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A Multi-Electrode Array Platform for Modeling Epilepsy Using Human Pluripotent Stem Cell-Derived Brain Assembloids.
Human brain organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that recapitulate aspects of fetal brain development. The fusion of dorsal with ventral regionally specified brain organoids in vitro generates assembloids, which have functionally integrated microcircuits with excitatory and inhibitory neurons. Due to their structural complexity and diverse population of neurons, assembloids have become a useful in vitro tool for studying aberrant network activity. Multi-electrode array (MEA) recordings serve as a method for capturing electrical field potentials, spikes, and longitudinal network dynamics from a population of neurons without compromising cell membrane integrity. However, adhering assembloids onto the electrodes for long-term recordings can be challenging due to their large size and limited contact surface area with the electrodes. Here, we demonstrate a method to plate assembloids onto MEA plates for recording electrophysiological activity over a 2-month span. Although the current protocol utilizes human cortical organoids, it can be broadly adapted to organoids differentiated to model other brain regions. This protocol establishes a robust, longitudinal, electrophysiological assay for studying the development of a neuronal network, and this platform has the potential to be used in drug screening for therapeutic development in epilepsy.
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Patient-Derived Cortical Organoids Reveal Senescence of Neural Progenitor Cells in Hutchinson-Gilford Progeria Syndrome.
Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by premature aging and primarily caused by the accumulation of progerin, a mutant form of lamin A. Although the effects of progerin on multiple tissues have been previously studied, its impact on brain development is not completely understood. We established cortical organoids derived from HGPS patient-induced pluripotent stem cells (iPSCs) from patients with HGPS to investigate the role of progerin in the brain. HGPS cortical organoids showed hallmarks of HGPS pathology, including elevated progerin expression and irregular nuclear morphology during early developmental stages. Additionally, we observed abnormal morphology and increased cellular senescence specifically in the rosette regions of HGPS organoids. This senescence appeared to interfere with normal neuronal differentiation, resulting in a significant reduction in mature neuron development and synapse formation in HGPS cortical organoids. Transcriptome profiling of HGPS cortical organoids revealed the downregulation of key genes related to neural development and synapse formation, with these changes persisting over time, potentially contributing to impaired neuronal differentiation and maturation. These findings suggest the role of progerin in early neural development and establish cortical organoids as a model for studying HGPS-related brain development.
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Functional neuronal circuitry and oscillatory dynamics in human brain organoids.
Human brain organoids replicate much of the cellular diversity and developmental anatomy of the human brain. However, the physiology of neuronal circuits within organoids remains under-explored. With high-density CMOS microelectrode arrays and shank electrodes, we captured spontaneous extracellular activity from brain organoids derived from human induced pluripotent stem cells. We inferred functional connectivity from spike timing, revealing a large number of weak connections within a skeleton of significantly fewer strong connections. A benzodiazepine increased the uniformity of firing patterns and decreased the relative fraction of weakly connected edges. Our analysis of the local field potential demonstrate that brain organoids contain neuronal assemblies of sufficient size and functional connectivity to co-activate and generate field potentials from their collective transmembrane currents that phase-lock to spiking activity. These results point to the potential of brain organoids for the study of neuropsychiatric diseases, drug action, and the effects of external stimuli upon neuronal networks.
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Assay of brain particulate neuraminidase. I. Determination of N-acetylneuraminic acid released by the enzyme from endogenous substrates.
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Three-Dimensional Models of the Human Brain Development and Diseases.
Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21st century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer's disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases.
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Compact Calm1 promoter enables AAV mediated neuron-targeted expression in human iPSC-derived brain organoids.
Compact neuron-specific promoters enable targeted gene expression in the brain, especially when using size-limited adeno-associated virus (AAV) vectors. The human synapsin 1 gene promoter (hSyn) promoter is widely used, but the recently described Calm1 promoter (120 bp long) offers a smaller alternative with demonstrated excitatory and inhibitory neuron-specificity in animal models. Here, we compared the commonly used hSyn promoter and the compact Calm1 promoter in human iPSC-derived brain organoids using AAV reporter constructs. Our study evaluating reporter gene expression and immunohistology showed comparable performance in human neurons. Our findings suggest that the compact Calm1 promoter could be used for future central nervous system-targeted human gene therapies.
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SARS-CoV-2 infects human neural progenitor cells and brain organoids.
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Human cerebral organoids and consciousness: a double-edged sword.
Human cerebral organoids (HCOs) are three-dimensional in vitro cell cultures that mimic the developmental process and organization of the developing human brain. In just a few years this technique has produced brain models that are already being used to study diseases of the nervous system and to test treatments and drugs. Currently, HCOs consist of tens of millions of cells and have a size of a few millimeters. The greatest limitation to further development is due to their lack of vascularization. However, recent research has shown that human cerebral organoids can manifest the same electrical activity and connections between brain neurons and EEG patterns as those recorded in preterm babies. All this suggests that, in the future, HCOs may manifest an ability to experience basic sensations such as pain, therefore manifesting sentience, or even rudimentary forms of consciousness. This calls for consideration of whether cerebral organoids should be given a moral status and what limitations should be introduced to regulate research. In this article I focus particularly on the study of the emergence and mechanisms of human consciousness, i.e. one of the most complex scientific problems there are, by means of experiments on HCOs. This type of experiment raises relevant ethical issues and, as I will argue, should probably not be considered morally acceptable.
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Insights into neurodevelopmental features of Huntington's disease from stem cell-derived models including organoids.
Two- and three-dimensional (2D and 3D) cell models derived from human stem cells have shed light on a wide range of molecular and cellular features of Huntington's disease (HD). Here we review the use of human stem cell-derived models to explore neurodevelopmental contributions to HD. We provide a timeline of key advances made in 2D and 3D model systems, ranging from differentiated monocultures to brain-like organoids and assembloids. Models along this spectrum have advanced our understanding of various disease-associated characteristics including disease protein (huntingtin) aggregation, somatic repeat instability, transcriptional dysregulation, perturbations in neurodevelopmental staging, and neural circuitry. We highlight recent findings in brain-like organoids which, despite being a relatively recent innovation, are proving to be a promising tool with which to study aberrant neurodevelopmental features of HD. All models have their limitations, and we compare and contrast the utility and limitations of various stem cell-based methods to study HD. Finally, we speculate on future advances employing advanced computational and transcriptomic methods that will expand the power of 3D model systems for the study of HD and related neurodegenerative disorders.
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[Ultrastructure of parasitophore vacuoles containing Toxoplasma gondii].