full potential of brain organoids. In this review, we highlight key technologies for brain organoid development and characterization, then discuss current electrophysiological methods for brain organoid analysis. While electrophysiological approaches have improved rapidly for two-dimensional cultures, only in the past several years have advances been made to overcome limitations posed by the three-dimensionality of brain organoids. Here, we review major advances in electrophysiological technologies and analytical methods with a focus on advances with applicability for brain organoid analysis.

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Section: Discussionmentioning

confidence: 99%

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

Passaro

Stice

2021

Front. Neurosci.

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“…A recently published report showed that neuronal cell studies focused on disease use 5 cell lines per study (3 diseased, 2 control) however, the use in brain organoids was not discussed [8]. PD research utilizing organoids typically differentiate from 1 health and 1 diseased hiPSC line [11]. In depth analysis of preliminary concepts requires substantial resources and time that is not justifiable for pilot studies, especially when generating organoids [8].…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, most studies utilizing PD cerebral brain organoids evaluate morphology but not systemic differences in innate immunity and neurotransmission [10; 11]. Most organoid modeling of PD is based on midbrain organoids that recapitulate PD pathologies of the dopaminergic networks, neurite disfunction and abnormal localization of α-synuclein [11].…”

Section: Introductionmentioning

confidence: 99%

Differences between Cerebral Organoids Derived from a non-PD and a Parkinson’s Patient: A Potential Vulnerability for Neuroinvasive Viruses

Schultz¹,

Jones²,

Xu³

et al. 2021

Preprint

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The development of 3D cerebral brain organoids which accurately resemble aspects of the human brain permits a more accurate characterization of physiological processes and neurological diseases. Cerebral organoids can be grown from stem cell lines with various genetic backgrounds allowing multiple neurodegenerative diseases to be modeled. While dysfunction in neurotransmission of patients with neurodegenerative diseases is expected, the impact of chronic neurodegeneration on the response to viral infection of the CNS is poorly understood. For instance, several mosquito-borne viruses like Dengue virus and West Nile Virus cause post-viral parkinsonism. How CNS infection might impact a host with inherent CNS dysfunction such as Parkinson’s Disease in poorly understood. This preliminary, observational study aimed to understand dysfunction in intrinsic and innate expression of a patient with a neurodegenerative disease and a non-affected individual in relation to potential viral infection in the CNS. Cerebral organoids were generated from human induced pluripotent stem cells with a normal genetic background or with idiopathic Parkinson’s Disease. After differentiation and maturation, organoid size, gene expression and immunofluorescence were evaluated to assess neurotransmission and innate immunity. While there was no significant difference in size of the organoids with a normal or Parkinson’s genetic background, gene expression studies identified multiple differences in innate immunity and neurotransmission. Immunofluorescence also identified differences in protein expression related to neurotransmission and innate immunity. Of note, organoids derived from a Parkinson’s patient exhibited endogenous up-regulation of dopamine and muscarinic acetylcholine receptors, GABA, glycine, and glutamate targets, and the majority of cytokines. This expression pattern suggests a chronic state of neuroexcitation and neuroinflammation in this population of organoids.

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“…Brain organoids are self-assembled cell aggregates in which cells are not just randomly organized and interacting with each other, but exhibit a high degree of organization that closely resembles the brain tissue polarity, for which the cell-to-cell interplay is spatially and temporally regulated [ 125 , 126 ]. These bioengineered tissues can either reflect brain structures at large, in which case they are referred to as brain or cerebral organoids ( Figure 4 B), or rather resemble specific brain regions, in which case they are referred to as region-specific organoids ( Figure 4 C), such as adenohypophysis [ 127 ], cerebellar [ 128 ], forebrain [ 129 , 130 , 131 ], midbrain [ 132 ], hippocampal [ 133 ], hypothalamic [ 134 ], choroid plexus [ 135 ], optic-cup [ 136 ], or retinal organoids [ 137 ].…”

Section: Methods For Generating Brain-on-chipmentioning

confidence: 99%

Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology

et al. 2021

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Brain-on-Chip (BoC) biotechnology is emerging as a promising tool for biomedical and pharmaceutical research applied to the neurosciences. At the convergence between lab-on-chip and cell biology, BoC couples in vitro three-dimensional brain-like systems to an engineered microfluidics platform designed to provide an in vivo-like extrinsic microenvironment with the aim of replicating tissue- or organ-level physiological functions. BoC therefore offers the advantage of an in vitro reproduction of brain structures that is more faithful to the native correlate than what is obtained with conventional cell culture techniques. As brain function ultimately results in the generation of electrical signals, electrophysiology techniques are paramount for studying brain activity in health and disease. However, as BoC is still in its infancy, the availability of combined BoC–electrophysiology platforms is still limited. Here, we summarize the available biological substrates for BoC, starting with a historical perspective. We then describe the available tools enabling BoC electrophysiology studies, detailing their fabrication process and technical features, along with their advantages and limitations. We discuss the current and future applications of BoC electrophysiology, also expanding to complementary approaches. We conclude with an evaluation of the potential translational applications and prospective technology developments.

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Midbrain Organoids: A New Tool to Investigate Parkinson’s Disease

Cited by 56 publications

References 124 publications

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

Electrophysiological Analysis of Brain Organoids: Current Approaches and Advancements

Differences between Cerebral Organoids Derived from a non-PD and a Parkinson’s Patient: A Potential Vulnerability for Neuroinvasive Viruses

Electrophysiology Read-Out Tools for Brain-on-Chip Biotechnology

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