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Generating Homogeneous Brain Organoids from Human iPSCs.
There is a high demand for the development of in vitro models for human brain development and diseases due to the inaccessibility of human brain tissues. The human iPSC-derived brain organoids provide a promising in vitro model for studying human brain development and disorders. However, it is challenging to generate a large number of brain organoids with high consistency for modeling human neurological diseases. Here, we describe a method for generating high-yield brain organoids with high consistency by combining large-scale embryoid body (EB) generation and incorporating a quality control screening step during differentiation. The method described in this chapter provides a robust way to generate brain organoids for studying human brain development and modeling neurological diseases.
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Towards Advanced iPSC-based Drug Development for Neurodegenerative Disease.
Neurodegenerative diseases (NDDs) are a heterogeneous group of diseases that are characterized by the progressive loss of neurons leading to motor, sensory, and/or cognitive defects. Currently, NDDs are not curable and treatment focuses on alleviating symptoms and halting disease progression. Phenotypic heterogeneity between individual NDD patients, lack of robust biomarkers, the limited translational potential of experimental models, and other factors have hampered drug development for the treatment of NDDs. This review summarizes and discusses the use of induced pluripotent stem cell (iPSC) approaches for improving drug discovery and testing. It highlights challenges associated with iPSC modeling and also discusses innovative approaches such as brain organoids and microfluidic-based technology which will improve drug development for NDDs.
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Rapid and Efficient Invasion Assay of Glioblastoma in Human Brain Organoids.
Glioblastoma (GBM) possesses glioma stem cells (GSCs) that exhibit aggressive invasion behavior in the brain. Current preclinical GBM invasion assays using mouse brain xenografts are time consuming and less efficient. Here, we demonstrate an array of methods that allow rapid and efficient assaying of GSCs invasion in human brain organoids. The assays are versatile to characterize various aspects of GSCs, such as invasion, integration, and interaction with mature neurons of brain organoids. Tissue clearing and quantitative 3D imaging of GSCs in host organoids reveal that invasiveness is inversely correlated with the organoids' age. Importantly, the described invasion assays can distinguish the invasive behaviors of primary and recurrent GSCs. The assays are also amenable to test pharmacological agents. As an example, we show that GI254023X, an inhibitor of ADAM10, could prevent the integration of GSCs into the organoids.
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Mapping human brain organoids on a spatial atlas.
Brain organoids are tridimensional, self-organizing cultures derived from pluripotent stem cells that recapitulate aspects of human neurodevelopment and can be applied toward investigating neural disease and evolution. In this issue of Cell Stem Cell, Fleck et al. (2021) describe a computational platform for mapping cell identity in organoids.
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Primitive and Definitive Neural Precursor Cells Are Present in Human Cerebral Organoids.
Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity.
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Progress and potential of brain organoids in epilepsy research.
Epilepsies are disorders of the brain characterised by an imbalance in electrical activity, linked to a disruption in the excitation and inhibition of neurons. Progress in the epilepsy research field has been hindered by the lack of an appropriate model, with traditionally used 2D primary cell culture assays and animal models having a number of limitations which inhibit their ability to recapitulate the developing brain and the mechanisms behind epileptogenesis. As a result, the mechanisms behind the pathogenesis of epilepsy are largely unknown. Brain organoids are 3D aggregates of neural tissue formed in vitro and have been shown to recapitulate the gene expression patterns of the brain during development, and can successfully model a range of epilepsies and drug responses. They thus present themselves as a novel tool to advance studies into epileptogenesis. In this review, we discuss the formation of brain organoids, their recent application in studying genetic epilepsies, hyperexcitability dynamics and oxygen glucose deprivation as a hyperexcitability agent, their use as an epilepsy drug testing and development platform, as well as the limitations of their use in epilepsy research and how these can be mitigated.
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Organoids required! A new path to understanding human brain development and disease.
Our ability to study the developing human brain has recently been dramatically advanced by the development of human 'brain organoids', three-dimensional culture systems that recapitulate selected aspects of human brain development in reductionist, yet complex, tissues in vitro. Here I discuss the promises and challenges this new model system presents.
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Impact of alcohol exposure on neural development and network formation in human cortical organoids.
Prenatal alcohol exposure is the foremost preventable etiology of intellectual disability and leads to a collection of diagnoses known as Fetal Alcohol Spectrum Disorders (FASD). Alcohol (EtOH) impacts diverse neural cell types and activity, but the precise functional pathophysiological effects on the human fetal cerebral cortex are unclear. Here, we used human cortical organoids to study the effects of EtOH on neurogenesis and validated our findings in primary human fetal neurons. EtOH exposure produced temporally dependent cellular effects on proliferation, cell cycle, and apoptosis. In addition, we identified EtOH-induced alterations in post-translational histone modifications and chromatin accessibility, leading to impairment of cAMP and calcium signaling, glutamatergic synaptic development, and astrocytic function. Proteomic spatial profiling of cortical organoids showed region-specific, EtOH-induced alterations linked to changes in cytoskeleton, gliogenesis, and impaired synaptogenesis. Finally, multi-electrode array electrophysiology recordings confirmed the deleterious impact of EtOH on neural network formation and activity in cortical organoids, which was validated in primary human fetal tissues. Our findings demonstrate progress in defining the human molecular and cellular phenotypic signatures of prenatal alcohol exposure on functional neurodevelopment, increasing our knowledge for potential therapeutic interventions targeting FASD symptoms.
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Brain organoids restore cortical damage.
Cortical damage is irreparable and poses a challenge to regenerative medicine. Whether brain organoids can compensate for injured brain regions remains unclear. In this issue of Cell Stem Cell, Jgamadze et al. report that human forebrain organoids transplanted into the rat visual system show long-term structural connectivity and the restoration of visual function following lesions.
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How Brain Organoids Are Revolutionizing Neuroscience.
Measuring just a millimeter or two in diameter, brain organoids are a far cry from a fully functioning human brain. But these miniature tissues, typically derived from stem cells, are increasingly able to mimic the structure and function of our most complex organ, unlocking exciting possibilities for neuroscience, artificial intelligence, and beyond.